5-HTP is known to exist as two isomers, the D (dextratory) and L (levoratory) forms. Only the L-isomer is biologically active, while the D-isomer is mostly excreted unchanged in the urine (3, 4).

 

 

Numerous trials have been conducted evaluating the efficacy of 5-HTP as a pharmacological treatment for depression. Reviews have been published in attempts to summarize and make conclusions based on the available evidence, however most agree that more conclusive research is called for due to the heterogeneity of the results and variety of outcome measures assessed (1, 5-7). In the most recent systematic review, Turner et al. identified a total of 27 studies (total n=990), consisting of 11 double-blind, placebo-controlled studies, five active comparator studies, and 11 open-label trials (5). Overall the studies seem to suggest a positive effect of 5-HTP in treating depression, but additional trials of larger sample sizes and higher quality are needed to confirm this. No placebo-controlled, monotherapy trials on 5-HTP on depression have been conducted since the early 1980’s, possibly due to the already widespread use of the supplement. In this review the trials have been arranged into the following sub-headings: double-blind, placebo-controlled monotherapy studies; active comparison monotherapy studies; open-label monotherapy studies; and combination therapy studies. The controlled monotherapy studies will be discussed in detail, followed by a brief overview of the other studies.

 

In many of the trials, a peripheral decarboxylase inhibitor (PDI) was administered along with 5-HTP, for the purposes of inhibiting the conversion of 5-HTP into serotonin in the periphery, thus increasing its concentration in the central nervous system, as well as preventing some of the peripheral side effects that have been associated with 5-HTP (8, 9). However, in several comparative studies the addition of a PDI did not appear to affect the antidepressant property of 5-HTP (9, 10). Thus the co-administration of PDIs with 5-HTP will still be considered a monotherapy.

There have been seven published trials documenting double-blind, placebo-controlled studies using 5-HTP alone (11-17). Only two of these reported statistically significant results when compared with placebo (11, 12), while two others reported some efficacy of 5-HTP but failed to make any comparison with the placebo arm (13, 17). The three remaining trials were unable to detect statistical difference between the 5-HTP and placebo groups (14-16). Details of the trials, where possible, will be discussed below in reverse chronological order.

 

In a recent trial, van Praag et al. administered either 5-HTP (200mg/day) in combination with the peripheral decarboxylase inhibitor carbidopa (150mg/day), tryptophan (5g/day), or placebo to patients diagnosed with “vital (endogenous) depression” (11). Each treatment was administered to a group of 15 patients, and was continued for a period of four weeks. The 5-HTP group experienced a 67% decrease in Hamilton Depression Rating Scale (HAM-D) scores, statistically significant compared to both the 48% decrease in the tryptophan group as well as the 30% decrease in the placebo group. The authors postulated that the differences observed between 5-HTP and tryptophan, both precursors of serotonin, exist due to the additional effect of 5-HTP on catecholamine metabolism (see Pharmacology). Details regarding randomization (if any) and statistical analyses were not provided.

 

Mendlewicz and Youdim conducted a trial in which patients diagnosed with unipolar or bipolar depression were randomly assigned to receive either combination therapy (n=18): 5-HTP (900mg/day) plus benzerazide, a peripheral decarboxylase inhibitor, (225mg/day) plus L-Deprenil (15mg/day); 5-HTP therapy (n=21): 5-HTP plus benzerazide; or placebo alone (n=19) (15). Dosage regimen was three times daily for 32 days. The groups were reported to be comparable at baseline with respect to disease state, depression score, age, and sex. Results of the 32-day study were that the Hamilton Depression scores of the combination therapy group improved significantly compared to those of the placebo group, but not compared to those of the 5-HTP group. Scores of the 5-HTP group were also not significantly different than those of the placebo group. The efficacy of 5-HTP as an adjunctive therapy to L-Deprenil is hard to interpret based on these results, as the effects of L-Deprenil alone were not tested. Regardless, 5-HTP used alone did not appear to be superior over placebo.

 

In 1972 van Praag published a pilot study which found that 5-HTP treatment appeared more effective in individuals with lower endogenous levels of serotonin (14). The group carried out two additional trials to test their hypothesis that an inherent deficit of serotonin is the predisposing factor to many cases of depression.As such, serotonin therapies that aim to correct this deficit, such as 5-HTP, should be more effective in these individuals (13). Individual levels of serotonin were measured by the accumulation of its metabolite, 5-HIAA, in the cerebrospinal fluid after localization by probenecid, in a method described previously (14). In the first study, 40 patients with “vital depression” were given either 5-HTP (200mg/day); clomipramine, a tricyclic antidepressant (225mg/day); combination of 5-HTP and clomipramine; or placebo (n=10 in each group, randomization unspecified). 5-HTP treatment was always co-administered with MK 486, a peripheral decarboxylase inhibitor (150mg/day). After a study period of 21 days, mean scores on the Hamilton Depression Scale were highest in the placebo group, followed by 5-HTP alone, then clomipramine, with the combination of 5-HTP and clomipramine having the lowest scores (statistical testing not shown). The authors further pointed out that the efficacy of both 5-HTP and clomipramine were greater in those with subnormal 5-HIAA, although significance was once again not reported.

 

In the second study (12), 20 patients with “recurrent vital depressions” (unipolar and bipolar; baseline depression scores not reported) were enrolled in a long-term, crossover trial comparing 5-HTP with placebo. All 20 of the participants had previously been hospitalized for depressive episodes, and had been taking lithium (length/dose of treatment unspecified) prophylactically.  Lithium was discontinued at the time of enrollment. The participants were randomized into two groups of ten, to be administered the active treatment (5-HTP 200mg/day in combination with carbidopa 150mg/day) either before or after placebo treatment, for one year each. Dosage of 5-HTP was slowly increased to the desired dosage over a few weeks (exact schedule not specified) to minimize gastrointestinal disturbance. During the two-year total study period, the participants were evaluated every four weeks with respect to HAM-D scores and number of “relapses” of depressive episodes.  In the event of a depressive relapse, the patients were treated with clomipramine without discontinuation of study treatment. Measurements of patients’ baseline 5-HIAA levels were once again made. Results indicated that both the mean relapse rate and mean depression score were significantly lower during the 5-HTP periods than during the placebo periods. It should be noted that three manic phases occurred while patients were taking 5-HTP, and all were treated with haloperidol for three to six weeks. Subgroup analyses further indicated that the relapse rate was significantly lower in the “low 5-HIAA” individuals than in the “normal 5-HIAA” ones. In a comparative analysis of relapse rates between the two years on 5-HTP and the two years on lithium prior to 5-HTP initiation, it appeared that 5-HTP was inferior to lithium in patients with bipolar depression, but superior to lithium in the “low 5-HIAA” group.

 

Finally, two additional double-blind, placebo-controlled trials have been conducted investigating 5-HTP as a single agent for treatment of depression (16, 17). The full-length papers for both trials could not be located for this review, but details of both have been described elsewhere (5).  Zarcone et al. conducted a small trial of six treatment-resistant depressed patients in a crossover study comparing 5-HTP to placebo (16). Patients were given between 500 to 3,250mg 5-HTP daily dose schedule unspecified) over five days, and placebo for the remaining six to ten days. It was reported that two of the six patients had decreased depressive ratings while on 5-HTP, however results of the placebo treatment were unclear, and statistical significance was not achieved. In a previous study, Barlet and Pailard compared a group of unipolar depressed patients given 5-HTP (between 200 to 800 mg/day) to another group given placebo for a period of ten to 240 days (17). Nineteen of the 25 patients given 5-HTP had reportedly “improved,” although the criteria for these assessments are unknown. Again, results of the placebo group were unclear, making the results difficult to interpret. Further details of both trials could not be found for this review.

Three trials have compared the efficacy of 5-HTP alone to marketed antidepressants for their ability to treat depression (18-20). One additional trial has used 5-HTP as an adjunctive therapy to tryptophan in an active comparison study (21). Medications to which 5-HTP have been tested against include the tricyclic antidepressant imipramine, the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, the monoamine oxidase inhibitor (MAOI) tranylcypromine, and the dopamine-reuptake inhibitor nomifensine. Trial results have suggested that 5-HTP alone is as effective as imipramine (20) and fluvoxamine (18), and superior to nomifensine when used in conjunction with tryptophan (21). On the other hand, it was found to be inferior to tranylcyrpomine for treatment-resistant depression (19). More studies are needed to confirm these findings. The trials will be discussed below in reverse chronological order.

 

In a randomized, double-blind, comparative study, the efficacy of Triptum 100® (100mg 5-HTP per capsule) versus Floxyfral® (50mg fluvoxamine per tablet) was compared (18). Sixty-nine participants suffering from depression were randomly given either one 5-HTP active capsule with a placebo fluvoxamine tablet, or vice versa, three times daily with meals. During the six-week trial, participants were evaluated every two weeks using various assessment tools, including the Hamilton Depression Rating Scale (HDRS) and a self-assessment depression scale (SAD). Changes in the HDRS and SAD at all time points showed significant improvements in both groups compared to the previous time point, with no notable difference between the 5-HTP and the fluvoxamine groups. No significant differences were found between the groups with respect to other outcome measures. Overall, the clinical picture of 5-HTP was comparable to that of fluvoxamine.

 

In 1985 an open, cross-over study was published comparing the efficacy of 5-HTP versus a MAOI antidepressant in treating “treatment-resistant depression” (19). The rationale behind the study was that approximately 20 to 30% of patients do not respond to first-line treatments of depression such as tricyclic antidepressants and reuptake inhibitors (22). Thus the authors wanted to test the usefulness of 5-HTP compared to a second-line treatment option such as MAOIs in a population of treatment-resistant depressed patients. Inclusion criteria include failure to respond to at least one trial of selective serotonin and noradrenaline reuptake inhibitors, as well as a treatment involving sleep deprivation (19). Twenty-six eligible patients were administered either 5-HTP (in combination with carbidopa, a peripheral decarboxylase inhibitor; n=12) or tranylcyrpomine, a MAOI (n=14) for four weeks. Dosage of 5-HTP started from 10mg twice daily, increasing to 100mg twice daily over 14 days if patients were found to be unresponsive (mean daily dose 182mg). Likewise, dosage of tranylcypromine started at 10mg twice daily, increasing to 50mg twice daily if needed (mean daily dose 82mg). A treatment was considered effective if the patient’s Hamilton Depression score at the end of the treatment period showed at least a 50% decrease relative to the baseline score at the beginning of the study. Of the twelve patients treated with 5-HTP, none reported a clinical improvement in HRSD scores, compared to the six of 14 patients treated with tranylcypromine who reported statistically significant improvements. Patients who did not respond to treatment were then crossed over to four weeks of the opposite therapy, after a one-week washout period. None of the five patients now given 5-HTP (one patient dropped out between treatments) showed a response, while eight of the twelve patients now given tranylcypromine improved. Overall, the mean HRSD scores during tranylcypromine showed a significant improvement over those during 5-HTP treatment.

 

In 1984, Quadbeck et al. randomized 24 participants suffering from depression into three study groups of eight participants each: tryptophan only (1500mg/day during the first week, doubling in dose thereafter), tryptophan (475mg/day during the first week, doubling in dose thereafter) plus 5-HTP (25mg/day during the first week, doubling in dose thereafter), and nomifensine (consistent dose of 50mg) (21). Dosing regimen was three doses daily for a total of three weeks.  Depressive symptoms were measured weekly using the HAM-D Scale, the AMP system, and the v. Zerssen and Zung self-evaluation scales. After three weeks of treatment, scores on the HAM-D scale were significantly lower in the tryptophan/5-HTP group than the two other groups. Subscale analysis revealed that the tryptophan/5-HTP combination was superior to nomifensine with respect to depressive retardation, depressive agitation, anxiety reaction, and somatic complaints. It was also superior to nomifensine with respect to two of the AMP subscales (somatic depressive syndrome, retarded depressive syndrome) but not to the apathy subscale. No statistically significant differences were detected in the self-evaluation scales between the groups. Thus it appears that 5-HTP, as an adjunctive therapy to tryptophan, is more effective in ameliorating depressive symptoms than a low dose of the dopamine-reuptake inhibitor nomifensine.

 

Finally, a randomized, double-blind study was published comparing 5-HTP to imipramine, a tricyclic antidepressant (20). Thirty untreated depressive patients were randomly assigned into two groups: one that received 5-HTP (mean dose 800mg/day) plus benzerazide, a peripheral decarboxylase inhibitor (mean dose 375mg/day), another that received imipramine (mean dose 150mg/day). Both groups were blinded by providing placebo capsules along with the assigned treatment capsules.. The study period was 20 days, during which the patients were evaluated at several time points using various depression scales. Only results from the Hamilton scale and AMP-system (evaluation of various psychological syndromes) were presented. Both the 5-HTP and imipramine groups showed significant end-of-treatment values for the Hamilton scale and two subscales of the AMP-system (somatic-depressive syndrome, retarded-depressive syndrome), when compared with baseline values. Inter-group differences were not significant, suggesting comparable efficacy between the two types of therapy. 

There have been at least 13 open-label studies of 5-HTP as a single agent for the treatment of depression (9, 10, 23-33). In particular, one was a study of depression associated with Parkinson’s Disease (23), one of “treatment-resistant” depression (24), while another investigated the use of 5-HTP as an adjunctive therapy to monoamine oxidase inhibitor (MAOI) antidepressants (25). All have reported some level of efficacy in decreasing depression scores; however, they are limited by the lack of internal control groups.

In addition, two studies have been performed using 5-HTP in conjunction with other therapeutic agents in the treatment of depression (34, 35). It was reported that 5-HTP in combination with dihydroergocristine (34) or the tricyclic antidepressant chlorimipramine (35), showed potent antidepressant properties. However, it should be kept in mind that results from these combination studies are limited in value when trying to determine the efficacy of 5-HTP as an antidepressant, since it is unknown how much of the observed responses, if any, is due to 5-HTP alone.

In conclusion, numerous trials have been carried out to determine a possible role of 5-HTP in treating depression. While it appears that 5-HTP might have some efficacy for this condition, the results from the trials have mostly been mixed, and so its effectiveness has not been conclusively determined. Part of this uncertainty lies in the fact that antidepressant trials have been criticized as lacking assay sensitivity due to their frequently high placebo effects (5, 36, 37).  It has been found that as much as 50% of antidepressant trials do not show superiority over placebo, even when the agents are known to be effective (38). Therefore, it is now considered standard practice to employ a placebo run-in period prior to the start of antidepressant trials. Unfortunately most of the trials of 5-HTP were too old to have employed this approach.

 

Overall, results obtained from the trials of 5-HTP for depression have been mixed. 5-HTP has been found to be superior to placebo (11, 12), and as effective as the antidepressants imipramine (20) and fluvoxamine (18). 5-HTP has also been found to be superior to nomifensine when used in combination with  tryptophan (21), and to placebo when used as an adjunctive therapy to L-Deprenil (15). Unfortunately, most of these trials contained some methodological flaws, and no recent advances have been made in the area. Thus, while it appears that 5-HTP might have some efficacy in the treatment of depression, the evidence to date is still inconclusive, and more high-quality evidence is needed to strengthen this claim.

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

 

The “serotonin hypothesis” of depression has been discussed for many years, in which the disease state is thought to originate from a deficiency of serotonin or serotonergic activity in the brain (30, 43). Human studies have found lower levels of 5-hydroxyindoleacetic acid (5-HIAA, metabolite of serotonin) in the cerebrospinal fluid of depressed patients than in healthy volunteers, suggesting a diminished turnover of serotonin (43). Therefore, much work has been done in this area to correct this deficiency using serotonin precursors, which include tryptophan and 5-HTP (8). Comparison of the effects of 5-HTP versus tryptophan has found 5-HTP to be the superior antidepressant agent, possibly due to an additional effect on elevating catecholamines. In both animal and human studies, 5-HTP alone was able to increase the metabolism of not only serotonin, but also of the catecholamines dopamine and noradrenaline (8, 11). A comparative study of 5-HTP and tryptophan confirmed 5-HTP to be superior to both tryptophan and placebo in its ability to ameliorate depressive symptoms (11).

 

The role of 5-HTP in depression has been further elucidated in neuroendocrine and position emission tomography (PET) studies between depressed and healthy participants. Following 5-HTP administration, serum cortisol levels were found to be higher in depressed patients than in normal controls, suggesting a supersensitivity in at least a subset of serotonin receptors (44-46). Additionally, PET scans have revealed a significantly lower uptake of radiolabelled 5-HTP across the blood-brain barrier in depressed patients compared with controls, thus indicating a flawed or inadequate 5-HTP transport system as a possible basis for depression (47, 48).

Fibromyalgia, also referred to as primary fibromyalgia syndrome or fibrositis (older terminology), is a clinical syndrome characterized by multiple symptoms including generalized musculoskeletal aching, multiple tender points, fatigue, morning stiffness, lowered pain threshold, and disturbed sleep (49, 50). The condition affects approximately two to six percent of the general population, and is more prevalent in females between 25 to 40 years old (51). Due to the complexity of the condition, it was still considered poorly recognized in the early 1990’s, with no proven effective treatment available. As such 5-HTP has been used in two clinical trials in attempts to treat the pain and discomfort associated with fibromyalgia. One is a randomized, double-blind, placebo-controlled trial (49) while the other is an open-label trial (52). Both have reported favourable results, however due to the small number of trials conducted, more research is required to strengthen the present level of evidence.

 

In 1990 Caruso et al. (49) carried out a randomized, double-blind, placebo-controlled trial in 50 patients diagnosed as suffering from primary fibromyalgia syndrome (PFS), based on criteria set out by previous researchers (51). The patients were randomized to receive either 5-HTP (100mg) or placebo three times daily for 30 days (n=25 in each group). Assessments were completed at baseline, and after 15 and 30 days. Outcome measures included improvements in number of tender points, intensity of pain, quality of sleep, morning stiffness, anxiety, and fatigue. Results indicated that all of the parameters were significantly improved in the 5-HTP group compared to baseline values, as well as to the placebo group after 30 days of treatment. In addition, efficacy of treatment was assessed by both the patients and the researchers, and both groups rated the 5-HTP group as having significantly greater improvements than the placebo group, after both 15 and 30 days of treatment.

 

Subsequent to these promising results, the same group of researchers then decided to test the long-term efficacy and tolerability of 5-HTP in a 90-day, open-label study (52). Again, 50 participants fulfilling the diagnostic criteria (51) were administered 5-HTP 100mg three times daily for the duration of the trial. Evaluations were performed at baseline, and following 15, 30, 60, and 90 days of treatment, using the same scales and clinical measurements described above. Number of tender points, intensity of pain, quality of sleep, morning stiffness, anxiety, and fatigue were all found to be significantly improved at all time points relative to baseline values, with no further improvements noted after 60 days of treatment. However, with respect to the patients’ assessment of efficacy, most reported only a fair (30 to 39%) or else poor (26 to 35%) improvement of symptoms at all time points. This study is mostly limited by its lack of randomization and control.

 

In total only two studies have assessed the efficacy of 5-HTP in the treatment of fibromyalgia. While both have reported favourable results, only one of the studies is a methodologically sound, placebo-controlled trial, and so more research is needed to confirm these results.

 

The link between serotonin and fibromyalgia is well-established (50), as studies of patients suffering from the condition have shown decreased cerebrospinal fluid levels of serotonin (53, 54) as well as of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) (55, 56). Symptomatic relief has been achieved in patients using antidepressants (49, 57), indicating a potential value of serotonergic treatments (58, 59). Serotonin has been found to interact with substance P (pain-inducing neuropeptide) in the cerebrospinal fluid to increase pain threshold (50), and indeed, low serum serotonin levels have been correlated with increased pain perception (60). Women on average produce serotonin at a slower rate than men (61), which might explain the female-predominant nature of the condition. Lastly, the incidence of fibromyalgia is frequently correlated with a cluster of other conditions including irritable bowel syndrome (IBS), chronic low back pain, chronic fatigue syndrome, and chronic headache (62), most of which have been proposed to have a common serotonergic etiology (50, 63).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

Four human trials have been conducted to evaluate the efficacy of 5-HTP in the treatment of obesity (64-67). All four were randomized, placebo-controlled trials carried out by the same research group, and all reported favourable results. Due to small sample sizes and the lack of blinding in one of the trials, however, bigger trials of higher quality are needed to confirm these results. There also have not been any trials conducted comparing 5-HTP to prescription medications used for appetite suppression, therefore the clinical usefulness of 5-HTP remains unclear.

 

In the latest trial reported for 5-HTP used in the treatment of obesity, Cangiano et al. recruited 25 overweight, type 2 diabetics, with body mass indices (BMI) between 25 and 30, in a double-blind, placebo-controlled study (64). They were randomized to receive either 5-HTP (250mg three times daily; n=12) or placebo (n=13) for a two-week treatment period, preceded by an observation period of one week. Both 5-HTP and placebo capsules were produced by Sigma-Tau Industries, Pomezia, Italy. No dietary restrictions were imposed on the participants during the treatment period, and urine levels of 5-hydroxy-indole-acetic acid (5-HIAA), the metabolite of 5-HTP, were measured to verify their compliance to treatment (although it should be noted that the amount of metabolite produced could also reflect an individual’s rate of metabolism). Results of the 20 participants who completed the trial (nine in 5-HTP group, eleven in placebo group; baseline comparison not reported) were analyzed with respect to energy intake, eating behaviour, body weight, and metabolic indices.  The results are presented below.  In the placebo group, no significant changes were observed in any of the parameters.  On the other hand, mean daily energy intake significantly decreased during both treatment weeks in the 5-HTP group, compared to baseline as well as placebo values. With respect to macronutrient selection, fat intake significantly decreased after both weeks when compared to baseline and placebo, while carbohydrate intake reduced significantly after the second week versus baseline and placebo. It was noted that reduction in carbohydrate intake accounted for 75% of the observed energy intake decline, while fat accounted for the remaining 25%. In addition, a significant weight loss versus baseline (-2.1kg) was found in the 5-HTP group after two weeks of treatment, but no statistical comparison was made to the placebo group. Blood concentrations of fasting glucose, insulin and glycosylated haemoglobin did not change significantly. The authors concluded that 5-HTP is possibly useful for diabetic patients to control weight and eating behaviour, thereby delaying potential complications associated with the disease. This study has been criticized for having a treatment period was possibly too short at two weeks.

                                                                                                                               

The same group of researchers had previously carried out two methodologically similar trials to determine the effect of 5-HTP on obese but otherwise healthy participants (65, 66). While both were randomized, placebo-controlled trials, one was double-blinded (65) while blinding was not specified in the other (66). Inclusion criteria for both trials included hyperphagism (over-eating), and BMI values between 30 and 40. Participants were randomized to receive either 5-HTP (300mg 30 minutes prior to each meal; 900mg/day) or placebo (both from Sigma-Tau Industries, Pomezia, Italy). The overall length of treatment was twelve weeks, divided into two six-week intervals. During the first six weeks, no dietary restrictions were imposed (no-diet period), while an energy-limited diet (5040 kJ or 1200 kcal per day) was prescribed during the last six weeks (diet period). Compliance to treatment was confirmed by measurement of urinary 5-HIAA, as described above. In the study in which blinding was unspecified, 14 women (mean age 38 years) were enrolled, with no reports of drop-outs (66). Results suggested that the women in the 5-HTP group had a greater degree of weight loss (-4.7kg versus -1.2kg) and higher incidence of “anorexia” (defined as at least one of the following: meat aversion, taste or smell alterations, early satiety, nausea and/or vomiting), although no statistical testing was described or presented. Among the anorexic symptoms, early satiety was reported as having the greatest effect on reduced food intake, while other symptoms mostly disappeared during the second period of treatment. This trial is limited by many methodological flaws, including an all-female participant population, small sample size (N = 14), lack of baseline test of comparability, as well as the lack of blinding and statistical testing mentioned above.

 

In the second, double-blinded study, 28 women (mean age 43.2 years; eight drop-outs) were compared with respect to changes in body weight, macronutrient selection, and anorexia after receiving either 5-HTP (900mg, taken three times daily 30 minutes before meals) or placebo (65). Results of the ten per protocol participants in the 5-HTP group indicated a significant decline in body weight after the no-diet period (versus baseline), and a further significant reduction after the diet period (versus end of no-diet period). Total weight loss was 5.0kg, or approximately 5% of the starting body weight. Likewise, energy intake declined significantly after both periods. With respect to macronutrient intake, carbohydrate and fat intake significantly dropped after both treatment periods, while protein intake decreased significantly after no-diet period but no further decrease occurred after dieting commenced. Anorexic symptoms, as described above, indicated that early satiety was present in a significantly higher proportion in the 5-HTP group than the placebo group, during both periods. Reports of nausea/vomiting were significantly higher in the 5-HTP group during the no-diet period, but significantly dropped during the diet period to be comparable to placebo group. No significant changes occurred in the ten women in the placebo group who completed the trial for any of the measured parameters. These findings supported those of the first trial, including that the administration of 5-HTP causes a significant drop in body weight, due mainly to induction of early satiety, and also allows better adherence to a dietary plan. This study is limited by its small sample size, particularly after its high drop-out rate.

 

Finally, in 1989 Ceci et al. enrolled 19 obese, hyperphagic female participants (mean age 41 years, BMI 30 to 40) in a randomized, double-blind, placebo-controlled, crossover trial (67). Either 5-HTP (8mg/kg/day) or placebo was administered for two five-week study periods, with a one-week washout period in between. No diet restriction was imposed, and weekly measurements of feeding behaviour, mood state, body weight, as well as urinary 5-HIAA for verification of compliance (described above), were taken. Analysis of the results indicated that, while total caloric intake was found to be significantly different in both the 5-HTP and placebo group compared to baseline values, the mean 5-HTP value was significantly lower than that for placebo. No change in protein intake was observed for either group, while carbohydrate intake decreased significantly in the 5-HTP group only, as compared to baseline and to the placebo group. Incidence of “anorexia,” as described above, was significantly higher in the 5-HTP group, in particular for the symptoms ‘taste alteration’ and ‘nausea/vomiting’. The Silverstone self-evaluation test of appetite and satiety was also given to the participants, and a significant decrease was found in the 5-HTP group versus placebo group, with no change in appetite observed in either group. Also significant in the 5-HTP group (versus placebo) was the degree of weight loss (approximately -1.5kg on graphical representation), with the authors noting that no relationship was found between the weight loss and vomiting observed. No drop-outs were reported.

 

In conclusion, four human studies have been published describing the positive effect of 5-HTP on obesity and weight loss. However, methodological limitations of these trials prevent a more definitive classification of the effectiveness of 5-HTP. In particular, all trials had relatively small sample sizes, and in all but one trial, participants included only females. Nevertheless, the results reported appear promising, and in one of the trials consisting of type 2 diabetic participants, 5-HTP was found to have a beneficial effect on weight loss and eating behaviour without affecting blood glucose and insulin levels, which could potentially be a safe weight-loss aide in diabetes. More large-scale, high-quality clinical trials are needed to confirm these results.

 

Serotonin has been found to have inhibitory effects on eating behaviour of both animals and humans (64, 68). In animals, serotonin stimulation resulted in decreased food intake (67, 69-71), in particular of carbohydrate foods (72-75), although decreased fat consumption has also been found (64, 65, 76). Depressed serotonergic transmission in the brain has been linked to hyperphagia (over-eating) (68, 77). In addition, serotonin has also been attributed to causing anoretic effects, or anorexia-related symptoms, and has been linked to the pathogenesis of cancer anorexia (64, 67, 78). Serotonin levels have been found to be decreased in diabetic rats (79, 80), and tryptophan, the amino acid precursor of serotonin, was also found to occur at lower levels in diagnosed type 2 diabetic patients (64), suggesting a pathogenic link of serotonin to the disease. 

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

In addition to its central activity, a peripheral component of 5-HTP has also been suggested, as its anoretic effects have been partially blocked by the peripheral serotonin receptor blocker xylamidine (81).

 

5-HTP has mostly been studied as a treatment for panic disorder, but has also been tested as a treatment for mixed anxiety disorders. The published trials have employed a variety of study designs, involving patients and healthy volunteers, as well as both chronic and acute administration of 5-HTP. In total there have been at least four trials investigating 5-HTP as a therapeutic treatment of anxiety-related psychiatric disorders (82-85). All except one (85) have been randomized, double-blind, placebo-controlled trials. Overall, positive results have been reported for the use of 5-HTP in patients suffering from panic- and anxiety-related disorders (83-85), while results in healthy volunteers are mixed (82, 83). The randomized controlled trials will be discussed first, with respect to both a patient population and to healthy volunteers, followed by the open-label study.

 

In the most recent trial, Schruers et al. randomized 24 patients suffering from panic disorders to receive either 200mg of 5-HTP or placebo (n=12 each), 90 minutes prior to undergoing an experimental panic challenge with 35% CO₂ (83). In previous studies inhalation with CO₂ has been found to be able to induce or augment panic (86-88). Symptoms of anxiety were measured before and after CO₂ inhalation using a visual analogue scale of anxiety (VAAS) and a panic symptom list (PSL) consisting of 13 items. Serotonin function was assessed in the patients using salivary cortisol (89). Subsequent to CO₂ administration, it was found that patients in the placebo group experienced significant increases in the VAAS and PSL measures, while the changes in the 5-HTP group were not significantly different from pre-CO₂ values. Post-CO₂ VAAS and PSL values were also found to be significantly higher in the placebo group compared to the 5-HTP group. With respect to the number of panic attacks, which were calculated using subscores from both the VAAS and PSL, it was found to be significantly higher in the placebo group than in the 5-HTP group. Taken together, these results indicated a therapeutic effect of 5-HTP in decreasing anxiety and panic.

 

In addition, Kahn et al. have also published a randomized controlled study of a group of 45 patients with “anxiety disorders” (agoraphobia with panic attacks, n=30; generalized anxiety disorder, n=7; panic disorder, n=5; obsessive compulsive disorder, n=3) (84). The patients were randomly assigned into three groups of 15 each: one group received 5-HTP (maximum dose 150mg/day) in conjunction with carbidopa (150mg/day), another group received clomipramine, a serotonin uptake inhibitor (25mg/day), while the last group received placebo. Treatment length was eight weeks. Outcome measures included the patient-assessed State-Anxiety Inventory (A-STATE) and Self Rating Depression Scale (SDS), as well as the psychiatrist-assessed Hamilton Anxiety Scale (HAS) and Hamilton Depression Scale (HDS), all evaluated periodically throughout the treatment duration. A Present State Examination (PSE) and a 90-item symptom checklist (SCL-90) of various symptom factors were additionally completed at the beginning and end of the trial. After eight weeks, a significant improvement in PSE from baseline was found in the clomipramine group, but not in the 5-HTP nor placebo groups. Due to poor baseline comparability between the groups, however, statistical analyses between the groups could not be completed. With respect to the A-STATE, the SCL-90 and the HDS, significant improvements were found in both the clomipramine and 5-HTP groups compared to placebo. However, significant improvements on the HAS and the SDS could only be found in the clomipramine group, but not the 5-HTP group, when compared to placebo. An interesting observation was the initial deterioration in A-STATE scores in the 5-HTP after the first two weeks of treatment, prior to an improvement (statistically significant) observed after four weeks. The authors concluded that 5-HTP is superior to placebo, but inferior to clomipramine, in treatment of anxiety disorders, and may initially induce anxiety prior to relieving it. One limitation of this study was the small and possibly inadequate dose of 5-HTP used, as 200mg/day is the dose more commonly used in clinical trials.

 

The effect of an acute dose of 5-HTP on healthy volunteers administered prior to a panicogenic stimulant has been investigated in two randomized, double-blind, placebo-controlled trials (82, 83). It should be kept in mind, however, that laboratory-induced conditions do not necessarily mirror those in diseased states. Maron et al. matched 32 healthy participants according to sex, then randomly administered either placebo or 200mg of 5-HTP (TRIPT-OH®, Sigma-Tau, Rome, Italy) 90 minutes prior to injection with 50μg of cholecystokinin tetrapeptide (CCK-4; Clinalfa AG®, Laufelfingen, Switzerland) (82). CCK-4 has been previously documented to possess panicogenic properties (90). Responses to this panic challenge were evaluated using the Panic Symptom Scale (PSS) and a visual analogue scale (VAS) of subjective anxiety, while primary outcome measure was identified as the number of panic attacks. Analysis of results found no significant differences between the 5-HTP and placebo groups in any of the parameters, except intensity of choking was found to be significantly lowered after 5-HTP treatment compared with placebo. Interestingly, subsequent gender-specific analyses found that the female participants, on average, experienced fewer panic attacks and greater improvements in the “cognitive symptoms” of the PSS after taking 5-HTP as compared to their placebo controls (both statistically significant). Decreases in intensity of choking in females and intensity of hot flashes/cold chills in males, were also found to be significant compared to placebo. In another study which was described above (83), Schruers et al. randomized 24 healthy volunteers alongside panic disorder patients in a double-blind, placebo-controlled trial to investigate their response to 35% CO₂ challenge (details previously described). Administration of 200mg 5-HTP 90 minutes prior to CO₂ inhalation was not found to have any significant effects than administration of placebo, when measured on the visual analogue scale of anxiety and panic symptom list.

 

Finally, an open-label study has been completed in which ten patients suffering from “anxiety disorders” of various etiology were treated with 5-HTP (maximum dose 300mg/day) in conjunction with carbidopa (150mg/day) for 12 weeks (85). Results indicated that scores on the Hamilton Rating Scale for Depression, the Hamilton Anxiety Scale, as well as the Spielberger State-Trait Anxiety Scale were all significantly improved from baseline following 5-HTP treatment. Likewise, some subscores on the Symptom Checklist-90 were found to have significantly improved. These clinical improvements were observed in nine of the ten patients. However, results from this trial are largely limited by its open-label methodology and its small sample size.

 

Two additional trials have reported that 5-HTP does not cause anxiety or panic attacks in either patient and healthy subjects (91, 92). 

 

In conclusion, mostly positive results have been reported for the use of 5-HTP to improve the clinical symptoms of panic disorder and other anxiety-related psychiatric conditions. Due to variation in methodology of the reported studies, however, it is difficult to draw a definitive conclusion of the efficacy of 5-HTP. It currently appears that 5-HTP is possibly useful in those with panic disorder and anxiety disorders, when used acutely before a panic episode, or chronically for up to eight weeks. More high-quality research is required to confirm these findings.

 

The role of serotonin in panic disorders has been well-supported by various human studies, including those that found an effectiveness of serotonergic antidepressants in treating panic disorders (93), with a superiority of serotonin-selective ones over non-selective ones (94). Other supporting studies include tryptophan depletion studies (causing decreased serotonin levels) that were found to increase the vulnerability of both healthy and panic disorder subjects to a laboratory-induced panic attack (86-88). Serotonin agonists have also been found to acutely induce panic and/or anxiety symptoms in panic disorder patients (95-97). Therefore, while the hypersensitivity of serotonin receptors as the cause of panic disorders is still controversial (91, 92, 98), it is widely suggested that the serotonergic pathway is somehow involved in the pathophysiology of the condition. Recently, genetic polymorphisms in certain serotonin transporters and monoamine oxidase-A genes have been found to correlate with the susceptibility to panic attacks in healthy female subjects (99). 

 

The relationship between serotonin and anxiety is questionable, as various trials have found a tendency for 5-HTP to initially increase symptoms of anxiety (84, 85, 92). The reason for this remains unknown.

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

One randomized, double-blind, placebo-controlled trial reported that  5-HTP  did not appear to prolong or maintain abstinence in alcoholic patients (100). Another study found that 5-HTP was able to improve fragmentation of REM sleep in recovering alcoholics, although no measures of their ability to abstain from alcohol were assessed (101). Due to the small number of trials conducted, further research is required to determine the role of 5-HTP for this indication.

 

A group of 45 recently abstinent alcoholic participants (44 men, mean age 41.6 years; 1 woman, age 49 years) participated in a one-year abstinence study comparing the effects of 5-HTP and levodopa with placebo (100). The subjects were randomized into three groups: one received 5-HTP (initially at 100mg/day, gradually increasing to a maximum of 400mg/day or the highest tolerated dose; mean dose unspecified), another received levodopa (precursor of dopamine), while the last group received placebo. Carbidopa, a peripheral decarboxylase inhibitor used to prevent peripheral breakdown of neurotransmitters, was also present in the 5-HTP and levodopa capsules at a dose of 100mg/day. During the one-year study period, participants were monitored weekly during the first month, biweekly during the second month, then monthly thereafter, for treatment compliance and incidence of relapse. Of the 31 participants who completed the study, only eight (25.8%) remained abstinent for the entire duration, with no significant difference between their group assignments. Analysis of baseline cerebrospinal fluid levels revealed that ability to maintain abstinence was correlated with the concentration of dopamine metabolite but not to the serotonin metabolite. From these results the authors suggested that alcoholism does not appear to be related to the serotonin pathway, while dopamine may possibly play a role.

 

Zarcone and Hoddes undertook a study using 5-HTP to correct sleep abnormalities in a group of alcoholics, based on the observation that many former alcoholics experience persisting fragmentation of sleep patterns, particularly during REM periods (101). Twelve recovering alcoholic men (mean age 40.7 years) who had been abstinent from alcohol for at least 23 days, participated in this 14-night open-label study, during which they received 5-HTP (300mg) before bed on nights 7 to 11. Placebo pills were administered on the remaining nights. Sleep patterns were monitored by polygraphs, and scored by technicians kept blind from the treatment assignments. Overall, the authors noted that only slight, non-significant differences were found for the group as a whole. Subgroup analysis, however, did reveal a significantly greater efficacy of 5-HTP to correct REM fragmentation in those with lower “REM efficiency” (i.e. greater fragmentation; n=9) at baseline than those with normal efficiency (n=3).  Given the small sample size in this study, larger, long term studies are required to further support the use of 5-HTP for improving sleep abnormalities in alcoholics.

 

Preliminary evidence suggests that 5-HTP may not play a role in treating alcoholism by promoting alcohol abstinence, but may possibly improve sleep in a subgroup of individuals. However, due to the small number of trials that have been conducted each with small sample sizes, more research is required to confirm these results.

 

Evidence of the role of serotonin in the pathophysiology of alcoholism has come from both animal and human studies. In rats, breeds that have been selected for alcohol preference have been found to have lower serotonin levels in various regions of the brain than control rats (102), while 5-HTP has been found to be able to decrease alcohol consumption (103). In human alcoholic subjects, the cerebrospinal fluid concentration of the major serotonin metabolite was found to be lower than normal subjects, and decreased with the length of sobriety (104, 105). Selective serotonin reuptake inhibitors have been found to be effective at decreasing alcohol consumption in heavy drinkers (106).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

 

 

One randomized, double-blind, placebo-controlled human study has found that an acute oral dose of 5-HTP (4mg/kg) was able to significantly increase the blood concentration of serotonin in a group of male, teenaged autistic patients (13 to 19 years old; n=18) but not in a group of age- and sex-matched, healthy volunteers (n=20) (107). The authors suggested that administration of 5-HTP in autistic individuals might promote the synthesis of serotonin in the body. Unfortunately, no therapeutic or behavioural effects of 5-HTP were measured in the study, making the clinical usefulness of 5-HTP in autism unclear. Further research is required in this area in order to gain a better understanding of 5-HTP’s role in autism. It should be noted that onset of autism occurs before three years of age, and that prognosis is strongly dependent on the child’s development by 7 years old (108). Therefore trials of 5-HTP in younger autistic children may possibly result in better clinical outcome.

 

There is some evidence that serotonin may play a role in developmental disorders such as autism, as serotonin levels have been found to be elevated in groups of autistic children (109, 110). Selective serotonin reuptake inhibitors have also been found to have beneficial effects in some autistic patients (111).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

 

 

One human study has found that an intravenous infusion of 5-HTP (0.4mg/kg for 30 minutes) resulted in lowered prolactin and growth hormone responses in female bulimia nervosa patients (n=8) when compared to female control participants (n=8) (112). Another interesting observation was the significantly higher level of 5-HTP found in the plasma of bulimic patients than in that of normal controls, following the same dose of 5-HTP infusion. Unfortunately, no therapeutic or behavioural effects of 5-HTP were measured in the study, making the clinical usefulness of 5-HTP in bulimia nervosa unclear. Further research is required in this area in order to gain a better understanding of 5-HTP’s role in this condition.

 

Serotonin has been suggested to be linked to the pathogenesis of bulimia nervosa, based on studies that have found serotonin to be the primary neurotransmitter responsible for control of satiety and macronutrient selection (68, 113). Reduction of serotonin activity in animal models has been found to affect satiety signals and increase carbohydrate consumption (114), behaviours which are clinically seen in bulimic patients (115, 116). Furthermore, deficiencies or defects in the serotonergic pathway have been linked to the pathogenesis of various conditions which are often found to co-exist with bulimia nervosa, including depression, anxiety, and alcoholism (112, 117).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

Cerebellar ataxia is a neurodegenerative disease involving the part of brain that regulates body posture and limb movements, thus causing mobility, balancing, and speech difficulties (2). Cerebellar ataxia can be genetic or spontaneous in etiology, and has been classified into many types (www.ataxia.org.uk), but will be treated as a single condition in this review in accordance with the practice of most of the reported trials.  There have been at least ten published studies testing the ability of 5-HTP to treat diagnosed cases of cerebellar ataxia (4, 118-126), however only three of these were randomized, double-blind, placebo-controlled trials (4, 120, 121),  from which mixed results have been reported. Therefore more research is required in order to establish the role of 5-HTP, if any, for this indication. The trials will be reviewed in reverse chronological order, starting with the randomized controlled trials.

 

In 1995, Wessel et al. conducted a randomized, double-blind, placebo-controlled, crossover trial to determine whether 5-HTP could improve symptoms of cerebellar ataxia in 39 patients with mixed etiology (120). During the first treatment phase, the patients were randomized to receive either 5-HTP (initial dose 100mg/day, increasing in 100mg increments up to 1000mg/day) or placebo for ten months, after which they were crossed over to the opposite treatment for another ten months. The treatment phases were separated by a one-month washout period. Clinical outcome was measured by an ataxia clinical rating scale, which scored patients using a list of 26 items related to movement, speech, and gait. Results, however, indicated no significant change in clinical scores between the treatment and placebo phases for the duration of the study period.

 

Trouillas et al. have published two randomized, double-blind, placebo-controlled studies on 5-HTP for use in cerebellar ataxia (4, 121). In one of these trials, 19 patients suffering from Friedreich’s ataxia (a form of early-onset hereditary ataxia) were randomized to receive either 5-HTP (n=11) or placebo (n=8) for six months (121). Treatment with 5-HTP was administered according to the weight of the patients (mean age 25.9 years): those weighing less than 50kg were given 200mg/day during the first month and 400mg/day for the remaining trial; those weighing more than 50kg were given 600mg/day in the first month and 900mg/day thereafter. The ataxia rating scale used in this study consisted of a “kinetic” score and a “static” score, which were obtained using various functional subtests. Quantitative measurements of writing and speaking times were also evaluated. Statistical analysis revealed there to be a significant improvement in kinetic scores of the 5-HTP group when compared to those of the placebo group. However, no other statistically significant differences between the groups were observed in the static and quantitative parameters, making the clinical value of the results unknown. In a previous study, 30 patients with various forms of ataxia were paired by diagnosis, then randomly given 5-HTP (10mg/kg/day) or placebo for four months (4). Once again, global ataxia scores, which were made up of subscores from various static and kinetic functional tests, were used to evaluate the patients’ severity of symptoms. Other quantitative measurements, including walking, writing and drawing times, were also made before and after treatment. After four months, global ataxia scores were found to be significantly improved in the 5-HTP patients compared to their placebo controls, as were the changes in scores from baseline values. With respect to the quantitative measurements, some statistically significant improvements were found in the 5-HTP group relative to the placebo group. Furthermore, analyses of brain CT and MRI scans from patients who responded well to 5-HTP prompted the authors to suggest that 5-HTP is more effective in improving ataxia symptoms arising from lesions located in the anterior lobe of the vermis.

 

At least seven open-label trials of 5-HTP used for various forms of cerebellar ataxia have been carried out (118, 119, 122-126). One trial specifically studied Friedreich’s ataxia (124), another only sporadic adult-onset ataxia (cortical cerebellar atrophy) (118), but most studied mixed forms of ataxia (119, 122, 123). Two further trials enrolled patients with various cerebellar syndromes and lesions (125, 126). Some positive effects in the treatment of ataxia have been reported from the trials. Trouillas et al. reported a regression of ataxia (statistical significance unknown) in an open label series of 21 patients administered 5-HTP (16mg/kg/day) for 12 months (122), as well as statistically significant improvements in static ataxia (from baseline ) in another group of 18 patients (123). Some therapeutic effects have also been reported by Wessel et al. (124) and Rascol et al. (126), but both failed to report any statistical analysis. Other trials did not find any observable differences before and after 5-HTP treatment (118, 119, 125). Unfortunately, due to the lack of placebo groups to act as negative controls in these studies, not much information can be discerned from them regarding the efficacy of 5-HTP. Other open-label studies published in foreign languages have also been reported (127), but will not be reviewed here due to lack of study details.

 

Overall, the efficacy of 5-HTP for the treatment of cerebellar ataxia remains unclear due to lack of unequivocal evidence. Many clinical studies have been reported, however most of them have been open-labelled, uncontrolled trials. Randomized controlled trials that have been conducted generally had small sample sizes, and furthermore reported mixed results, thus making it hard to draw conclusions from them. It is worthwhile to note that dosage of 5-HTP used in these trials have ranged from under 100mg/day in the earlier trials, to 1000/day in the most recent trials, which further compounded the variation in the results. Furthermore, a range of sensitivity to 5-HTP has been reported for individuals with various types of cerebellar ataxia (127, 128), but the evidence remains weak. In conclusion, further research is required in order to evaluate the efficacy of 5-HTP for this condition.

 

A deficiency in serotonin has been proposed as the underlying mechanism behind cerebellar ataxia (118-121, 129). Serotonergic nerve terminals have been found to exist in the cortex of the cerebellum, therefore serotonin appears to be an important cerebellar neurotransmitter (4). This hypothesis has been further supported by various animal studies, including the discovery of decreased serotonin neurotransmission in the cerebellum in animal models of ataxia (130).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

Eight clinical trials have studied the efficacy of 5-HTP in the prevention of headaches in adults. Both positive and negative results have been reported; however due to methodological limitations of most of the trials, more research is needed to confirm these results. Four of the trials were placebo-controlled, which will be discussed first, followed by three controlled trials which lacked a placebo arm. One open, uncontrolled trial has also been conducted, which will be discussed last.

 

In 2000, Ribeiro et al. enrolled 78 participants suffering from chronic tension headaches to a double-blind, placebo-controlled trial (131). They were randomized to either 5-HTP (300mg/day in three divided doses; n=43) or placebo (n=35) for eight weeks, followed by a two-week follow-up period. The main outcome measure was the number of days with headache, while other parameters such as headache severity and consumption of prescription analgesics were also noted. Analysis of the per protocol population found that the number of headache days had decreased for both groups during the treatment period, but was not significantly lower for the 5-HTP group (n=34) versus the placebo group (n=31). Interestingly, during the two weeks follow-up in which treatment was discontinued, the 5-HTP group underwent a post-treatment reduction in headache days which achieved statistical significance versus placebo. With respect to the other parameters, ingestion of analgesics was found to be significantly lower in the 5-HTP group, while severity of headaches was comparable between the groups.

 

De Benedittis et al. published two double-blind, placebo-controlled, crossover trials to evaluate the use of 5-HTP 400mg/day (in four doses) versus placebo for two months in 31 participants (50 enrolled with 19 drop-outs) suffering from chronic primary headache (CPH) (132), then in another 31 participants (40 enrolled with 9 drop-outs) suffering from migraine (133). Of the 31 CPH sufferers, 16 were identified as having migraine, six had mixed headache, five had psychogenic headache, and four had muscle contraction headache. In both trials, a headache index (defined as number of headache days per month) and headache density (defined as severity of attack multiplied by frequency) were used as outcome measures of efficacy. It was found that, for both trials, headache frequency and severity reduced after treatment, but the reductions were not statistically significant compared to those of the placebo groups.

 

In addition, in 1978 an abstract was presented describing a randomized, double-blind, placebo-controlled, crossover trial (134). Twelve migraine patients were given 5-HTP (300mg/day) and placebo for two months each, in one of two possible orders. Analysis of the results did not indicate superiority of 5-HTP over placebo in reducing the Headache Index. Other details are not known, as the trial does not appear to have been published as a longer report.

 

Three trials have been conducted comparing the efficacy of 5-HTP to medications used conventionally in migraine prevention. In the latest documented trial, a proprietary preparation of 5-HTP, Tript-HO® (Sigma Tau, Italy; 100mg three times daily) was compared with propranolol (40mg three times daily) for a period of four months (135). Thirty-nine migraine sufferers participated in this double-blind trial (group assignment not described), which found that treatment with both 5-HTP and propranolol was able to significantly reduce the frequency of migraine attacks, with the effects of 5-HTP comparable to those of propranolol. Other details are not available because the full report is not available in English.

 

Two additional trials compared 5-HTP to methysergide, an ergot alkaloid used in the prevention of migraines. Titus et al. randomized 124 migraine sufferers to either 5-HTP (600mg/day; n=63) or methysergide (3mg/day; n=61) for six months (136). Outcome measures were reduction in the number and severity of attacks, for which significance was determined to be ≥ 50% reduction. This was achieved for 71% of the 5-HTP group, versus 75% of the methysergide group (statistical testing not performed). Analysis of the specific complaints of the proportion of the 5-HTP group who did not experience a ≥ 50% clinical effect prompted the authors to suggest that 5-HTP is more effective for the reduction in the intensity and duration, than in the frequency, of migraine attacks. Similar results were obtained in an early trial by Sicuteri et al., in which 40 migraine sufferers randomly received either 5-HTP (300mg/day; Falorni, Florence, Italy) or methysergide (2mg/day; Deserril, Sandoz, Basle, Switzerland) in a 40-day preliminary, open-label trial (137). Parameters evaluated were number of attacks and migraine index, both of which were found to be significantly reduced from baseline values in both treatment arms. A significant difference was not found between the groups.

 

Finally, in 1984 an open label, uncontrolled trial was undertaken to evaluate the efficacy of Tript-OH® (Sigma Tau, Italy) to reduce the frequency of headaches, the pain tolerance of headache sufferers, and their analgesic use (138). One hundred participants who suffered from primary headaches were administered Tript-OH® capsules (100mg each, three doses daily) for four months. At the end of the trial, a subgroup of 5-HTP “responders” (defined as having at least 60% reduction in the Pain Total Index score) was identified, and their results analyzed. It was found that, among the responders, no significant reduction in frequency of headaches was seen, however both pain tolerance and analgesic use improved significantly. Analysis of the subgroup characteristics revealed that response to 5-HTP is likelier if: the individual has a history of depression, the age of headache onset is < 20 years old, and previous positive response to other treatments (e.g. pizotifen).

 

In conclusion, evidence for the efficacy of 5-HTP in the prevention of headaches in adults has been mixed. There have been some positive results reported, but due to methodological limitations in most of the trials, the evidence is still inconclusive. An additional compounding issue is that some trials do not differentiate between different types of headaches, such as migraines and tension-type, which are thought to occur via different physiological mechanisms (138). More research is required to confirm the available evidence for this indication.

 

Migraine headaches have been described as a “serotonin deficiency” disorder, originating from over-activity of monoamine oxidase (MAO) causing excessive breakdown of serotonin in the brain (137, 139). A cerebral deficiency of serotonin lowers the pain threshold, and sensitizes nociceptors to pain-producing substances such as bradykinins and potassium (137, 140, 141). Plasma serotonin levels have been found to be decreased in migraine sufferers, especially in those who experience aura prior to attacks (142). Thus migraines can be thought of as serotonin supersensitivity, or “hyperalgesia” (143, 144).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

5-HTP appears to be able to strengthen and normalize the serotonin-dependent analgesia system, as well as desensitize some serotonin receptors, thus restoring normal sensitivity (137, 144, 145). Over time, increased production of serotonin can decrease the sensitivity of migraine-triggering receptors, while increasing the sensitivity of migraine-inhibiting receptors, thereby decreasing the occurrence of attacks (139). Furthermore, 5-HTP has also been found to increase plasma levels of endogenous opioids, including β-endorphins (146, 147) and enkephalins (148), exerting additional analgesic effects.

 

 

There have been a total of five clinical trials studying the efficacy of 5-HTP in prevention of childhood headaches. A systematic review of drugs used to prevent migraine headache in children was published in 2003, which analyzed results from three trials of 5-HTP, two of which were placebo-controlled while one was compared to pizotifen (149). The reviewers were unable to perform meta-analysis on the two placebo-controlled trials due to a lack of comparable variables, but concluded that 5-HTP did not appear to be effective in the reduction of frequency of attacks based on the available data and results. On the other hand, in addition to the review there have been two trials published, both of which reported statistically significant results compared with placebo (144, 150). Due to these ambiguous results, more quality trials are needed in order to ascertain the ability of 5-HTP in the prevention of childhood headaches. The trials assessed in the systematic review will be discussed first, followed by the remaining two trials in reverse chronological order.

 

In 2003, Victor and Ryan published a systematic review evaluating the available literature on pharmacological therapies being used to prevent childhood migraine (149). 5-Hydroxytryptophan was evaluated as one of the therapies, with three trials found to have assessed its efficacy. Two of these compared 5-HTP to placebo (140, 151), while one compared it to pizotifen, an antihistamine commonly used in migraine prevention (152). In the two placebo-controlled studies, migraine index was measured as a common parameter, however the results of the Longo trial were displayed only graphically, and claimed by the authors to be statistically significant (151). The formula for calculating the migraine index was also not defined in the paper. Meta-analysis of the two trials was therefore not possible. In the Santucci trial, headache frequency was reported as an additional outcome measure. Results for both migraine index and headache frequency were not statistically significant (140). With regards to the pizotifen-controlled study, 34 children with migraines (mean age 12 years) were assigned to either 5-HTP (150mg/day for 10 years and under, 200mg/day for over 10 years; n=19) or pizotifen (0.75mg/day for 10 years and under, 1mg/day for over 10 years; n=15) for a period of 90 days in a randomized, double-blind manner (152). Headache index and pain total index were measured every 30 days, which were found to have dropped significantly at all time points for both treatment groups. There was no statistically significant difference between the groups. In conclusion, the reviewers declared that while 5-HTP did not appear to reduce frequency of migraine attacks in children, the small number of trials and their poor quality resulted in a need for more high-quality trials in order to reach a conclusion regarding the efficacy of 5-HTP for the prophylaxis of pediatric migraines.

 

Two additional trials have been conducted to evaluate the efficacy of 5-HTP in the prevention of migraine in children, which were not identified in the Victor review. Nicolodi and Sicuteri performed a prospective, randomized, placebo-controlled trial to investigate whether or not the long-term administration of 5-HTP to children predisposed to migraines could prevent the “cropping out” of attacks in the future (144). To be eligible for the study, participants had to demonstrate at least one “familial/genetic risk factor” (defined as one or more first or second degree relative(s) suffering from primary pain), and at least one “individual serotonergic risk factor” (including recurrent primary abdominal pain, growing pains, hyperactivity, attention deficit, sleep abnormalities), which according to the authors predisposed children to developing migraine attacks. In the study 413 migraine-prone children (mean age 5.2 years) were enrolled and randomized to 5-HTP treatment (100mg/day up to 5 years of age, 200mg/day for 6 years and over; n=207) or placebo (ascorbic acid 100mg/day; n=206) for three years. The two groups were matched with respect to age and sex. Follow-up period was 17 years, during which time participants were asked to record their frequency of headache attacks. It was found that a significantly lower number of attacks were reported in the 5-HTP group (3) than in the placebo group (55) during the 17 years following 5-HTP or placebo administration. Thirteen participants could not be contacted at the end of the follow-up, but their group/treatment assignment was not indicated. The authors concluded that administration of 5-HTP is effective for the prevention of headache attacks in children prone to primary pain.

 

In the second study, De Giorgis et al. studied the effect of 5-HTP versus placebo for headache in association with sleep disorders in children (150). In a randomized, double-bind, placebo-controlled crossover trial, 39 children (mean age 10.8 years) who suffered from headaches and sleep disorders were randomized into two groups: 5-HTP (4.5mg/kg/day; n=20 with three drop-outs) or placebo (n=19 with two drop-outs). Treatment duration was two months, during which the participants were evaluated monthly by a questionnaire concerning headache frequency and intensity, as well as sleep quality. After two months, participants were given the opposite treatment (without a washout period) for an additional two months. The authors reported that treatment with 5-HTP, but not with placebo, was able to reduce the Headache Index (intensity x frequency) significantly in both groups. It should be noted that the baseline scores were not shown to be statistically comparable between the groups, however these differences are less of an issue given the crossover design of the study.

 

In conclusion, both positive and negative trials have been reported for the use of 5-HTP as a preventative treatment of migraine headaches in children. Due to methodological shortcomings in all the trials, however, the efficacy of 5-HTP for this condition remains unclear. An additional compounding issue is that some trials do not differentiate between different types of headaches, such as migraines and tension-type, which are thought to occur via different physiological mechanisms (138). There is some preliminary evidence for the use of 5-HTP to prevent headaches in a subgroup of children who suffer other disruptive conditions such as sleep disorders, with or without a family history of migraine attacks, but more research is required to verify this claim.

 

 

5-HTP has been reported for use in various other conditions for which formal randomized, controlled trials have not been performed. These include delirium tremens (153), Lesch-Nyhan syndrome (154-158), and LSD-induced psychosis (159). Further research is required to validate these claims.

Myoclonic disorders are neurological deficits characterized by sudden, involuntary contractions of the skeletal muscles (http://neurology.health-cares.net/myoclonus.php).  They are a large group of disorders consisting of many types, and include conditions such as postanoxic intention myoclonus (Lance-Adams syndrome), essential myoclonus, palatal myoclonus, and progressive myoclonus epilepsy (PME). PME itself is a class of syndromes that includes Unverricht-Lundborg disease (Baltic myoclonus), Ramsay Hunt Syndrome, Lafora disease, mitochondrial encephalomyopathy, and cherry-red spot-myoclonus (www.epilepsy.com/epilepsy/epilepsy_promyoclonic.html) (160). Therefore myoclonic disorders are a complex group of conditions with diverse etiologies and pathologies, but are generally associated with myoclonus, one of the predominant features. Due to the poor prognosis in most cases of myoclonic disorders, alternative treatments such as 5-HTP have been investigated as possible forms of therapy. Numerous case reports have been published on the use of 5-HTP to treat various forms of myoclonic disorders, most of which have reported beneficial results. However, randomized controlled trials have only been found for PME (160, 161) and pediatric opsoclonus-myoclonus (162), from which negative results were reported. Thus the authors have advised against the use of 5-HTP for these conditions, however its use in other forms of myoclonus is still unclear. It should be noted that 5-HTP has orphan drug status for the treatment of postanoxic intention myoclonus (2). The randomized controlled trials will be discussed first, followed by a brief overview of the case reports.

 

In 1996 Pranzatelli et al. reported a double-blind, placebo-controlled crossover study in which eight patients with progressive myoclonus epilepsy (Unverricht-Lundborg disease, n=3; Lafora disease, n=2; mitochondrial encephalomyopathy, n=3; mean age 20.5 years) were evaluated for the efficacy of 5-HTP in improving PME-associated ataxia (161). Patients were treated with both placebo and 5-HTP, in random order, separated by a two-week washout period. 5-HTP was administered starting at 2mg/kg/day, titrating up over one month until a “best dose” or maximum of 15mg/kg/day was reached, which was then maintained for two weeks. Carbidopa, a peripheral decarboxylase inhibitor, used to prevent the breakdown of 5-HTP in the periphery, was administered throughout the trial at a maximal dose of 200mg/day. Ataxia was evaluated using scores on both subjective and objective tests. It was found that scores between 5-HTP and placebo treatments were not statistically different, indicating a lack of effect for 5-HTP. The authors noted that a possible reason for the lack of significant results was the small sample size, particularly since two of the patients had discontinued their 5-HTP treatment because they felt it “made them worse.”

 

Pranzatelli had previously reported another double-blind crossover trial of what appeared to be the same group of PME patients from patient characteristics (160). Placebo or 5-HTP (Circa Pharmaceuticals, Copiaque, NY, USA) was randomly administered to six of the patients, after which they received the opposite treatment after a two-week washout period. The dose of 5-HTP was titrated up from 2mg/kg/day over six weeks until an optimal dose or 15mg/kg/day was reached, which was continued for one week. Carbidopa (Merck, Sharp and Dohme, West Point, PA, USA) was once again administered throughout the trial at a maximal dose of 200mg/day. Two patients didn’t participate in the double-blind study because they had been given open-label 5-HTP for “compassionate use.” Results revealed no significant differences between the 5-HTP and placebo treatment periods as evaluated on myoclonus or ataxia evaluation scores. Two of the six patients reported “much improvement” while on 5-HTP treatment, however two other patients also reported worsening of symptoms. Of the two patients given open-label use of 5-HTP, one showed marked improvement in myoclonus and overall functional level, while the other experienced no change in symptoms. Results from both these studies might have been confounded by the heterogeneity in disease states of the patients, and their concurrent use of two or more antiepileptic drugs.

 

A randomized, double-blind, placebo-controlled crossover trial has been carried out to evaluate the effects of 5-HTP on children diagnosed with opsoclonus-myoclonus (162). The five children in the study (mean age 7.9 years) were all afflicted with myoclonus, opsoclonus, ataxia, behavioural problems, and learning disabilities. Dosage of 5-HTP (Circa Pharmaceuticals, Copiaque, NY, USA), as above, was started at 2mg/kg/day and gradually increased over six weeks to an optimal dose up to a maximum of 15mg/kg/day. The maximum tolerated dose of 5-HTP or placebo (randomly assigned) was administered for one week, then tapered off and washed out for two weeks before the opposite treatment was given. Carbidopa (Merck, Sharp and Dohme, West Point, PA, USA) was administered throughout the trial from1.5 to 3mg/kg/day in divided doses. Overall, no significant differences between the 5-HTP and placebo treatments could be found with respect to clinical symptom scores. Two of the patients’ parents reported subjective improvement while on 5-HTP, however the remaining three had an overall negative assessment, due mainly to the behavioural changes observed (most commonly aggressiveness, emotional lability, and irritability). The authors recommended that 5-HTP should not be used for the condition of pediatric opsoclonus-myoclonus, due to lack of clinical improvements, and potential exacerbation of behavioural problems.

 

In addition to these randomized controlled trials, numerous case reports have been published on the use of 5-HTP to treat various myoclonic disorders. 5-HTP has been used to treat postanoxic intention myoclonus (163-167); essential myoclonus (164); palatal myoclonus (168, 169), as well as myoclonus associated with phenylketouria (PKU) (170). It has also been reportedly used for progressive myoclonus epilepsy (PME) (164, 171), in particular Unverricht-Lundborg disease (160); Ramsay Hunt Syndrome (165); Lafora disease (160, 165, 172); and cherry-red spotmyoclonus (165, 166, 173). Of the 42 patients treated in these case reports, most have reported either a marked (20) or slight (12) clinical improvement. It should be mentioned, however, that there have been two cases of deteriorations observed in patients with cherry-red spot myoclonus treated with 5-HTP (166).

 

In conclusion, the efficacy of 5-HTP in treating myoclonic disorders is still unclear. It is difficult to make a generalization for this condition due to the clinical heterogeneity of the disorder. Randomized controlled trials have suggested that 5-HTP is possibly ineffective or not recommended for PME and pediatric opsoclonus-myoclonus, respectively, but more research is required to determine its role in the other types of myoclonic disorders.

 

The use of serotonergic agents such as 5-HTP was based on the finding of low levels of serotonin metabolites in the cerebrospinal fluid of patients with several myoclonic disorders (162, 171).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

 

The role of 5-HTP in schizophrenia has been studied in a randomized, double-blind, placebo-controlled, crossover trial (174). In addition, a case study has been published to determine the effects of 5-HTP on sleep quality and behaviour on two schizophrenic children, however no measures of behavioural outcome were reported (175). Due to the small number of trials reported for this indication, further research is required to verify the effects of 5-HTP in schizophrenia.

 

In 1987 Irwin et al. enrolled five schizophrenic patients (mean age 34.2 years) in a randomized, controlled, crossover study of 200mg 5-HTP (administered with carbidopa, a peripheral decarboxylase inhibitor) or placebo taken 30 minutes before administration of D-amphetamine to induce acute psychosis (174).  Sub-scores of the Brief Psychiatric Rating Scale (BPRS) were used to measure positive schizophrenic symptoms (i.e. thought disturbance, activation, hostile suspiciousness). Comparison of the results between baseline and the 90-minute time point revealed a statistically significant increase in the positive symptoms when d-amphetamine was preceded by placebo, but no significant changes when it was preceded by 5-HTP. Both the positive and psychotic symptoms at 90 minutes were also significantly higher in the placebo group than in the 5-HTP group. These results, however, are largely limited by the small sample size of the study.

 

In an uncontrolled case study, two schizophrenic children (ages 5 and 7) were administered 5-HTP following REM sleep deprivation in order to study any behavioural changes (175). The authors hypothesized that insufficient REM sleep in schizophrenic children led to REM activity being released during the waking state, manifesting as “hyperarousal and driveness,” thus a normalization of REM sleep patterns may result in therapeutic effects. The study was conducted over 19 consecutive nights, during which 3mg/kg/night 5-HTP was administered for eight nights (night 10 to 17), and the REM sleep deprivation occurred on nights 12 to 13. Sleep patterns were monitored by polygraphs, and scored by technicians unaware of the study design. Statistical analysis revealed no significant increase in REM minutes following REM deprivation compared to baseline, however a significant increase was found when compared to the REM minutes following a non-treated (i.e. no 5-HTP given) REM deprivation of the same patients. The authors noted that “the systematic behavioural observations revealed no consistent change related to either 5-HTP administration or REM deprivation,” but no data were reported. It should be noted that the age of the patients in this case study are below the general guidelines for childhood schizophrenia as set out by the Merck Manual (108).

 

It has been proposed that serotonin is involved in the mechanism of disease of some forms of schizophrenia (174, 176, 177).  Low cerebrospinal fluid levels of serotonin metabolite have been found in subgroups of schizophrenic patients (178-180), and have been associated with increased occurrence of suicidal and aggressive acts in schizophrenic patients (181, 182).

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

5-HTP has been found to be able to prolong the duration of REM (rapid eye movement) sleep time in humans (175, 183, 184). As such its efficacy has been investigated as treatment for various sleep disorders, including sleep terrors in children (185), sleep fragmentation in alcoholics (101), and conditions associated with decreased REM sleep including Down’s Syndrome (186) and childhood schizophrenia (175).  Due to the difference in nature of these conditions, and the open-label methodology used by all of the reported studies, further research is required to determine the role of 5-HTP in various sleep disorders.

 

In 2004 Bruni et al. published an open-label trial describing the effects of 5-HTP on 31 children (mean age 6.8 years) diagnosed with sleep terrors, compared to 14 children (mean age 7.4 years) with the same diagnosis but not receiving any intervention (185). The group assignments were random, and dosage regimen of 5-HTP was 2mg/kg/day, administered at bedtime for 20 days. Outcome measure was the frequency of night terrors, with “responders” to treatment identified as those with a greater than 50% reduction in the number of night terror episodes from baseline values. Evaluations were completed after one and six months. It was found that both groups of children experienced a significant decrease in number of night terrors at both the one-month and six-month follow up, with the 5-HTP group reporting lower values at both time points (statistical significance not reported). Also, there were significantly higher proportions of responders in the 5-HTP group at both time points.

 

Zarcone and Hoddes undertook a study using 5-HTP to correct sleep abnormalities in a group of alcoholics, based on the observation that many former alcoholics experience persisting fragmentation of sleep patterns, particularly during REM periods (101). Twelve recovering alcoholic men (mean age 40.7 years) who had been abstinent from alcohol for at least 23 days, participated in this 14-night open-label study, during which they received 5-HTP (300mg) before bed on nights 7 to 11. Placebo pills were administered on the remaining nights. Sleep patterns were monitored by polygraphs, and scored by technicians kept blind from the study design. Overall, the authors noted that only slight, non-significant differences were found for the group as a whole. Subgroup analysis, however, did reveal a significantly greater efficacy of 5-HTP to correct REM fragmentation in those with lower “REM efficiency” (i.e. greater fragmentation; n=9) at baseline than those with normal efficiency (n=3).

 

The purported ability of 5-HTP to alter REM sleep has also been investigated in Down’s syndrome (186) and childhood schizophrenia (175), conditions which have been found to affect REM sleep times. In an open-label case study, 5-HTP was administered to six mongoloid infants greater than two weeks of age, for periods ranging from 12 to 36 months (186). Dosage of 5-HTP administered was individually tailored to each infant’s tolerance level, and ranged from 1 to 9mg/day. Analysis of the results found that treatment with 5-HTP was able to normalize eye-movement density in only two of the infants, and that the effects were short-acting. The authors did note that the infants were found to have increased muscle tone and improved motor behaviour, however no quantifiable measures were taken and no non-treated control group was used for comparison.

 

In an uncontrolled case study, two schizophrenic children (ages 5 and 7) were administered 5-HTP following REM sleep deprivation in order to study any behavioural changes (175). The authors hypothesized that insufficient REM sleep in schizophrenic children led to REM activity being released during the waking state, manifesting as “hyperarousal and driveness,” thus a normalization of REM sleep patterns may result in therapeutic effects. The study was conducted over 19 consecutive nights, during which 3mg/kg/night 5-HTP was administered for eight nights (night 10 to 17), and the REM sleep deprivation occurred on nights 12 to 13. Sleep patterns were monitored by polygraphs, and scored by technicians unaware of the study design. Statistical analysis revealed no significant increase in REM minutes following REM deprivation compared to baseline, however a significant increase was found when compared to the REM minutes following a non-treated (i.e. no 5-HTP given) REM deprivation of the same patients. The authors noted that “the systematic behavioural observations revealed no consistent change related to either 5-HTP administration or REM deprivation,” but no data was reported. It should be noted that the age of the patients in this case study are below the general guidelines for childhood schizophrenia as set out by the Merck Manual (108).

 

Serotonin has been found to be involved in the regulation and maintenance of REM (rapid eye movement) sleep, as well as the initiation of non-REM sleep (101, 187). 5-HTP, the precursor of serotonin, has been found to have effects on prolonging the duration of REM sleep time in humans (175, 183, 184). This action is possibly mediated via the production of sleep-promoting factors (188). In cats, 5-HTP has also been found to be able to correct sleep difficulties caused by a deficit of serotonin, whether from ρ-chlorophenylalanine (189) or a midline Raphe nucleus lesion (190).

At least six studies have been published on the use of 5-HTP in children with Down’s syndrome (trisomy 21). Three were placebo-controlled studies (191-193), while two were uncontrolled case studies (3, 194). One additional case study investigated the effect of 5-HTP on sleep parameters in infants with Down’s syndrome (186). While early evidence of efficacy had been found in case reports (194), results of the placebo-controlled trials failed to reveal a superiority of 5-HTP over placebo in improving physiological and developmental parameters in Down’s syndrome patients. Therefore the evidence currently suggests 5-HTP to be an ineffective treatment for Down’s syndrome. The controlled trials will be discussed first, followed by a brief overview of the uncontrolled studies.

 

Encouraged by early positive results reported when 5-HTP was administered to children with Down’s syndrome (194), several groups sought to confirm these beneficial effects in randomized controlled trials. In the most recent, large-scale trial to be carried out, 89 newborns with Down’s syndrome were randomly assigned into four study groups: placebo (n=20), 5-HTP (n=22), pyridoxine hydrochloride (n=23), and a combination of 5-HTP/pyridoxine (n=24) (191). Pyridoxine, also known as vitamin B6, is a coenzyme required in the conversion of 5-HTP into the neurotransmitter serotonin, and has previously been reported to increase serotonin levels in children with Down’s syndrome (192). Dosage of 5-HTP started at 1mg/kg/day, gradually increasing to a maximum of 2mg/kg/day if tolerable. Treatment assignments were kept double-blinded until the end of the study, when the patients turned three years old. Outcome measures included the children’s muscle tone, which was rated independently by three examiners; their cognitive-adaptive function, as evaluated by the Bayley Scales of Infant Development and the Vineland Social Maturity Scale; and their language skills at three years of age, as determined by the Receptive-Expressive Emergent Language Scale (REEL). Analysis of the results at the end of the study showed no clinically significant differences in Bayley and REEL scores between the groups at any time point. Muscle tone ratings were initially found to be higher in the 5-HTP group compared to the other three groups; however, this was no longer the case after exclusion of the children with moderate and severe heart disease (which were found to be unequally distributed amongst the groups, with a disproportionately low number in the 5-HTP group). The only other finding of interest was a statistically significant interaction effect of 5-HTP and pyridoxine, resulting in lowered Vineland Social Maturity scores (i.e. decreased functioning) in the 5-HTP/pyridoxine group at 6, 12, and 18 months of age, a phenomenon which the authors were unable to explain. Overall, 5-HTP with or without co-administration of pyridoxine did not appear to improve any clinical parameters in children with Down’s syndrome.

 

Another randomized, double-blind, placebo-controlled trial describing the effects of 5-HTP on the development of infants with Down’s syndrome was published in an extensive report (192). Nineteen infants with trisomy 21 were enrolled into the study before six days of age, and randomized to receive either placebo or 5-HTP (L-isomer or D,L racemic mixture) for a period of three years. Dosing of 5-HTP was individualized by patient, and adjusted (according to occurrence of side effects, etc.) annually as needed. Between 4.8 to 19.1mg/kg/year of the L-isomer (more biologically active), and 9.7 to 41.2mg/kg/year of the mixed isomer, were administered. Results of the three-year study indicated that 5-HTP demonstrated no significant superiority over placebo with respect to the following: age of walking, neonatal temperature, tongue protrusion, strabismus, cardiac function, and growth patterns. 5-HTP appeared to positively affect tonus during the first four months of life, followed by a negative effect during the next 2.5 years. At the end of the study, however, no discernible difference in muscle tonus was found between the groups. Another significant finding was the elevation of epinephrine levels in children in the 5-HTP group, over those in the placebo group, but the clinical significance of this unknown. The authors further suggested that the progression of disease in Down’s syndrome did not appear to be affected by 5-HTP treatment as much as the presence of a supportive and loving rearing environment, which was found to have a positive effect on muscle tonus and age of walking in some of the patients.

 

In addition, Partington et al. published a small trial of 12 children with mental retardation, six of which had Down’s syndrome (mean age 4.5 years), who were administered three dosages of 5-HTP for one week each (193). Initially, the investigators had planned to administer placebo plus 5-HTP at two different doses, in liquid form, to each patient. However, dosage adjustments had to be made during the study, such that results were obtained for placebo (administered to  4 Down’s syndrome patients) plus four different dosages of 5-HTP: 1, 2, 3, and 6mg/kg/day (3 patients each). Results indicated that 5-HTP, at any dose, did not have any significantly different effects on the motor activity and neurological status of Down’s syndrome children, when compared to placebo. Limitations of this study included small sample size, use of an older population (most other studies enrolled newborn infants), and short duration of treatment.

 

Two open-label case studies have also been reported on the effects of 5-HTP on children with Down’s syndrome. The first study reported the positive results which all the subsequent controlled trials attempted unsuccessfully to replicate. In it, Bazelon et al. found that chronic administration of the L-isomer (0.15 to 0.5mg/kg/day) or the D,L-mixed isomer (0.05 to 2.5 mg/kg/day) of 5-HTP, was able to improve hypotonia in a group of 14 newborns with Down’s syndrome (age of enrolment two to 102 days) (194). They reported that increased muscle tone, as evaluated clinically by the Landau posture, was observed in 13 of the children within seven weeks of 5-HTP treatment. Traction responses, reflexes, and activity levels were also found to have increased in these children. These positive results were followed by a study of 19 children with Down’s Syndrome (mean age 7 months) who were given 5-HTP (D,L-type, International Chemical & Nuclear Corp.) until they reached 3 to 4 years of age (3). The dose of 5-HTP started from 0.5 to 1.5mg/kg/day, gradually increasing to a maximum of 5mg/kg/day. Over the course of the study period, no statistically significant improvements in muscle tone and developmental quotient (composed of motor, adaptive, language, and personal-social behaviours) could be found.

 

Finally, the purported ability of 5-HTP to alter REM sleep has also been investigated in six infants with Down’s syndrome (over two weeks of age) in an open-label case study (186). Dosage of 5-HTP administered was individually tailored to each infant’s tolerance level, and ranged from 1 to 9mg/day, for 12 to 36 months. Analysis of the results found that treatment with 5-HTP was able to normalize eye-movement density in only two of the infants, and that the effects were short-acting. The authors did note that the infants were found to have increased muscle tone and improved motor behaviour, however no quantifiable measures were taken and no non-treated control group was used for comparison.

 

In conclusion, several studies have evaluated the use of 5-HTP in Down’s syndrome, of which all but one reported negative results. The only study that reported positive results was uncontrolled and open-label, meaning that the natural progression of the condition was not taken into account. The clinical symptoms and manifestations of Down’s syndrome have been found to be greatly affected by the attention and care provided by the primary caretakers, and in fact clinically significant results have been obtained using placebo alone, in children raised in a loving, positive home environment (192). Therefore the uncontrolled positive results could arguably have been due to the special attention and care the children received by participating in such a study. Therefore, based on the multitude of negative results that have been reported, 5-HTP is probably ineffective for improvement of muscle tone and other functional symptoms associated with Down’s syndrome.

 

Decreased levels of serotonin (194-196) and of its metabolite (197), have been found in neonates and children with Down’s syndrome.

 

5-HTP is an aromatic amino acid naturally produced by the body, and is formed from tryptophan by tryptophan hydroxylase in the serotonin synthesis pathway (5). It is the immediate precursor of serotonin, and is converted to the active neurotransmitter by aromatic-L-amino-acid-decarboxylase (2, 39). 5-HTP is able to cross the blood-brain barrier while serotonin cannot (2), and can effectively increase the level of serotonin in the central nervous system (CNS) (1, 5), possibly via increased synthesis by the kidneys (40). 5-HTP may interact with the 2A/2C classes of serotonin receptors (41, 42).

Behavioral problems, including aggression, emotional lability, and irritability, were experienced by all of five children treated with 5-HTP (2 to 15mg/kg/day) for symptoms of opsoclonus-myoclonus (162). All children were known to have histories of behavioral problems prior to the study, but during 5-HTP treatment these were reported to be worsened in three children, and “unmanageable” in the remaining two. The authors of the study have suggested that 5-HTP may exacerbate existing behavioral problems in children. No such problems have been reported in other studies of healthy children.

Drowsiness, usually mild, have been reported in clinical trials following ingestion of 5-HTP (4, 134). Slight drowsiness was reported in 50% (n=20) of migraine sufferers taking 5-HTP (300mg/day) in a comparison study with methysergide (137). In another active comparator study, one of 17 adolescents (mean age 12 years) experienced drowsiness after ingestion of 5-HTP (150 to 200mg/day); however this was significantly less than the number of subjects who experienced drowsiness on pizotifen (152). In an uncontrolled trial of 14 patients with instability of gait and balance being given 5-HTP (16mg/kg/day), 12 cases of drowsiness were reported (125). No cases of drowsiness leading to impairment have been reported.

Gastrointestinal disturbances have commonly been reported with oral use of 5-HTP. Diarrhea (4, 14, 52, 85, 121, 125, 134), stomach/abdominal pains (18, 52, 121), and indigestion (121, 125) have been frequently reported. General gastrointestinal discomforts or intolerances have also been reported in various uncontrolled clinical trials of 5-HTP, at 17% (10 of 59 subjects) (29), 5% (6 of 129) (138), and 17% (4 of 24) (125). Most reported cases were mild enough to allow continuation of 5-HTP treatment, but a few were severe enough to require discontinuation of study severe stomach pain (n=1) (18), gastric pain (n=1) (52), indigestion (n=2) (121).

 

Attempts to control gastrointestinal discomfort have been made by co-administration of peripheral decarboxylase inhibitors such as carbidopa and benzerazide, to prevent the breakdown of 5-HTP in the periphery, however this was not always found to be effective. It has been suggested that gastrointestinal effects of 5-HTP are not correlated with plasma levels, but are instead due to a direct effect on the stomach and intestines (24). Improvements in side effects have been noted with the use of enteric-coated tablets, and small, frequent dosings.

 

Nausea and vomiting are the most common side effects associated with ingestion of 5-HTP, and have been reported in numerous clinical trials (12, 18, 21, 31, 64-67, 125, 134). Nausea was reported in 80% of participants taking 5-HTP, compared to approximately 35% of placebo participants (statistically significant) (65). Nausea with or without vomiting was reported by 63% of obese participants taking 5-HTP, compared to 21% of those given placebo (statistically significant) (67). Most cases of nausea and vomiting were temporary, and improved or went away after four to eight weeks of treatment (12, 64-66). In addition, only a few of the reported cases were severe enough to require discontinuation of 5-HTP therapy (18, 21, 31). Nausea and vomiting have been reported to occur at a wide range of 5-HTP doses, from as low a dose as 100mg (198). It has been suggested that gastrointestinal effects of 5-HTP are not correlated with plasma levels, but are instead due to a direct effect on the stomach and intestines (24).

 

Attempts to control nausea and vomiting have been made by co-administration of peripheral decarboxylase inhibitors such as carbidopa and benzerazide, to prevent the breakdown of 5-HTP in the periphery, however this was not always found to be effective. Improvements in side effects have been noted with the use of enteric-coated tablets, and small, frequent dosing.

Psychological disturbances have been reported in clinical trial subjects during use of 5-HTP. In an uncontrolled trial of 14 patients with instability of gait and balance being given 5-HTP (16mg/kg/day), impaired concentration (8 cases), thought disturbances (5), mood elevation (5), disinhibition (5), as well as unspecified cases of aggression and delusions, were reported (125). In patients with myoclonic disorders, hallucinations, euphoria, irritability, toxic psychosis, and depression on withdrawal, have been reported after 5-HTP treatment (164, 166). “Regressive hysteria” was also observed in one subject with an underlying psychoneurotic personality disorder (167).

Taste alteration was reported by 27% of 19 obese female subjects given 5-HTP (8mg/kg/day) in a study of eating behaviour, compared to no reports when the same subjects were given placebo (statistically significant) (67).

From 1989 to 1990, ingestion of L-tryptophan (natural precursor to 5-HTP) was associated with an epidemic of EMS (199). These were eventually discovered to originate from a single source, caused by a new fermentation process coupled with inadequate purification processes (200, 201). Symptoms of EMS, aside from eosinphilia and severe myalgia, also include weakness, abdominal pain, skin rash, increased serum aldolase, leukocytosis, and death in serious cases. Due to the structural similarity of 5-HTP to tryptophan, there had been previous concern that ingestion of 5-HTP would lead to the same risk, despite the fact that commercial production of 5-HTP does not require fermentation as L-tryptophan does. As of August 1998, ten cases of EMS-like illnesses had been linked to 5-HTP use, none of which resulted in death, and none in which a direct causation could be proven (5, 199).

 

In what appeared to be the only report of EMS to be investigated, a 28-year-old mother and her two children (33 and 13 months old) developed EMS-like illnesses that were thought to be related to 5-HTP use (202). The boys had been treated with 5-HTP (5 to 7mg/kg daily), tetrahydrobiopterin (50mg every other day), and L-dopa/carbidopa (50mg/5mg daily) for an enzyme deficiency for approximately 12 months when both developed mild leukocytosis and eosinophilia. Their mother, who regularly prepared and came into contact with her children’s treatments, developed diffuse muscle soreness, arthralgias, and eosinophilia, and was eventually diagnosed with EMS. Analysis of the case-implicated 5-HTP sample initially revealed an impurity on high-performance liquid chromatography, identified as “peak X”, which was thought to be responsible for the adverse reactions. However, additional attempts by other researchers to isolate and identify this “peak X” have failed, and furthermore it was found to occur below the threshold of tolerance for organic impurities, as according to guidelines set out by the United States Food and Drug Administration (FDA) (200). The authors also noted that so much assumption was put into 5-HTP as the source of the adverse reactions, that the other ingredients in the case report (i.e. tetrahydrobiopterin, L-dopa/carbidopa) were never tested for impurities.

 

Subsequent to these reports of “EMS-like illnesses” associated with 5-HTP, in 1998 the United States FDA implemented a requirement that all commercial lots of 5-HTP be tested for “peak X” prior to marketing. No cases of “peak X” contamination or EMS-related illnesses have since been reported (200). It is therefore currently believed that there is no good evidence to implicate 5-HTP in any case of EMS or related disorders.

One case of a scleroderma-like illness was reported in a 70-year-old man after taking a high dose of 5-HTP (1400mg/day) in conjunction with carbidopa (150mg/day) for 20 months for “severe idiopathic intention myoclonus involving the face and extremities” (203). The man was later found to have an enzyme abnormality that was consistent in cases of idiopathic scleroderma, therefore the authors postulated that 5-HTP only acted to unmask the inherent enzyme deficiency in the individual by elevating his plasma serotonin load. An additional case of “scleroderma-like illness with unusual pseudobullous morphea and eosinophilia” was reported in a patient receiving 5-HTP in conjunction with carbidopa (204), however further details are unknown, as the original reference could not be found for this review.

 

Two other cases of scleroderma-like conditions have been reported to be associated with 5-HTP and other medications in patients with Parkinson’s disease (205, 206). Both were published in French, but have been described elsewhere (207). In one case, a 72-year-old man had been taking 5-HTP (150mg/day), carbidopa-levodopa (750mg/day), bromocriptine (5mg/day), and clobazam (10mg/day) for approximately two years when he was found to have developed a “sclerodermiform and poikilodermal syndrome,” symptoms which included poikiloderma (skin atrophy) of the light-exposed areas and diffuse sclerosis of the trunk and arms (205). Another 79-year-old Parkinson’s disease patient was found to have developed a similar scleroderma-like syndrome with “pseudobullous morphea” while taking 5-HTP (750mg/day), carbidopa (750mg/day), and flunitrazepam (2mg/day) for approximately three years (206). Massive edema of the superficial dermis, thickening and hyalinization of dermal collagen, as well as lymphocytic infiltrates, were reported. Since additional medications had been taken in these two cases, the role of 5-HTP in the causation of these events, if any, remains unclear.

Increased frequency in seizures were observed in three patients with myoclonic disorders who were being treated with 5-HTP: a 60-year-old man with postanoxic intention myoclonus (1200mg/day), a 26-year-old female with myoclonic epilepsy associated with a lipid storage disease (400mg/day), and a 2-year-old boy with Tay-Sachs disease (75mg/day) (166). No cases of seizures have been reported in other studies of healthy volunteers.

High levels of serotonin in the body can lead to a condition known as serotonin syndrome, characterized by agitation, confusion, delirium, tachycardia, diaphoresis, and fluctuations in blood pressure (1, 208). It can theoretically be caused by any drug that affects the serotonergic pathway, such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) (5). In animal studies, serotonin syndrome has been experimentally induced in rodents with high dosages of 100 to 200mg/kg (209, 210). In humans, cases of serotonin syndrome have not been reported from 5-HTP use alone, or in combination with any other medications (5, 200). No cases were reported when 5-HTP was taken in conjunction with MAOIs (63), tricyclic antidepressants (211), SSRIs (35, 211, 212), or tryptophan (21).

5-HTP has been reported anecdotally to cause nightmares or very vivid dreams when used at high concentrations (1). However, it should be noted that 5-HTP has been found to be effective in decreasing occurrence of sleep terrors in children (185).

Following acute dosing of 5-HTP (200mg/day) in conjunction with citalopram, a selective serotonin reuptake inhibitor (20mg/day) in 12 healthy Asian males, six cases of nausea and seven cases of vomiting were reported in individuals who did not experience the same symptoms on citalopram or 5-HTP alone (212). However, it should be noted that nausea and vomiting are side effects commonly associated with 5-HTP use (1, 2).

Cases of scleroderma-like conditions have been reported following therapy with 5-HTP and other medications (205, 206). One case involved a 72-year-old Parkinson’s disease patient who had been taking 5-HTP (150mg/day), carbidopa-levodopa (750mg/day), bromocriptine (5mg/day), and clobazam (10mg/day) for approximately two years (205), the other involved a 79-year-old Parkinson’s disease patient who had been taking 5-HTP (750mg/day), carbidopa (750mg/day), and flunitrazepam (2mg/day) for approximately three years (206). It is not clear whether or not the scleroderma were caused by an interaction between 5-HTP and the other medications. 

 

Co-administration of 5-HTP with serotonergic antidepressants, such as SSRIs (selective serotonin reuptake inhibitors) and MAOIs (monoamine oxidase inhibitors) can cause high levels of serotonin to accumulate in the body. This can theoretically lead to a condition known as serotonin syndrome, which is characterized by agitation, confusion, delirium, tachycardia, diaphoresis, and fluctuations in blood pressure (1, 208). In humans, cases of serotonin syndrome have not been reported from 5-HTP use alone, or in combination with any other medications (5, 200). No cases were reported when 5-HTP was taken in conjunction with MAOIs (63), tricyclic antidepressants (211), SSRIs (35, 211, 212), or tryptophan (21).

 

Since 5-HTP is the immediate precursor of serotonin, and is thought to exert its effects by increasing serotonin levels in the body, it can theoretically have additive effects with serotonin-receptor agonists such as drugs used in the treatment of migraines (e.g. sumatriptan, zolmitriptan, rizatriptan) (2). No instances of drug interactions between 5-HTP and serotonin-receptor agonists have been reported.

 

Drowsiness has been reported in clinical trials following ingestion of 5-HTP (4, 125, 134, 137, 152), and can theoretically cause additive effects with sleeping aids. No instances of drug interactions between 5-HTP and sleeping aids have been reported. 

 

Oral dosage of 5-HTP in clinical trials have greatly varied, and in many cases were individually titrated and adjusted according to the therapeutic versus side effects observed. Clinical trial doses of 5-HTP have ranged from 20 to 3250mg/day, with the majority being 200 to 300mg/day (5). Older trials have considered a “typical dosing regimen” to be 1000mg/day in a 65 to 70kg adult (162, 164, 166). However, due to the common occurrence of gastrointestinal side effects with high doses, the current recommended dosing schedule for adults is 50mg three times daily to start, gradually titrating upwards in dose if necessary (1).

 

Some dosage regimens that have been used in clinical trials for various indications are as follows (2):

 

Oral dosage of 5-HTP in clinical trials have greatly varied, and in many cases were individually titrated and adjusted according to the therapeutic versus side effects observed. 5-HTP has been used in children for the treatment of schizophrenia, opsoclonus-myoclonus, sleep terrors, and Down’s syndrome, and for the prevention of headaches, but supporting evidence has only been found for its use in headaches and sleep terrors. 5-HTP is currently not recommended in children for treatment of Down’s syndrome due to evidence of inefficacy (3, 191-193), nor in opsoclonus-myoclonus due to potential exacerbation of behavioral problems (162).

 

 

Due to some evidence that gastrointestinal side effects of 5-HTP are dose-related (24, 85, 198), it is generally recommended that treatment with 5-HTP be started at the lowest possible dose, gradually titrating upwards if necessary. Avoid taking 5-HTP on an empty stomach, since it can lead to gastrointestinal disturbances such as nausea and vomiting. The current recommended dosing schedule is three times daily with meals, as food intake does not appear to affect absorption of 5-HTP (1). 

 

5-HTP is well-absorbed orally, with a bioavailability of approximately 70% (213). Its absorption is not affected by the presence of other amino acids, therefore supplements can be taken with meals without decreasing its bioavailability (1). Small, frequent doses with meals are recommended to minimize gastrointestinal effects (5).

 

The use of peripheral decarboxylase inhibitors (PDIs), such as carbidopa and benzerazide, as part of a dosing regimen with 5-HTP is controversial (10). The rationale for their use is two-fold: by prevention of 5-HTP metabolism into serotonin in the periphery, it is thought that higher levels will be available to enter the central nervous system (since 5-HTP but not serotonin can enter the blood-brain barrier (2)); also, it is thought to decrease the incidence of adverse gastrointestinal effects. Use of PDIs have been found to increase the plasma concentration of 5-HTP ten-fold (39, 213), while a direct correlation between plasma and cerebrospinal fluid concentrations have been found (198). Co-administration with a PDI has also been found to increase the half-life and decrease the clearance of 5-HTP (214). On the other hand, there has also been some evidence that addition of a PDI does not change the uptake of 5-HTP into the central nervous system (215). 5-HTP has been found to reach significant levels in the plasma in human subjects within 1 to 2 hours, even in the absence of a PDI (71). Regardless of the available evidence, commercially available 5-HTP supplements do not contain PDIs, therefore their efficacy may not be comparable to those found in clinical trials that used 5-HTP in conjunction with PDIs (216).  The concurrent use of 5-HTP and PDIs needs to be recommended and managed by qualified healthcare professionals. 

 

5-HTP has not been studied for its long-term safety, but has been taken for up to three years in children (up to 200mg/day) without serious adverse effects (144).

 

5-HTP is available commercially as a crude extract of the plant Griffonia simplicifolia, the West African plant from which it is extracted, or as oral tablets or capsules (in 25, 50, or 100mg doses). It is available in Europe under the brand names oxitriptan and Ro-0783/B (5).

 

Enteric-coated oral formulations are preferred to minimize gastrointestinal upset (24, 43).

Cases of eosinophilia-myalgia syndrome (EMS) have been associated with a batch of L-tryptophan, eventually discovered to be caused by contamination from a new strain of bacteria during fermentation, combined with faulty purification processes (200, 201). Due to the structural similarity of 5-HTP to tryptophan, there had been previous concern that ingestion of 5-HTP would lead to the same risk, despite the fact that commercial production of 5-HTP does not require fermentation as L-tryptophan does. Case reports of EMS-like illnesses associated with 5-HTP use have been identified, but never verified (199, 202, 203). In one case, analysis of the implicated source of 5-HTP revealed an impurity on high-performance liquid chromatography, identified as “peak X”, which was thought to be responsible for the adverse reactions. However, additional attempts by other researchers to isolate and identify this “peak X” have failed, and furthermore it was found to occur below the threshold of tolerance for organic impurities, as according to guidelines set out by the United States Food and Drug Administration (FDA) (200).

 

Subsequent to these reports of “EMS-like illnesses” associated with 5-HTP, in 1998 the United States FDA implemented a requirement that all commercial lots of 5-HTP be tested for “peak X” prior to marketing. No cases of “peak X” contamination or EMS-related illnesses have since been reported (200). It is therefore currently believed that there is no good evidence to implicate 5-HTP in any case of EMS or related disorders.

 

No standardization procedures have been found for 5-HTP (2).

All natural health products in Canada are now regulated by the Natural Health Products Directorate of Health Canada (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/index-eng.php).  The new regulations for the manufacturing, packaging, labeling and importing of natural products are being phased in over a six year period that began on January 1, 2004.

In general, natural health products in the United States are regulated as "dietary supplements", as defined by The Dietary Supplement Health and Education Act of 1994 (DSHEA). This definition encompasses herbs, non-herbal nutritional supplements, vitamins, minerals and amino acids. Companies marketing "dietary supplements" cannot make product claims regarding diagnosis, treatment, cure or prevention of diseases.  However, they may claim that dietary supplements alter the structure and/or function of the human body.  In addition, minor symptoms commonly associated with life stages (e.g., premenstrual symptoms, wrinkles and acne) are no longer considered diseases and thus product claims are allowed for these ailments.  Under the DSHEA regulations, manufacturing companies may also indicate to customers possible areas of concern such as potential side-effects and contraindications. If manufacturers make any claims that the product affects the structure or function of the body, they must also print the following disclaimer on the label: “This statement has not been evaluated by the Food and Drug Administration.  This product is not intended to diagnose, treat, cure, or prevent any disease.”

 

However, it is important to note that this regulatory framework does not require testing for efficacy, testing for safety or manufacturing standards.  In addition, this Act does not require manufacturers to assay their products to ensure that product labeling is accurate and thus lot-to-lot variation in quality and quantity may occur.  The current DSHEA allows products to be sold until they are proven to be unsafe.  Thus, significant morbidity or mortality may occur before the adverse effects associated with a specific product are identified and it is removed from the market.

No information available.