5-Hydroxytryptophan (5-HTP) for Treatment of Depression
November 2000; Volume 3; 121-124
By Teresa Klepser, PharmD, and Nicole Nisly, MD
Seventeen percent of americans have a major depressive
disorder in their lifetime. More than 10% have had an episode within the past 12 months.1 Females have two or three times the prevalence as males, and adults 25-44 years have the highest prevalence. Between 10-20% of institutionalized patients have depression.
These objective data have lead to the widespread use of antidepressants, some of which enhance neurotransmission. Although prescription medications may provide some symptomatic relief, many are associated with a list of unwanted side effects and drug interactions.
Several dietary supplements have been suggested for use in the management of depression. St. John’s wort, S-adenosylmethionine (SAMe), tyrosine, 5-hydroxytryptophan (5-HTP), and ginkgo are among them. This review will focus on 5-HTP, a dietary supplement manufactured from the seeds of the African plant Griffonia simplicifolia,2 metabolized to serotonin, and touted to enhance neuro-
transmission and alleviate depression.
Pathophysiology of Depression
Most theories suggest an insufficiency of brain monoamine neuro-
transmitters such as norepinephrine (NE), serotonin, and dopamine. The biogenic amine hypothesis suggests that depression is caused by an inadequate monoamine neurotransmission. The permissive hypothesis suggests that decreased levels of serotonin allow depression to occur and that decreased levels of NE actually cause depression. The dysregulation hypothesis emphasizes a dysregulation of homeostasis of neurotransmitters, instead of an increase and decrease in the neurotransmitters’ activities. The role of dopamine in depression is unclear but may be indirectly involved in antidepressant activity.
Indications
People use 5-HTP to aid in the treatment of depression, fibromyalgia, insomnia, binge-eating associated with obesity, attention deficit disorder, and chronic headaches.3 5-HTP has an orphan drug indication for the treatment of post-anoxic myoclonus, also known as Lance-Adams’ syndrome, a rare complication of successful cardiopulmonary resuscitation. The syndrome is clonic movement secondary to the hypoxia. There is some clinical evidence to support the use of 5-HTP in the treatment of anxiety, obesity, fibromyalgia, cerebellar ataxia, palatal myoclonus, segmental myoclonus, Ramsay-Hunt syndrome, and tardive dyskinesia.4
Pharmacokinetics
5-HTP is absorbed in the small intestine and peak concentrations are noted within one to two hours following oral administration. Following ingestion, 5-HTP easily crosses the blood-brain barrier and enters the central nervous system. The half-life of 5-HTP is approximately four hours so steady state will be reached within one day. 5-HTP has a shorter half-life than prescription antidepressants, such as fluoxetine (Prozac®) two to three days, sertraline (Zoloft®) one day, paroxetine (Paxil®) 21 hours, and amitriptyline (Elavil®) 15 hours. Therefore, patients may see a response sooner with 5-HTP than with prescription antidepressants. Approximately 25% of the administered drug is eliminated by first-pass metabolism. The major metabolite is serotonin.5
In some studies, researchers administered a decarboxylase inhibitor (carbidopa or benzerazide) with 5-HTP to prevent the conversion of 5-HTP to serotonin in the gut and other peripheral organs. Such a combination allows more 5-HTP to be converted to serotonin in the brain.5
Mechanism of Action
5-HTP is the intermediate metabolite of the essential amino acid L-tryptophan in the biosynthesis of serotonin. The rate-limiting step in the synthesis of serotonin is the conversion of L-tryptophan into 5-HTP by the enzyme tryptophan hydroxylase. To make more serotonin, it is more efficient to supply 5-HTP than to supply tryptophan (conversion rate 70% vs. 1-3%), because the body uses a large percentage of dietary L-tryptophan to make other compounds, such as kynurenine and vitamin B3.4 These differences make dietary 5-HTP more efficient than L-tryptophan at increasing serotonin levels in the brain. Serotonin has been shown to be involved in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behavior, and pain sensation.3
Clinical Studies
In the 1970s and early 1980s, studies showed 5-HTP to be more effective than placebo in managing patients with depression. Several small studies also have compared 5-HTP to standard antidepressants.
Angst et al conducted two open dose-finding studies with L-5-HTP in combination with benzerazide, and a double-blind trial comparing L-5-HTP plus benzerazide vs. imipramine in 30 patients with depression.6 In the double-blind trial, patients received either a mean dose of 800 mg L-5-HTP and 375 mg benzerazide or 150 mg imipramine daily for 20 days. Endpoints included Hamilton Rating Scale for Depression (HRDS), the AMP-
system (scale 5 = somatic-depressive syndrome; scale 8 = retarded-depressive syndrome; scale 11 = automonic syndrome; scale 12 = neurological syndrome), a Global Rating Scale of Severity of Depression, and a Brief Rating Scale for the Behavior on the ward. The AMP-system and HRDS showed no significant difference in efficacy between L-5-HTP and imipramine in the double-blind trial. L-5-HTP caused mainly gastrointestinal side effects; imipramine caused mainly dryness of the mouth and tremor that seemed to be dose dependent.
A randomized, double-blind, double-dummy, multicenter Swiss study evaluated 63 subjects with major depression.7 Each received either 100 mg 5-HTP (oxitiptan, Triptum) or 50 mg fluvoxamine tid for six weeks. Endpoints included the HRDS, a self-assessment scale, the Clinical Global Impression (CGI), and adverse events. Equal benefit was found between 5-HTP and fluvoxamine. 5-HTP was slightly more effective at reducing depressed mood, anxiety, physical symptoms, and insomnia, but the differences were not statistically significant. 5-HTP caused fewer and less severe side effects with the most common complaint being mild digestive distress.
Although 5-HTP may be beneficial when given in combination with a monoamine oxidase inhibitor (MAOI) to patients who are unresponsive to MAOI therapy alone,8 this strategy is not endorsed universally. Nolen et al compared L-5-HTP to tranylcypromine, a MAOI, in a controlled, open, crossover study to evaluate the treatment of depression that was resistant to serotonin reuptake inhibition.9 Fifteen of the 26 patients responded to tranylcypromine, whereas none of the 17 patients responded to L-5-HTP.
Nardini et al evaluated the combination of L-5-HTP and a tricyclic antidepressant (chlorimipramine) in 26 depressed inpatients in Italy.10 Patients were randomized to receive 300 mg/d L-5-HTP or placebo for one month. Each patient also received 50 mg/d chlorimipramine. Endpoints included the HRDS, Zung’s Depression Status Inventory (ZDSI), and CGI. HRDS scores in both groups improved during the month; however, the combination group had a greater improvement (no P value given). For the ZDSI, the improvement in patients with endogenous depression receiving combination therapy was statistically significant. As for the CGI, 12 of the patients receiving combination therapy had marked or fair improvement, whereas seven patients receiving chlorimipramine had marked or fair improvement.
Van Praag et al evaluated the effectiveness of preventing relapse of depression when 5-HTP was used prophylactically after a therapeutic course of a tricyclic antidepressant.11 Twenty patients were treated for depression with clomipramine for three to six months. Three to four weeks after clomipramine was discontinued, patients were randomized to receive either 200 mg/d 5-HTP plus 150 mg/d carbidopa, or placebo. The relapse rate for 5-HTP was statistically significantly lower on the HRDS.
Unfortunately, many of these generally positive studies have limitations, including small sample sizes, short durations of therapy, open-label trials, no placebo arm, poor definition of depression, and inclusion of patients with bipolar depression. Also, studies used either 5-HTP or L-5-HTP, and it is unknown whether there is a therapeutic difference between 5-HTP and L-5-HTP.
Adverse Effects
The most common side effects associated with 5-HTP are dose-related and include nausea, vomiting, diarrhea, and anorexia. Reported central nervous side effects include euphoria, hypomania, restlessness, rapid speech, anxiety, insomnia, aggressiveness, and agitation. These symptoms resolved upon discontinuation of 5-HTP.
Regulation
The U.S. Food and Drug Administration (FDA) in 1998 issued a statement confirming the presence of impurities in some 5-HTP products currently marketed as dietary supplements.12 One of the impurities, known as "Peak X," has been associated with more than 1,500 cases of eosinophilia-myalgia syndrome, including 38 deaths in 1991. Eosinophilia-myalgia syndrome is a serious systemic illness associated with increased eosinophils and severe muscle pain. More than 95% of these cases were traced to L-tryptophan supplied by Showa Denko K.K. of Japan. However, the FDA could not conclude that other brands of L-tryptophan were not a cause or contributor to eosinophilia-myalgia syndrome. As a result, tryptophan supplements were pulled off the market. There is at least one case of eosinophilia-myalgia syndrome with 5-HTP. However, based on this, it is difficult to establish a link between eosinophilia-myalgia syndrome and 5-HTP. At this time, the FDA encourages health care practititioners to report adverse events to FDA’s MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), or mail (FDA,
HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787).
Contraindications and Precautions
According to one report, 5-HTP may cause seizures in children with Down syndrome.2 Although safety in children has not been proven, children have been given 5-HTP in studies without any apparent harmful effects.2 Safety in pregnant or nursing women and those with liver or kidney disease has not been established.2 Patients who have peptic ulcer disease, platelet disorders, and/or renal disease should not take 5-HTP, mainly because tryptophan has been associated with scleroderma, autoimmune thrombocytopenia, and eosinophilia-myalgia syndrome.5 Since 5-HTP is eliminated renally, patients who have renal disease should not take 5-HTP. These cautions are based on in vitro and animal data.
Drug Interactions
Concurrent use of 5-HTP with MAOIs or reserpine is not recommended since the combination may increase the risk of hypertensive reactions. The latter agents should be discontinued for at least two weeks before 5-HTP is initiated. Some studies, however, have demonstrated additional benefit when the combination of tryptophan and a MAOI was used.13 Tricyclic antidepressants, serotonin reuptake inhibitors, and the pain medication tramodol should be discontinued before 5-HTP initiation, as these drugs raise serotonin levels, and
dangerously, may induce serotonin syndrome.2 Methysergide, cyproheptadine, and other serotonin receptor agonists may decrease the therapeutic effects of 5-HTP.5
Another safety issue with 5-HTP involves an interaction with carbidopa, used for Parkinson’s disease. Several reports suggest that the combination can create skin changes similar to those that occur in scleroderma.2
Dosage and Formulation
The usual starting dose of 5-HTP for the orphan drug indication of treating post-anoxic myoclonus is 25 mg qid; this may be increased by 100 mg/d every three to five days to reach a dose between 600 and 1,000 mg/d.5 An orphan product that has been approved for marketing is available through the normal pharmaceutical supply channels. Some health insurers will pay the cost of orphan products that have been approved for marketing.
A recommended dose of 5-HTP in the management of depression has not been determined. The doses used in clinical studies have ranged from 150-300 mg/d14 to 100-200 mg tid.2 Some studies administer a decarboxylase inhibitor, such as carbidopa, in addition to 5-HTP to prevent peripheral conversion of 5-HTP. Carbidopa usually is given as 150 mg/d. Patients may see some response during the first week of use.
Conclusion
5-HTP has been studied for treating depression. Clinical data to support its use for this indication are positive, but flawed. Side effects appear to be rare as long as the product does not contain "Peak X," an impurity that has been associated with eosinophilia-myalgia syndrome. Unfortunately, 5-HTP as a dietary supplement is not regulated by the FDA, so there is no guaranteed quality.
Recommendation
At this time, 5-HTP may be considered an option for the treatment of depression. However, patients who have peptic ulcer disease, platelet disorders, and/or renal disease should not take 5-HTP. 5-HTP should not be taken with other antidepressants or serotonin receptor agonists. Patients should be aware of the possibility of 5-HTP products containing impurities.
Dr. Klepser is Assistant Professor, University of Iowa College of Pharmacy, Division of Clinical and Administrative Pharmacy, and College of Medicine, Department of Family Medicine; Dr. Nisly is Assistant Professor, University of Iowa College of Medicine, Department of Internal Medicine in Iowa City.
References
1. Kando JC, et al. Depressive Disorders. In: Dipiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. Stamford, CT: Appleton & Lange; 1999.
2. 5-hydroxytryptophan. The Natural Pharmacist. Available at: www.tnp.com/substance.asp?ID=127. Accessed October 4, 2000.
3. Birdsall TC. 5-Hydroxytryptophan: A clinically effective serotonin precursor. Altern Med Rev 1998;3:271-280.
4. IV. 5-HTP: A Mood-Boosting Botanical Chemical. Available at: www.mothernature.com/news/1998_09_24/5htp.stm#safety. Accessed October 4, 2000.
5. Hermes AE. Drugdex® Drug Evaluation: Hydroxytryptophan. Denver, CO: MICROMEDIX; March 1998.
6. Angst J, et al. The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Arch Psychiatr Nervenkr 1977;224:175-186.
7. Poldinger W, et al. A functional-dimensional approach to depression: Serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology 1991;24:53-81.
8. Alino JJ, et al. 5-hydroxytryptophan (5-HTP) and a MAOI (nialamide) in the treatment of depression. A double-blind controlled study. Int Pharmacopsychiatry 1976;11:8-15.
9. Nolan WA, et al. L-5HTP in depression resistant to re-uptake inhibitors. An open comparative study with tranylcypromine. Br J Psychiatry 1985;147:16-22.
10. Nardini M, et al. Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study. Int J Clin Pharmacol Res 1983;3:239-250.
11. van Praag H, de Haan S. Depression vulnerability and 5-hydroxytryptophan prophylaxis. Psychiatry Res 1980;3:75-83.
12. Food and Drug Administration. Impurities confirmed in dietary supplement 5-hydroxy-L-tryptophan. Rockville, MD: National Press Office; August 31, 1998. Talk Paper T98-48. Available at: http://www.fda.gov/bbs/topics/ANSWERS/ANS00891.html. Accessed October 4, 2000.
13. Coppen A. et al. Tryptophan in the treatment of depression. Lancet 1967;2:1178-1180.
14. Jellin J, ed. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Center; 1999.
November 2000; Volume 3; 121-124
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