Use of Neurotransmitter Precursors for
Treatment of Depression
by Stephen Meyers, MS
AbstractInsufficient activity of the neurotransmitters serotonin and norepinephrine is a centralelement of the model of depression most widely held by neurobiologists today. In thelate 1970s and 1980s, numerous studies were performed in which depressed patientswere treated with the serotonin precursors L-tryptophan and 5-hydroxytryptophan (5-HTP), and the dopamine and norepinephrine precursors tyrosine and L-phenylalanine.
This article briefly reviews the published research on the efficacy of neurotransmitterprecursors in treating depression, highlights the findings of studies, and discussesissues regarding the interpretation of those findings. The nature of the studies makesit difficult to draw firm conclusions regarding the efficacy of neurotransmitter precursorsfor treating depression. While there is evidence that precursor loading may be oftherapeutic value, particularly for the serotonin precursors 5-HTP and tryptophan, morestudies of suitable design and size might lead to more conclusive results. However, theevidence suggests neurotransmitter precursors can be helpful in patients with mild ormoderate depression.
(Altern Med Rev 2000;5(1):64-71.) Introduction
Insufficient activity of the neurotransmitters serotonin and norepinephrine is a central element of the model of depression most widely held by neurobiologists today.1 Nearly all ofthe drugs used to treat depression appear to enhance neurotransmission in one or both of thesesystems. In fact, understanding of the mechanism of action of antidepressant drugs in part gaverise to the model of depression.
The synthesis of most neurotransmitters is controlled within the brain. For some neu- rotransmitters, the amount of biochemical precursors present in the brain can influence theirrate of synthesis. During the 1970s, researchers established a body of evidence indicating in-gestion of dietary precursors of certain neurotransmitters could increase their levels in the brain.2This research suggested precursors of norepinephrine and serotonin might be useful in treatingdepression. In the late 1970s and 1980s, numerous researchers studied the use of the serotoninprecursors L-tryptophan and 5-hydroxytryptophan (5-HTP), and the norepinephrine precursorstyrosine and phenylalanine in depressed patients.
Interest in neurotransmitter precursors was partly a function of the shortcomings of anti-depressant medications (particularly in terms of side-effects) available prior to Prozac andother selective serotonin re-uptake inhibitor drugs (SSRIs). It was hoped dietary precursors ofkey neurotransmitters might provide a more easily tolerated way of treating depression.
Stephen Meyers, MS; Staff Scientist, Lawrence B erkeley National Laboratory, B erkeley, C A, and a writer in the fields of health and nutrition. Email: [email protected].
Page 64 Alternative Medicine Review ◆ Volume 5 Number 1 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Why Neurotransmitter Precursors
be balanced by adaptations within the system.
Might be Helpful in Treating
beneficial symptom-relieving effect of antide- Depression
pressant drugs suggests late-developing fac- tors may be more relevant to these drugs’ clini- ness of neurotransmitter precursors builds cal efficacy than their acute effect (inhibiting upon the idea that depression is a result of an re-uptake of neurotransmitters). Imipramine (a inadequate amount or insufficient activity of tricyclic antidepressant) can block neurotrans- one or more neurotransmitters. Within limits, mitter re-uptake in a matter of hours, but it availability of the necessary precursors deter- takes several weeks for patients to begin to feel mines the amount of neurotransmitter synthe- less depressed. This time lag posed a challenge sized. For example, serotonin production in the to the notion that the primary cause of depres- human brain can be increased two-fold by oral sion was related to a reduced level of neu- appears to result in increased neurotransmit- vestigated long-term adaptive changes pro- ter synthesis, it is less clear whether it leads to duced by antidepressant drugs on norepineph- augmentation of neurotransmitter release. An rine and serotonin systems.6 In addition, al- animal study found acute administration of L- though most current antidepressant drugs are tryptophan decreased the firing rate of seroto- known to act on norepinephrine and serotonin nin neurons,4 which might tend to counteract systems, other factors appear to be involved increased synthesis. However, results from in the mechanism of action of antidepressants.
other animal studies suggest L-tryptophan ad- ministration can enhance serotonin release intracellular second messengers, and modula- under some circumstances, and the same may tion of gene expression may play a role in the be true in humans.5 Administration of 5-HTP mechanism of action of antidepressant drugs.7,8 has been associated with a significant increasein cerebrospinal fluid levels of 5- Research on the Efficacy of
hydroxyindolacetic acid, the primary metabo-lite of serotonin, suggesting 5-HTP leads to Neurotransmitter Precursors for
Treating Depression
Issues in Evaluating the Research
not been answered—is whether increased neu- rotransmitter release leads to ongoing stimu- lation of neurotransmitter activity; i.e., the the scientific literature on antidepressant treat- strength of signaling. The latter depends not ments difficult. One is the quality and dura- only on the amount of neurotransmitter re- tion of response to a given treatment. Response leased by the presynaptic neuron, but also on in terms of a reduction in the level of symp- how long neurotransmitters remain in the syn- toms on a rating scale (“improvement”) is not aptic cleft, and on factors which influence fir- the same as remission from illness. The latter ing of the postsynaptic neuron. Neurotransmit- requires a longer time frame to evaluate than ter systems are characterized by feedback the one-to-two-month treatment period most mechanisms that help maintain equilibrium common in clinical studies, but is ultimately with respect to neurotransmitter activity. Thus, more important. Reduction in symptoms over changed conditions in the short run, such as the course of a study does not necessarily lead increased synthesis of a neurotransmitter, can Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 65
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 1. Serotonin
Serotonin Precursors:
5-HTP and
Therapeutic use of 5-HTP bypasses the con- version of L-tryptophan into 5-HTP by the general classes. In an open study, a treatment enzyme tryptophan hydroxylase, which is the is given to a group of patients and their re- rate-limiting step in the synthesis of serotonin sponse is measured; a hypothetical contrast of (see Figure 1). 5-HTP easily crosses the blood- the response to the treatment compared to that brain barrier, and unlike L-tryptophan, does seen with a known drug is possible. The sec- not require a transport molecule to enter the ond class contrasts the experimental treatment central nervous system. These factors might with a drug of established efficacy. The third account for the inconsistent results in studies compares a treatment with placebo, sometimes using L-tryptophan in the treatment of depres- using a standard drug as a third arm of the a number of studies with 5-HTP in the 1970s treatment is not considered effective without and early 1980s. Their first study found re- a placebo control. Placebo response rates vary duced depressive symptoms in 60 percent of widely across patient groups; it may be as high as 65 percent, even in a group with major de- pression.10 Thus, if an open study finds that a ment.12 A double-blind study with four groups particular treatment results in improvement of of 10 patients found 5-HTP (200 mg/day) was symptoms, it is difficult to judge how much of more effective than placebo and almost as ef- the effect was due to the treatment. Even if an fective as clomipramine (a tricyclic antidepres- experimental treatment appears comparable to sant).13 In seven open studies with a total of a standard drug in terms of response, it may 350 patients, 55 percent of the patients were be that a placebo would have done as well as considered to be responders to 5-HTP.14 Over- either treatment over the course of the study.
all, it was found to be effective in five and in-effective in two of those studies. In seven con-trolled studies with a total of 78 patients, a Page 66 Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission positive response was noted in 60 percent of tranylcypromine, 15 improved.20 The authors patients. In five of these studies, 5-HTP was felt 5-HTP was not an effective alternative in found to be effective. The scientists concluded, patients who had not previously responded to “there are strong indications that 5-HTP is of the therapeutic efficacy of 5-HTP was found conducted in Japan in the 1970s. In a large to be equal to traditional antidepressants.21 Best open trial, 100 patients were given 50-300 mg/ results were obtained among patients with an day.15 Significant improvement was observed anxious depressive syndrome and in patients in 69 percent of the patients, and no signifi- cant side-effects were reported. The response rate in most of the patients was less than two 100 mg three times per day with fluvoxamine weeks, which is interesting, as most antide- (an SSRI used for depression and obsessive- pressant drugs take two weeks to a month to compulsive disorder) 50 mg three times per show benefit. In a 1975 open study, 24 patients day. In a double-blind, multicenter study, 36 hospitalized for depression were given 5-HTP.
subjects were evaluated over six weeks using After two weeks of treatment, marked ame- four different diagnostic tools. Both treatment lioration of depressive symptoms was observed groups showed significant and nearly equal in seven patients (29%).16 In another Japanese reductions in depression beginning at week study, 5-HTP (50-100 mg three times per day) two and continuing through week six. By week was administered to 59 patients with mixed six, the two groups had about an equal num- types of depression; unipolar, bipolar, and ber of patients showing 50 percent improve- other subcategories, most with moderate-to- ment in the Hamilton Rating Scale for Depres- severe depression. Marked improvement was noted in 13 patients (22%) and moderate im- provement in 27 patients (46%). Again, all that most, if not all, of the subjects had been responders to 5-HTP therapy noticed improve- diagnosed with major depression. One double- ments within two weeks.17 Yet another open blind study compared L-tryptophan with ami- study administered 5-HTP to 18 patients and triptyline (a tricyclic antidepressant) over a diagnosed with mild or moderate depression.
Based on scores on the Hamilton Depression in 1977 compared 5-HTP (in combination with Scale and a global rating of depression, L-tryp- tophan at a dose of 3 g per day was more ef- inhibitor—to supposedly inhibit conversion of fective than placebo, as effective as amitrip- 5-HTP outside the CNS) to imipramine in 30 tyline, and produced significantly fewer side- patients. It found equal efficacy between the two treatments.19 A 1985 British study assessed the efficacy of 5-HTP among patients suffering above indicate a therapeutic benefit from serotonin precursors, reviews by others have responders to several neurotransmitter re- been more cautious. In a review published in uptake inhibitors. 5-HTP or tranylcypromine was given during four weeks in a crossover reviewed did not provide adequate evidence for an antidepressant effect of 5-HTP. They responded, whereas of 26 patients treated with also felt L-tryptophan without concomitant Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 67
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 2. Biosynthesis of Catecholamines
significant difference with a high degree of Norepinephrine Precursors:
Tyrosine and Phenylalanine

nephrine, and L-phenylalanine is the directprecursor of tyrosine. Tyrosine and phenyla- lanine are also precursors of dopamine, anotherneurotransmitter which may play a role in de- there appears to be less scope for increasingnorepinephrine synthesis with precursor load- ing than is the case for serotonin. Under nor-mal conditions in the rat brain, tyrosine hy- droxylase, the rate-limiting enzyme on thepathway from tyrosine to norepinephrine, isabout 75-percent saturated with tyrosine.5 the use of norepinephrine precursors for treat- antidepressant drug use did not appear to have ing depression than the use of serotonin pre- a well-documented antidepressant effect.24 cursors. Two 1980 case studies suggested L- Authors of a 1983 review were not convinced tyrosine may have potential as an antidepres- of L-tryptophan’s antidepressant efficacy in sant, but both had a very small sample size.27,28 marked-to-severe endogenous depression, but Later in the 1980s, a four-week clinical trial noted it might be more effective in moderate treated 65 outpatients with major depression in a double-blind comparison of L-tyrosine serotonin-deficient subgroup of depressed (100 mg/kg/day), imipramine, or placebo. It found no evidence that L-tyrosine had antide- stating, “results suggest that 5-HTP possesses antidepressant properties, but additional trials 1979, DL-phenylalanine (150-200 mg/day) or imipramine was administered to 40 depressed patients (20 in each group) for one month. No statistical difference was found between the neurotransmitter precursor studies. Promising results have been obtained in open studies and Scale and a self-rating questionnaire,30 lead- in comparisons with tricyclic antidepressants.
ing to a conclusion that DL-phenylalanine In the open studies, however, some or all of (DLPA) might have antidepressant properties.
might have been due to a placebo effect. Most major depressive disorder were treated with of the comparison studies also lacked a placebo D-phenylalanine (mean dose of 350 mg/day) control group, and the number of patients per for four weeks. The researchers found no evi- dence of antidepressant effect, but suggested normally be necessary to show a statistically Page 68 Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission re-evaluation at higher doses. 31 In a later open serotonergic or catecholaminergic precursors.
study, 31 of 40 depressed patients responded Studies which have investigated the ratio of to large doses of L-phenylalanine (up to 14 g/ plasma tryptophan to the sum of the other large neutral amino acids (leucine, isoleucine, va- line, tyrosine, phenylalanine) or erythrocyte membrane transport of these substances show pramine, and the relatively low dose of DLPA a predictable response to serotonergic or cat- which was used, it seems higher doses might echolaminergic precursors or drugs.33-35 This be helpful in cases of depression in which low type of testing might be one way of choosing norepinephrine activity is involved.
between serotonin or catecholamine stimula-tion in the depressed patient.
sors may be a reasonable course of action for difficulty of drawing firm conclusions from the treating many cases of depression, practitio- research on the use of neurotransmitter pre- ners should be aware that recent research on cursors for treating depression. While there is antidepressant drugs indicates they might have undoubtedly evidence that precursor loading a more complex and far-reaching action than may be of therapeutic value, particularly for that associated with neurotransmitter precur- the serotonin precursors 5-HTP and L-tryp- sors.6 In addition, if the intensive research into tophan, more studies of suitable design and development of faster acting antidepressant size might lead to more conclusive results. In drugs with fewer side-effects bears fruit, the addition, the complex nature of neurotransmit- advantages of neurotransmitter precursors in ter systems contributes to uncertainty whether terms of their better tolerability may be less the positive response seen in studies of rela- tively short duration would continue over the respect to neurotransmitter precursors and pre- scription antidepressant drugs is not necessar- relevant the clinical research on neurotrans- ily a case of “one or the other.” Growing num- mitter precursors is for the types of depres- bers of individuals are combining various pre- sion alternative practitioners are likely to see.
scription drugs with alternative treatments, and Nearly all of the studies have involved patients the ranks of M.D.’s integrating alternative with major depression, typically in a clinical treatments into their practice is increasing.
setting. One reasonably large study of outpa- Given this evolution, combined use of neu- tients with mild or moderate depression found rotransmitter precursors with antidepressant L-tryptophan was significantly better than pla- drugs may be worth considering. Nearly all of cebo.22 This study is also noteworthy because the studies of such use have been conducted it followed the response of the subjects for a with tricyclic drugs. A small study conducted relatively long period (three months). Thus, in 1986 found evidence of adverse effects from in cases of mild or moderate depression, it does combined administration of tryptophan and not seem unreasonable to use neurotransmit- Prozac.36 Yet it seems possible that use of low ter precursors, especially given their relatively dosages in combination might yield a positive low degree of side-effects and low cost.
research is combining serotonergic and cat- what limited guidance for choosing between echolaminergic precursors. Two studies in theearly 1980s investigated a mixture of 5-HTP Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 69
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission and tyrosine in depression. While these stud- Birdsall TC. 5-hydroxytryptophan: a clini- ies were too small for definite conclusions, the cally-effective serotonin precursor. Altern MedRev 1998;3:271-280.
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Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Thomson J, Rankin H, Ashcroft GW, et al. The Steiner W, Fontaine R. Toxic reaction follow- treatment of depression in general practice: a ing the combined administration of fluoxetine comparison of L-tryptophan, amitriptyline, and and L-tryptophan: five case reports. Biol a combination of L-tryptophan and amitrip- Psychiatry 1986;21:1067-1071.
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Alternative Medicine Review ◆ Volume 5, Number 1 ◆ 2000 Page 71
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