Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis*

Kelly Shaw, Jane Turner, Christopher Del Mar

Objective:

To review the literature regarding the effectiveness of 5-hydroxytryptophan (5-HT)and L-tryptophan in the treatment of unipolar depression.

Methods:

A systematic review of the literature from 1966 to 2000 using the search terms‘tryptophan’, 5-hydroxytryptophan

′

, ‘5-HTP’, ‘5-HT’ and ‘depression’. We extracted andgrouped data for meta-analysis by pooling odds ratios (OR) and relative risks where possible.

Results:

One hundred and eight studies were located of which only two studies, one of 5-HTand one of L-tryptophan, with a total of 64 patients met sufficient quality criteria to be included.These studies suggest 5-HT and L-tryptophan are better than placebo at alleviatingdepression (Peto OR = 4.1, 95% CI = 1.3–13.2). However, the small size of the studies, andthe large number of inadmissible, poorly executed studies, casts doubt on the result frompotential publication bias, and suggests that they are insufficiently evaluated to assess theireffectiveness.

Conclusions:

A large body of evidence was subjected to very basic criteria for assessingreliability and validity, and was found to largely be of insufficient quality to inform clinicalpractice. More well-designed studies are urgently required to enable an assessment of whatmay be an effective class of agents.

Key words:

Australian and New Zealand Journal of Psychiatry 2002; 36:488–491

depressive-disorder, tryptophan, 5-hydroxytryptophan.

Depression is a frequent and disabling disorder [1,2]where antidepressants and psychotherapy are the main-stay of treatment [3]. However, there is an increasingtrend by patients towards the use of ‘natural alternatives’to currently prescribed antidepressants to treat depres-sion [4,5]. The reasons for this trend are incompletelyunderstood [5–7], but the perception by the consumer

that currently prescribed pharmacological agents aremore harmful than complementary and the rise of alter-native medicine (CAM) plays a part [6,8].

Complementary treatments for depression include sub-stances such as St Johns Wort, Kava-Kava, tyrosine,tryptophan and 5-hydroxytryptophan (5-HT) [9,10]. StJohns Wort (hypericum) has been the subject of meta-analysis suggesting it has an antidepressant effect, buttryptophan and 5-HT have been less extensively studied.In view of the community interest in ‘natural’ treat-ments, we thought it worthwhile to examine the evidenceregarding tryptophan and 5-HTP for depression.

Tryptophan and 5-HT have a plausible physiologicalbasis for acting as antidepressants because they are pre-cursors of serotonin synthesis. 5-HT is synthesized fromthe amino acid tryptophan. The body absorbs tryp-tophan, converts it to 5-HT and then into serotonin bothcentrally and peripherally [3]. Both tryptophan and 5-HT

Kelly Shaw, Associate Lecturer (Correspondence); Christopher Del Mar,Professor

School of Population Health, Department of Public Health, Universityof Queensland Medical School, Herston 4006, Queensland, Australia. Email: k.shaw@sph.uq.edu.au

Jane Turner, Senior Lecturer

Department of Psychiatry, University of Queensland

*This meta-analysis is listed in the Cochrane Library of Systematic Reviewsand is updated regularly.

Received 27 June 2001; revised 13 November 2001; accepted 12 February2002.

K. SHAW, J. TURNER, C. DEL MAR 489

are transported across the blood–brain barrier [3]. Anormal Western diet contains about 0.5 g of tryptophandaily, of which only 2–3% is used in central serotoninproduction [11,12]. An increase in dietary tryptophanincreases the amount transported across the blood–brainbarrier. Increase in the other amino acids transported bythe same carrier reduces the transport of tryptophan [13,14].Therefore, there are some pharmacological and pharmaco-kinetic reasons why depressed patients administered 5-HTor tryptophan might experience improvement.

However, clinical trials in which patients have beenadministered tryptophan or 5-HT have given conflictingresults and reached differing conclusions [10,12,15–17].They also have side-effects (commonly nausea and gastro-intestinal distress) [14]. Additionally, tryptophan inges-tion has been associated with Eosinophilia–MyalgiaSyndrome, which affected nearly 1500 users in 1989 andled to over 30 deaths. The reason for the outbreak,whether it was directly due to tryptophan itself or due toan impurity within the tryptophan, is still not known[18–21].

Methods

Trials were searched for in electronic general (MEDLINE, Psych-LIT, and EMBASE) and specialized databases (Cochrane ControlledClinical Trials Register, Cochrane Collaboration Depression, Anxietyand Neurosis Controlled Trial Register) from 1966 to 2000; by check-ing reference lists of relevant articles; by hand-searching relevant spe-cialist journals; and by contacting relevant authors where appropriate.Publications in all languages were sought. Search terms used were‘tryptophan’, 5-hydroxytryptophan

′

, ‘5-HTP’, ‘5-HT’ and ‘depres-sion’. Trials were included if they were randomized, included patientswith unipolar depression or dysthymia, compared preparations of 5-HTor tryptophan with placebo, and included clinical outcomes assessed byscales assessing depressive symptoms.

We independently extracted the data onto collection forms. Inclu-sion criteria were applied to all potential studies independently and acoefficient of agreement (Kappa) was calculated for them. Disagree-ment was resolved by consensus. Trial quality was scored according torisk of bias.

Studies were scored according to the method of treatment assign-ment (whether correct, blinded, and method of randomizationdescribed or group similarity documented), control of selection biasafter treatment assignment (intention to treat analysis and < 15% loss

Table 1. Exclusion process

Number of studies Excluded studies Reason for exclusion

108

⇒

49 Not limited to 5 HTP or tryptophan as a treatment for depression

⇓

59

⇒

25 Not placebo controlled

⇓

34

⇒

4 5 HTP or tryptophan not evaluated as a monotherapy

⇓

30

⇒

6 Study not regarding unipolar depression

⇓

24

⇒

2 Duplicate publications of previous study

⇓

22

⇒

11 Randomization or blinding method not stated or not sufficient

⇓

11

Figure 1. Comparison: 01 L-Tryptophan and 5-HTP versus placebo for the treatment of depression.Outcome: 01 Numbers of the responders.

490 TRYPTOPHAN, 5-HYDROXYTRYPTOPHAN AND DEPRESSION

to follow-up), blinding (blinding of outcome assessor and patient/care-giver), and outcome assessment (all patients had standardizedassessment). Standardized assessment required that studies utilize aclinically recognized and tested depression rating scale. This was mostcommonly the Hamilton Depression Rating Scale. Preparation, doseand route of administration were also recorded to facilitate comparisonbetween studies.

Subjects with bipolar affective disorder were excluded from theanalysis because it is thought to be a different condition neurobiologic-ally, and because of a theoretical potential of 5-HT and tryptophan totrigger upward mood swings in patients with bipolar affective disorderreceiving serotonergic substances [22].

Studies of tryptophan and 5-HT were grouped for meta-analysis,which was undertaken by various techniques (Peto odds ratio, oddsratio (OR), relative risk and risk difference). When overall results weresignificant the relative risk reduction and number needed to treat werecalculated. Additionally, the number needed to harm and confidenceinterval around these measures was calculated.

Results

One hundred and eight clinical trials were located. Eleven trials metthe criteria for evaluation. Table 1 displays the exclusion process andreasons for exclusion of the other studies. The 11 remaining trials,including two non-English language trials, were evaluated:– Three were subsequently excluded on the basis of methodologic

weakness.– Six were excluded as they were crossover trials from which data

could not be extracted for the first period.Only 2 remaining trials, (total combined number of patients was 64)

met inclusion criteria [22,23] [Table 2]. Details regarding the twoincluded studies and nine excluded studies are presented in Tables 2and 3, respectively.

Because of the small number of patients included, which increasesthe risk of publication bias, conclusions about the efficacy of 5-HT andtryptophan are unreliable. The results suggested that 5-HT and tryp-tophan may be better than placebo at alleviating symptoms of depres-sion (Peto OR = 4.10, 95% CI = 1.28–13.15). Four patients on activetreatment reported side-effects (dizziness, nausea and diarrhoea). Nodeaths related to the use of 5-HT or tryptophan were reported.

Discussion

Evidence based medicine centres on a thorough evalu-ation of studies to ensure that reliable, trustworthy researchis influencing clinical practice [24]. In this review a largebody of evidence was subjected to very basic criteria forassessing reliability and validity, and was found to belargely of insufficient quality to inform clinical practice.There is a temptation to adopt a less stringent approachto assessing clinical evidence, however, this may resultin incorrect conclusions being drawn about treatmentefficacy.

The results of this meta-analysis suggest that 5-HT andtryptophan may have a positive effect in depression.However, well-designed studies are required before thetrue efficacy of these compounds is known.

Tabl

e 2.

Cha

ract

eris

tics

of i

nclu

ded

stud

ies

Au

tho

rM

eth

od

sP

arti

cip

ants

Inte

rven

tio

ns

Ou

tco

me

Mea

sure

Ou

tco

me

Tho

mso

n 19

82R

ando

miz

ed, d

oubl

e bl

ind

plac

ebo-

cont

rolle

d tr

ial.

28 p

atie

nts

with

mild

dep

ress

ion

of

at le

ast 2

wee

ks d

urat

ion,

age

d 18

–65

year

s, a

nd 2

6 co

ntro

ls.

7 pa

tient

s dr

oppe

d ou

t of t

he

trea

tmen

t gro

up a

nd 1

3 dr

oppe

d ou

t of t

he p

lace

bo g

roup

.

Pla

cebo

for 1

wee

k fo

llow

ed b

y 12

wee

ks o

f L-T

rypt

opha

n 1

gram

tds,

pla

cebo

gro

up

rece

ived

iden

tical

pla

cebo

ca

psul

es fo

r 13

wee

ks.

Ham

ilton

Dep

ress

ion

Rat

ing

Sca

le (

HR

S),

G

loba

l Rat

ing

Sca

le, a

nd

Vis

ual A

nalo

gue

Sca

le.

HR

S m

ean

scor

e 18

.21

at

wee

k 0

and

5.38

at w

eek

12

(pla

cebo

19.

43 a

nd 7

.93

resp

ectiv

ely)

.

Van

Pra

ag, 1

972

Ran

dom

ized

, dou

ble

blin

d pl

aceb

o-co

ntro

lled

tria

l.10

sev

erel

y de

pres

sed

inpa

tient

s fo

r w

hom

EC

T th

erap

y w

as b

eing

co

ntem

plat

ed.

3 w

eeks

of 5

-HT

P g

iven

at a

dos

e in

crea

sing

to 3

g d

aily

and

to a

to

tal o

f 50

g pe

r 3

wee

ks (

tota

l du

ratio

n 3

wee

ks)

follo

wed

by

2 w

eeks

of p

lace

bo. I

dent

ical

pl

aceb

o w

as g

iven

to th

e co

ntro

l gr

oup

for

a to

tal d

urat

ion

of

5 w

eeks

.

Ham

ilton

Dep

ress

ion

Rat

ing

Sca

le (

HR

S),

V

enab

les

Sca

le a

nd

Zun

g R

atin

g S

cale

.

HR

S m

ean

scor

e 26

.2 a

t w

eek

0 an

d 17

.8 a

t wee

k 3

(pla

cebo

23

and

24.4

, re

spec

tivel

y).

K. SHAW, J. TURNER, C. DEL MAR 491

The possible association between these substances andthe potentially fatal Eosinophilia–Myalgia Syndromeremains an element of concern. Because currently usedantidepressants are effective and usually well-tolerated,the clinical usefulness of 5-HT and tryptophan mustremain limited until more information is available.

Acknowledgements

We thank A. Spinks for her assistance in data entry,and L. Chen and A. Bardossy for translation of non-English language articles.

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Table 3. Characteristics of 9 excluded studies

Author Reason for exclusion

Farkas, 1976 Crossover study – data from first phase unable to be extractedCooper, 1980 Unable to extract data for unipolar patients alone, patients had major medical comorbiditiesMendlewicz, 1980 Unable to extract data for unipolar patients aloneSmith, 1984 Crossover study – data from first phase unable to be extractedMurphy, 1974 Crossover study – data from first phase unable to be extractedD’Elia, 1977 Electroconvulsive therapy was received by all patients. The therapeutic effect of this was deemed to

overwhelm any possible treatment effect of L-Tryptophan.Zhao, 1990 Crossover study – data from first phase unable to be extractedAyuso Gutierrez, 1971 No placebo, no group treated with tryptophan aloneMendels, 1975 Unable to extract data for unipolar patients alone