87
5-Hydroxytryptophan
Michael T. Murray, ND
OUTLINE
Introduction, 658
Tryptophan and 5-Hydroxytryptophan
Metabolism, 658
Pharmacology, 658
5-Hydroxytryptophan Versus l-Tryptophan, 660
Clinical Applications, 660
Depression, 660
Anxiety and Panic Disorder, 663
Weight Loss, 663
Insomnia, 665
INTRODUCTION
5-Hydroxytryptophan (5-HTP) is the intermediate between trypto-
phan and serotonin (Fig. 87.1).1 Although the use of 5-HTP may be
relatively new to most clinicians, it has been available through phar-
macies for several years and has been intensely researched for the past
three decades. It has been used clinically since the 1970s.  tryptophan to a transport molecule. Because tryptophan shares this
TRYPTOPHAN AND 5-HYDROXYTRYPTOPHAN
METABOLISM
Once tryptophan is absorbed from the intestines, it is carried by the
blood to the liver, along with other amino acids consumed during
the meal. Ingested tryptophan can pass into the general circulation,
metabolize into blood proteins, or convert to kynurenine (which then
goes on to form nicotinic acid, picolinate, and other important metab-
olites) in the liver (Fig. 87.2). After conversion to kynurenine, it cannot
be converted to serotonin. The same is likely true if the tryptophan is
incorporated into blood proteins. Unchanged tryptophan can be con-
verted to 5-HTP and then to serotonin. However, if this conversion
occurs outside the brain, brain chemistry will not be influenced. Even
under the best-case scenario, only 3% of a dosage of l-tryptophan in
supplemental or dietary form is likely to be converted to serotonin in
the brain.2
The manufacture of serotonin from tryptophan within the brain is
highly dependent on the level of tryptophan or 5-HTP that crosses the
blood–brain barrier. Although 5-HTP easily crosses the blood–brain
barrier, the delivery of tryptophan into the brain depends on several
factors. The first factor of importance is the level of free tryptophan
in the blood. In a number of situations, the liver’s conversion of tryp-
tophan to kynurenine occurs at an elevated rate (i.e., stress, elevated
cortisol levels, low B-vitamin status, and high doses of l-tryptophan
[greater than 2000 mg]). These situations lead to increased activity of
tryptophan oxidase and kynurenine formamidase, which convert tryp-
tophan to kynurenine. Elevated levels of kynurenine block the entry of
658
Migraine and Tension Headaches, 665
Juvenile Headache, 666
Fibromyalgia, 667
Parkinson’s Disease, 667
Seizure Disorders, 667
Irritable Bowel Syndrome and the “Leaky Gut”, 668
Dosage, 668
Toxicology, 668
Drug Interactions, 669
tryptophan into the brain and lower brain serotonin levels. Increasing
tryptophan intake makes matters worse when tryptophan oxidase
activity is increased.
Unlike 5-HTP, which easily enters the brain, the transport of
tryptophan across the blood–brain barrier involves the binding of
transport vehicle with several other amino acids, when the ratio of
tryptophan to these other amino acids is low, little tryptophan is
transported into the brain. The protein in almost all foods contains
relatively small amounts of tryptophan and larger proportions of
other amino acids. This generally leads to low serotonin levels with
a high-protein meal. The opposite occurs with a high-carbohydrate
meal. 
PHARMACOLOGY
Several pharmacokinetic studies showed that about 70% of a dose of
5-HTP taken orally is delivered to the bloodstream.3,4 The remaining
30% is metabolized by intestinal cells.
Ample evidence from these pharmacokinetic studies, and clinical
studies, indicates that once absorbed, 5-HTP is delivered to the brain,
resulting in increased formation of not only serotonin but also other
brain chemicals (e.g., the monoamines melatonin, endorphins, dopa-
mine, and norepinephrine; Fig. 87.3). By raising brain serotonin levels,
and through other effects, 5-HTP showed positive effects in the various
conditions associated with low serotonin levels.
Besides raising serotonin and melatonin levels, 5-HTP was shown
to raise β-endorphin levels. Many pain-relieving and mood-elevating
HO
O
OH
HN NH2
Fig. 87.1  Structure of 5-hydroxytryptophan.
 CHAPTER 87  5-Hydroxytryptophan 659

CH2.CH.COOH HO HO

NH2 Tryptophan dioxygenase O

5 hydroxy-
Tryptophan Tryptophan
N NH2
Tryptophan dioxygenase and N
Indoleamine 2,3 dioxygenase 1 and 2 H amino acid
decarboxylase NH2
CO.CH2.CH.COOH
Kynurenine NH2 Kynurenine
HO
aminotransferase
NH2 I, II and III Serotonin
Kynurenine hydroxylase
N
OH H
CO.CH2.CH.COOH
3-hydroxykynurenine NH2 Hydroxyindole-O-
methyl transferase
NH2
N COOH H3C O
OH
Kynureninase Kynurenic acid
COOH
3-hydroxyanthranilic HN CH3
HN
acid NH2
O
OH Melatonin
3-hydroxyanthranillic dioxygenase

CO2H
2-amino-3-
carboxymuconate- OHC
HOOC NH2
semialdhyde 2-Amino-3-carboxymuconae-
semialdehyde decarboxylase
non-enzymatic

COOH HO
Quinolinic Picolinic acid
acid O N
N COOH
O
Quinolinic acid
phosphoribosyl O- NH2
transferase
O P O N
O

O
OH OH NH2
N
N
O P O N N
O- O
Nicotinamide adenine
dinucleotide (NAD+)
OH OH
Fig. 87.2  Tryptophan metabolism pathways.

O Tryptophan hydroxylase HO
(TPH) O
OH
NH2 OH
N
H HN NH2
L-Tryptophan 5-Hydroxytryptophan
O
acid decarboxylase
Aromatic-L-amino

Hydroxyindole-O- H
methyl transferase N
(HIOMT)
N O
H
HO Melatonin
HO
H
N O NH2

HN N
Serotonin N-acetyl transferase
(NAT) H
N-acetyl-serotonin Serotonin
Fig. 87.3  Conversion of 5-hydroxytryptophan to serotonin and melatonin.
660 SECTION 4  Pharmacology of Natural Medicines
benefits of 5-HTP might be related more to its ability to enhance
endorphin levels than to its ability to increase serotonin levels. This
endorphin-increasing action is useful for both migraine and tension
headaches, fibromyalgia, and other painful situations. In addition,
raising endorphin levels produces significant effects on mood and
behavior.
By raising serotonin, melatonin, and β-endorphin levels, 5-HTP
has a significant effect on helping regulate and improve brain chemis-
try. 5-HTP was also shown to raise the levels of other important neu-
rotransmitters, such as dopamine and norepinephrine.5 The ability of
5-HTP to increase both serotonin (and other indolamines) and cat-
echolamines is quite significant and unique to 5-HTP. It is an effect
that 5-HTP does not share with l-tryptophan. The effective treatment
of depression requires more than simply raising serotonin levels; cat-
echolamine levels must also be increased; 5-HTP provides the brain
with both sets of tools.
5-Hydroxytryptophan Versus l-Tryptophan
Nutrition-oriented physicians have long used precursor therapy for
affecting brain chemistry. Unfortunately, l-tryptophan produced
inconsistent results. These results were likely a result of its varying ele-
vation of brain serotonin levels.
In a head-to-head comparison study of 5-HTP and l-tryptophan
in the treatment of depression, 5-HTP proved superior.6 The proposed
reason is the fact that 5-HTP easily crosses the blood–brain barrier and
is not affected by competing amino acids. 5-HTP affects brain chem-
istry in a broader and more positive fashion. l-Tryptophan is often
effective in cases of low serotonin, especially insomnia, but 5-HTP is
more broadly effective.
There are many advantages of 5-HTP over l-tryptophan. Chief
among them is that 5-HTP easily crosses the blood–brain barrier and is
one step further on the path to serotonin synthesis. The conversion of
tryptophan to 5-HTP by tryptophan hydroxylase is the most import-
ant step in the manufacture of serotonin. This enzyme is inhibited by
several factors, including the following:
• Stress
• Vitamin B6 insufficiency
• Low magnesium levels
• Insensitivity to insulin
• Various hormones
• Genetic factors
In addition, as noted earlier, these same factors and others are
known to increase the activity of tryptophan oxygenase, increasing the
conversion of l-tryptophan to kynurenine.
Perhaps the biggest advantage of 5-HTP over l-tryptophan is
that it is safer.7 Although l-tryptophan is safe if properly prepared
and free of the contaminants linked to eosinophilia myalgia syn-
drome (EMS), 5-HTP is inherently safer. The reasons are that tak-
ing l-tryptophan to produce positive effects in the treatment of
depression, insomnia, and other low-serotonin conditions requires
a relatively high dose (e.g., a minimum of 2000 mg in insomnia and
6000 mg in depression). At high doses such as these, l-tryptophan is
potentially problematic because more l-tryptophan will be shunted
toward the kynurenine pathway, and l-tryptophan promotes oxida-
tive damage. Excessive levels of dietary tryptophan or high doses of
l-tryptophan result in tryptophan actually acting as a free radical.8
In contrast, 5-HTP is an antioxidant.9 This antioxidant difference
is a result of the additional molecule of oxygen and hydrogen in
5-HTP. This simple change in molecular structure allows the phe-
nolic ring structure to effectively accept or quench the unpaired
electron of a free radical.  improvement in most cases ranged from excellent to very good.
BOX 87.1  Conditions Associated With Low
Serotonin Levels
• Depression
• Anxiety
• Obsessive-compulsive disorder
• Obesity
• Carbohydrate craving
• Bulimia
• Insomnia
• Narcolepsy
• Sleep apnea
• Migraine headaches
• Tension headaches
• Chronic daily headaches
• Premenstrual syndrome
• Fibromyalgia
• Epilepsy
• Myoclonus
• Chronic pain disorders
CLINICAL APPLICATIONS
A massive amount of evidence suggests that low serotonin levels are
a common consequence of modern living. The lifestyle and dietary
practices of many people living in this stress-filled era result in low-
ered levels of serotonin within the brain. As a result, many people are
overweight, crave sugar and other carbohydrates, experience bouts of
depression, get frequent headaches, and have vague muscle aches and
pains. All of these maladies are correctable by raising brain serotonin
levels. The primary therapeutic applications for 5-HTP are low-sero-
tonin states, as listed in Box 87.1.
Depression
Some of the first clinical studies on 5-HTP for the treatment of depres-
sion began in the early 1970s in Japan. The first study involved 107
patients with either unipolar depression or manic bipolar depression.10
These patients received 5-HTP at dosages ranging from 50 to 300 mg/
day. The researchers observed a quick response (within 2 weeks) in
more than half of the patients. Seventy-four of the patients either
experienced complete relief or significantly improved, and none expe-
rienced significant side effects. These promising results were repeated
in several other Japanese studies. An interesting aspect in two of these
studies was the fact that 5-HTP was shown to be effective in some
patients (50% in one study, 35% in another) who had not responded
positively to any other antidepressant agent.11,12
The most detailed of the Japanese studies was conducted in 1978.13
The study enrolled 59 patients with depression (30 males and 29
females). The groups were mixed, in that both unipolar and bipolar
depressions were included, along with a number of other subcategories
of depression. The severity of the depression in most cases was moder-
ate to severe. Patients received 5-HTP in dosages of 50 or 100 mg three
times a day for at least 3 weeks.
The antidepressant activity and clinical effectiveness of 5-HTP
were determined using a rating scale developed by the Clinical
Psychopharmacology Research Group in Japan. The improvements
among the various patients are detailed in Table 87.1. These results
indicated that 5-HTP was helpful in 14 of 17 patients with unipolar
depression and 12 of 21 patients with bipolar depression. The degree of
 CHAPTER 87  5-Hydroxytryptophan 661

TABLE 87.1  Improvement in Various TABLE 87.3  Level of Serotonin in

Subtypes of Depression Blood (nanograms per milliliter): Controls,
IMPROVEMENT
a
Responders, and Nonresponders
Subtype 1 2 3 4 5, 6, 7 8 1 + 2 + 3/ After 1 Wk (150 OR
b
total Before 300 mg/day 5-HTP)
First-episode depres- 1 1 0 1 0 0 2/3
Normal subjects 150
sion
Responders 78 148
Unipolar depression 3 8 3 1 2 0 14/17
Nonresponders 56 77
Bipolar depression 6 4 2 3 3 3 12/21
Mixed depression 0 1 0 1 0 0 1/2 5-HTP, 5-Hydroxytryptophan.
Presenile or senile 3 2 0 3 1 0 5/9
depression
Neurotic depression 0 1 2 1 0 0 3/4 TABLE 87.4  Hamilton Depression Rating
Reactive depression 0 1 1 0 0 0 2/2 Scale Scores From a Comparative Study of
Schizophrenic 0 1 0 0 0 0 1/1 5-Hydroxytryptophan (5-HTP), l-Tryptophan,
depression and Placebo
Total 13 19 8 10 6 3 40/59
% of total 22 32.2 13.6 16.9 10.2 5.1 67.8 5-HTP L-tryptophan Placebo

aImprovement:
Beginning of the study 26 25 23
1, marked improvement; 2, moderately improved; 3,
End of the study (30 days) 9 15 19
slightly improved; 4, unchanged; 5, 6, 7, felt worse; 8, dropped out.
bThe number of subjects who improved (improvement scores 1, 2, or

3) compared with the total number of subjects in that subtype.

depression given 5-HTP at a level of 150 or 300 mg/day experienced
good to excellent results.14 This percentage of responders is quite good,
TABLE 87.2  Day When Improvements but if the level of serotonin in the blood is viewed as a rough indicator
Were First Noticed of brain serotonin levels, some interesting conclusions can be made
(Table 87.3). In some cases, a higher dosage may be necessary.
DAY
Improvement The measurements in Table 87.3 suggest that serotonin levels in
Group 1 2 3 4–7 8–14 15 depressed individuals are considerably lower than those found in nor-
Marked 1 3 2 5 2 0 mal subjects and that individuals who respond to 5-HTP show a rise in
Moderate 0 1 13 1 4 0 serotonin to levels consistent with normal subjects. The level of sero-
Slight 0 2 2 2 1 1 tonin in those who do not respond to 5-HTP remains quite low. These
Total 1 6 17 8 7 1 results imply that nonresponders may require higher doses to raise
serotonin levels or that additional support may be necessary. When
prescribing higher doses, it is important that the 5-HTP be taken in
The results achieved in this open study were quite good, given divided doses not only to reduce the problem with nausea but also
how rapidly they were achieved. Thirty-two of the 40 patients who because the rate of brain-cell uptake of 5-HTP is limited.
responded to 5-HTP did so within the first 2 weeks of therapy. The first studies of 5-HTP were open trials.15 The antidepressive
Typically, in most studies with antidepressant drugs, the benefits are effects of 5-HTP were also compared with l-tryptophan in the early
not apparent until after 2 weeks to 1 month of use. For this reason, the 1970s.6 In one study, 45 subjects with depression were given l-trypto-
length of study when assessing antidepressant drugs should be at least phan (5 g/day), 5-HTP (200 mg/day), or a placebo. The patients were
6 weeks because it may take that long to significantly affect brain chem- matched in clinical features (e.g., age, sex) and severity of depression.
istry in a positive manner. In contrast, many of the studies with 5-HTP The main outcome measure was a rating scale called the Hamilton
were shorter than 6 weeks because statistically significant results were Depression Rating Scale (HAM-D), the most widely used assessment
achieved so soon (Table 87.2). However, the longer 5-HTP is used, the tool in clinical research on depression.
better the results. Some people may need to be on 5-HTP for at least 2 The HAM-D score is determined by having the test subject com-
months before they experience benefits. plete a series of questions in which he or she rates the severity of symp-
The only major side effect noted in this study was mild nausea. The toms on a numerical basis, as follows:
occurrence of nausea caused by 5-HTP is actually less frequent than • 0—not present
that experienced with other antidepressant drugs (roughly 10% of sub- • 1—present but mild
jects taking 5-HTP at a daily dose of more than 300 mg experience • 2—moderate
nausea compared with about 23% taking Prozac) and about the same • 3—severe
as that which occurs with a placebo. In double-blind studies, about • 4—very severe
10% or so of people taking the placebo typically complain of nausea. Symptoms assessed by the HAM-D include depression, feelings of
Nonetheless, mild nausea may be a natural consequence of elevated guilt, insomnia, gastrointestinal symptoms and other bodily symptoms
serotonin levels with 5-HTP. About 30% of the 5-HTP taken orally is of depression (e.g., headaches, muscle aches, heart palpitations), and
converted to serotonin in the intestinal tract. This can lead to a mild anxiety. The HAM-D is popular in research because it provides a good
case of nausea. Fortunately, this effect wears off after a few weeks of assessment of the overall symptoms of depression. Table 87.4 shows
use. the results of the study.
A 5-HTP dosage of 150 to 300 mg/day is sufficient in most cases. A review of head-to-head comparison studies showed that 5-HTP,
For example, in one study, it was shown that 13 of 18 subjects with at a dosage of 200 mg/day, produced therapeutic success on par with
662 SECTION 4  Pharmacology of Natural Medicines
TABLE 87.5  Change in Hamilton
Depression Rating Scale Scores
5-HTP + MAO MAO + PLACEBO
Initial measurement 28.67 26.33
After 8 days 16.67 19.23
After 15 days 11.77 6.03
5-HTP, 5-Hydroxytryptophan; MAO, monoamine oxidase.
Modified from Alino JJ, Gutierrez JL, Iglesias ML. 5-Hydroxytryptophan
(5-HTP) and a MAOI (nialamide) in the treatment of depressions. A
double-blind controlled study. Int Pharmacopsychiatry. 1976;11:8–15.
tricyclic antidepressant drugs.16 Research also showed that combining
5-HTP with clomipramine and other types of antidepressant drugs
produced better results than any of the compounds given alone.17–22
For example, in one study, 5-HTP combined with a monoamine oxi-
dase inhibitor demonstrated significant advantages compared with the
monoamine oxidase inhibitor alone (Table 87.5).21
This line of research suggests that 5-HTP might also be used in con-
junction with St. John’s wort extract and Ginkgo biloba extract, two
herbal medicines with proven antidepressant activity.
Because 5-HTP was expensive in 1972, researchers developed a test
to determine who was most likely to respond to it so that it would
not be wasted on people who were unlikely to respond.15,23 The test
involved the patients first having a spinal tap to measure the level of
5-hydroxyindoleacetic acid (5-HIAA, the breakdown product of sero-
tonin) in the cerebrospinal fluid (CSF). The drug probenecid, which
prevents the transport of 5-HIAA from the CSF to the bloodstream,
was administered for the next 3 days. As a result of this blocking action,
the amount of serotonin produced over a 4-day period could be cal-
culated by a repeat spinal tap on day 4. Because the 5-HIAA could not
leave the CSF, it accumulated and provided a measure of serotonin
manufacture.
The researchers discovered that the average level of 5-HIAA after
3 days of probenecid was significantly lower in depressed individuals
than in controls matched for age, sex, and weight. This low level of
serotonin reflected a decreased rate of manufacture within the brain.
5-HTP was most effective in patients with a low 5-HIAA response to
3 days of probenecid.23–25 In other words, 5-HTP is most effective as
an antidepressant when the amount of serotonin manufactured in the
brain is reduced.
As stated earlier, 5-HTP often produces good results in patients who
are unresponsive to antidepressant drugs. One of the more impressive
studies involved 99 patients described as having “therapy-resistant”
depression.26 These patients did not respond to any previous ther-
apy, including all available antidepressant drugs and electroconvulsive
therapy. These therapy-resistant patients received 5-HTP at dosages
averaging 200 mg/day but ranging from 50 to 600 mg/day. Complete
recovery was seen in 43 of the 99 patients, and significant improvement
was noted in 8 more. Such a significant improvement in patients with
long-standing, unresponsive depression is quite impressive, prompt-
ing the author of another study to state the following27:
l-5-HTP merits a place in the front ranks of antidepressants
instead of being used as a last resort. I have never in 20 years used
an agent that (1) was effective so quickly; (2) restored patients so
completely to the persons they had been and their partners had
known; and (3) was so entirely without side effects.
In an open-label study, 15 women with major depressive disorder
who had failed selective serotonin-reuptake inhibitor (SSRI) or sero-
tonin–norepinephrine-reuptake inhibitor (SNRI) monotherapy were
TABLE 87.6  5-Hydroxytryptophan (5-HTP)
Versus Fluvoxamine in Percentage Changes
in the Hamilton Depression Rating Scale
(HAM-D) Score
Fluvoxamine
Decrease in HAM-D 5-HTP (n = 34) (n = 29)
After 2 wk Mean decrease (%) 23 18.9
<35% decrease 20 19
35%–50% decrease 10 8
50%–75% decrease 4 2
After 4 wk Mean decrease (%) 46.2 46.1
<35% decrease 2 8
35%–50% decrease 7 3
50%–75% decrease 12 13
>75% decrease 3 5
After 6 wk Mean decrease (%) 60.7 56.1
<35% decrease 4 5
35%–50% decrease 8 3
50%–75% decrease 12 8
>75% decrease 10 13
treated with 5 g of creatine monohydrate daily and 100 mg of 5-HTP
twice daily for 8 weeks. Mean HAM-D scores declined from 18.9 at
pretreatment visits to 7.5 at the end of 8 weeks.28
A 1987 review article on 5-HTP in depression highlighted the need
for well-designed, double-blind, head-to-head studies of 5-HTP ver-
sus standard antidepressant drugs.29 Although 5-HTP was viewed as
an antidepressant agent with few side effects, the authors of this review
felt that the big question to answer was how 5-HTP compared with the
new breed of antidepressant drugs, the SSRIs like Prozac, Paxil, and
Zoloft. In 1991 a double-blind study comparing 5-HTP with an SSRI
was conducted in Switzerland.30 In the study, 5-HTP was compared
with the SSRI fluvoxamine (Luvox). Fluvoxamine is used primarily in
the United States as a treatment for obsessive-compulsive disorder, an
anxiety disorder characterized by obsessions and compulsions affect-
ing an estimated 5 million Americans. Fluvoxamine exerts antidepres-
sant activity comparable to (if not better than) other SSRIs like Prozac,
Zoloft, and Paxil.
In the study, subjects received either 5-HTP (100 mg) or fluvox-
amine (50 mg) three times a day for 6 weeks. The assessment meth-
ods used to judge effectiveness included the HAM-D, Self-Assessment
Depression Scale (SADS), and physician’s assessment (Clinical Global
Impression). As indicated in Table 87.6, the percentage decrease in
depression was slightly better in the 5-HTP group (60.7% vs. 56.1%).
5-HTP was quicker acting than the fluvoxamine, and a higher percent-
age of patients responded to 5-HTP than to fluvoxamine.
The advantages of 5-HTP over fluvoxamine are evident when
looking at the subcategories of the HAM-D: depressed mood, anxi-
ety, physical symptoms, and insomnia. For depressed mood, 5-HTP
produced a 65.7% reduction in severity compared with 61.8% for
fluvoxamine; for anxiety, 5-HTP produced a 58.2% reduction in
severity compared with 48.3% for fluvoxamine; for physical symp-
toms, 5-HTP produced a 47.6% decrease in severity compared
with 37.8% for fluvoxamine; and for insomnia, 5-HTP produced a
61.7% decrease in severity compared with a 55.9% decrease for flu-
voxamine. However, perhaps more important than simply relieving
insomnia was 5-HTP’s ability to improve the quality of sleep. In
contrast, antidepressant drugs greatly disrupt sleep processes. On
the SADS, 5-HTP produced a 53.3% drop in SADS values compared
 CHAPTER 87  5-Hydroxytryptophan 663

TABLE 87.7  5-Hydroxytryptophan (5-HTP) to mild. In contrast, most of the side effects experienced in the fluvox-
amine group were of moderate to severe intensity. The only subject to
Versus Antidepressant Drugs: Comparison of
drop out of the 5-HTP group did so after 35 days (5 weeks), whereas
Side Effects four subjects in the fluvoxamine group dropped out after only 2 weeks.
PERCENTAGE OF PATIENTS On the basis of studies on weight loss, the longer that 5-HTP is used
EXPERIENCING SIDE EFFECTS (e.g., after 4–6 weeks of use), the less the problem with mild nausea.
Side Effects 5-HTP Tricyclics SSRIs 5-HTP has been shown to have “equipotency” with SSRIs and tri-
Nausea 9 15 23 cyclic antidepressants in terms of effectiveness, but it offers several
Headache 5 16 20 advantages in that it is better tolerated and associated with fewer and
Nervousness 2.5 11 16 much milder side effects. In addition, many people prefer to use a nat-
Insomnia 2.5 7 17 ural substance like 5-HTP over synthetic drugs.
Anxiety 2.5 9 14
Drowsiness 7 23 11
l-Tyrosine: an Adjunct to 5-Hydroxytryptophan
Diarrhea 2.5 4 12 In the early 1970s, researchers discovered that in about 20% of patients
Tremor 0 18 11 who responded well to 5-HTP, the results tended to decrease after
Dry mouth 7 64.5 12 1 month of treatment. The antidepressant effects of 5-HTP in these
Sweating 2.5 15 9 subjects began to wear off gradually after the first month even though
Dizziness 5 25.5 7 the level of 5-HTP in the blood, and presumably the level of serotonin
Constipation 5 25 5.5 in the brain, remained at the same level as when they were experiencing
Vision changes 0 14.5 4 benefits.5
The researchers discovered that although serotonin levels appeared
SSRI, Selective serotonin-reuptake inhibitor. to stay at the same levels after 1 month of treatment, the levels of the
other important monoamine neurotransmitters, dopamine and nor-
with a drop of 47.6% for the fluvoxamine group. A drop greater epinephrine, declined. As discussed earlier, when depressed patients
than 50% is an excellent result. A 50% drop is the best SSRIs gen- are treated with 5-HTP, they experience a rise not only in serotonin
erally produce. but also in catecholamines like dopamine and norepinephrine. In
In another head-to-head comparison study, this time with fluox- about 20% of subjects, the catecholamine-enhancing effects of 5-HTP
etine, 5-HTP also showed q good antidepressant effect.31 The study tended to wear off. Providing these patients with l-tyrosine, the amino
consisted of 60 patients suffering from their first depressive episode acid precursor to the catecholamines, helped reestablish the efficacy
who were randomly divided to receive 5-HTP (group A) or fluoxetine of 5-HTP.5 The dosage was 200 mg/day for 5-HTP and 100 mg/kg
(group B) for a period of 8 weeks. 5-HTP was given at 150 mg in three body weight for l-tyrosine. This dosage for l-tyrosine is quite high and
divided dosages during the first 2 weeks, and then the dose was dou- requires substantial clinical supervision. 
bled (300 mg) after the second week. The dosages were increased to
400 mg in three divided dosages after the fourth week. Thereafter, the Anxiety and Panic Disorder
same dosages were continued. All patients in group B were given flu- 5-HTP showed an ability to relieve anxiety in studies in depressed
oxetine 20-mg capsules along with two placebo dosages during the first individuals. Lowering the availability of serotonin to the brain by tryp-
2 weeks and then increased to 30 mg along with placebo dosages after tophan depletion increased the vulnerability of patients with panic
the second week. All patients were administered the HAM-D to assess disorder to an experimental carbon dioxide panic challenge, and
the severity of depression at baseline, 2 weeks, 4 weeks, and 8 weeks. A increasing the availability of serotonin inhibited the response to such a
final evaluation of both efficacy and tolerance was conducted using the challenge. When 5-HTP or placebo was given to 24 patients with panic
Clinical Global Impression (CGI) scale at the end of the study. disorder and 24 healthy volunteers before a panic challenge, 5-HTP
Results showed that both treatment groups experienced a signifi- significantly reduced the reaction to the panic challenge in patients
cant and nearly equal reduction in HAM-D scores beginning at week 2 with panic disorder regarding subjective anxiety, panic symptom
and continuing through week 8. Twenty-two patients (73.33%) in the score, and number of panic attacks, as opposed to placebo.32 These
5-HTP group and 24 patients (80%) in the fluoxetine group showed a results indicate that 5-HTP might be helpful in relieving panic attacks. 
positive response at the end of the study. 5-HTP was very well toler-
ated, and it was concluded that 150 mg represents a minimal effective Weight Loss
dosage in depression for 5-HTP. A considerable body of scientific evidence documents the major role
The existing data indicate that 5-HTP is equal to or better than serotonin in the brain plays in influencing eating behavior. A key find-
standard antidepressant drugs, and the side effects are much less severe ing is that when animals and humans are fed tryptophan-free diets,
(Table 87.7). In the study comparing 5-HTP with fluvoxamine, this is appetite is significantly increased, resulting in binge eating—carbohy-
how the physicians described the differences among the two groups: drates would be preferable, but animals binge on whatever is avail-
Whereas the two treatment groups did not differ significantly in the able.2,3 A diet low in tryptophan leads to low brain serotonin levels; as a
number of patients sustaining adverse events, the interaction between result, the brain senses it is starving and stimulates the appetite control
the degree of severity and the type of medication was highly significant: centers in a powerful way. This stimulation results in a preference for
fluvoxamine predominantly produced moderate to severe side effects; carbohydrates. When animals or humans are fed a carbohydrate meal,
oxitriptan (5-HTP) produced primarily mild forms of adverse effects. more tryptophan is delivered to the brain, resulting in more serotonin
Fourteen (38.9%) of the patients receiving 5-HTP reported side being manufactured. This scenario led to the idea that low serotonin
effects compared with 18 patients (54.5%) in the fluvoxamine group. levels lead to “carbohydrate craving” and play a major role in the
The most common side effects with 5-HTP were nausea, heartburn, development of obesity and bulimia.
and gastrointestinal problems (flatulence, feelings of fullness, and Cravings for carbohydrates can be mild or quite severe. They may
rumbling sensations). These side effects were rated as being very mild range in severity from the desire to nibble one piece of bread or cookie
664 SECTION 4  Pharmacology of Natural Medicines

TABLE 87.8  Effect of 5-Hydroxytryptophan TABLE 87.9  Effect of 5-Hydroxytryptophan

(5-HTP) on Food Intake (5-HTP) on Weight Loss
Food Intake Protein Intake Carbohydrate Placebo 5-HTP
(calories/day) (g/day) Intake (g/day) Weight (lb)
Pretreatment 2903 101 274 Baseline 207.68 229.46
Placebo 2327 85 223 After 6 wk 206.58 225.94
5-HTP 1819 79 176 After 12 wk 205.4 219.12

Total weight loss (lb)

to uncontrollable binging. At the upper end of the spectrum of car- After 6 wk 1.1 3.52
bohydrate addiction is bulimia, a potentially serious eating disorder After 12 wk 2.28 10.34
characterized by binge eating and purging of the food through forced
vomiting or the use of laxatives. The serotonin theory of bulimia is
that low serotonin levels trigger binge eating, which leads to a rush of
serotonin being produced and released in the brain.33,34 This increased TABLE 87.10  Effect of 5-Hydroxytryptophan
serotonin effect produces a brief reduction in feelings of stress and (5-HTP) on Appetite and Satiety
tension. This serotonin “fix” is short-lived and followed by feelings 5-HTP PLACEBO
of guilt and low self-esteem. The current medical treatment for buli-
mia is the use of drugs that enhance the effects of serotonin. Although Wk 1–6 Wk 7–12 Wk 1–6 Wk 7–12
there are no reports in the medical literature of 5-HTP being used in Taste alteration 2/7 1/7 0/7 0/7
the treatment of bulimia, given its effects on serotonin levels, it merits Smell alteration 2/7 1/7 0/7 0/7
consideration. Meat aversion 3/7 1/7 0/7 0/7
5-HTP may help prevent the decline in serotonin levels associ- Early satiety 7/7 6/7 2/7 2/7
ated with reduced calorie intake. Concentrations of tryptophan in Nausea 5/7 0/7 1/7 2/7
the bloodstream and subsequent brain serotonin levels plummet with
dieting.35 In response to severe drops in serotonin levels, the brain
puts out a strong message to eat. This situation sets up the scenario to was a little more than 3 lb, compared with less than 1 lb of total weight
explain why most diets do not work. loss during the placebo period.
As far back as 1975, researchers demonstrated that giving 5-HTP Interestingly, evaluation of the various self-tests indicated that
to rats who were genetically bred to overeat and be obese resulted in a appetite or degree of initial hunger did not differ between the two
significant reduction in food intake.36 It turns out that these rats bred groups. What differed was satiety. In other words, the 5-HTP did
to be fat had decreased activity of the enzyme that converts tryptophan not reduce appetite before a meal, but after consuming an adequate
to 5-HTP and subsequently to serotonin. amount of food, the satiety centers in the brain were stimulated, and
There is circumstantial evidence that many humans are geneti- the women did not feel hungry. As a result, their caloric intake was
cally predisposed to obesity. This predisposition may involve the same dramatically reduced.
mechanism as rats genetically predisposed to obesity. By providing The level of 5-HIAA, the breakdown product of serotonin, in the
preformed 5-HTP, this genetic defect is bypassed, and more serotonin group receiving the 5-HTP increased by more than fiftyfold over
is manufactured. the control group. This increase provided two things: (1) it assured
The early animal studies with 5-HTP as a weight-loss aid were researchers that subjects actually took the 5-HTP, and (2) it clearly
followed by a series of three human clinical studies. The first study indicated that 5-HTP increased serotonin manufacture.
involved 19 significantly overweight female subjects with a body mass The next study sought to determine whether 5-HTP helped over-
index (BMI) ranging from 30 to 40 kg/m2.37 Analysis of the pretreat- weight individuals adhere to dietary recommendations.38 Fourteen
ment dietary intake concluded that these women tended to overeat overweight female subjects with a BMI between 30 and 40 kg/m2 were
carbohydrates. Food intake and eating behavior were assessed using a enrolled in the double-blind study.10 Again, analysis of the pretreat-
3-day diet diary at the beginning and end of the two treatment periods. ment dietary intake concluded that these women tended to overeat.
All food was carefully weighed before meals and weighed again if there The women were randomly assigned to receive either 5-HTP (300 mg)
were any leftovers. Participants also filled out a self-evaluation of appe- or placebo 30 minutes before meals. The 12-week study was divided
tite and satiety twice a week, and mood was evaluated using standard into two 6-week periods. For the first 6 weeks, there were no dietary
psychological tests. recommendations, and for the second 6 weeks, the women were placed
The daily dosage of 5-HTP used in the study was 8 mg/kg body on a 1200-calorie diet.
weight. Patients were given either 5-HTP or placebo 20 minutes before The women were seen every 2 weeks to evaluate body weight, diet
meals for 5 weeks, and after a 1-week interval, they were switched to diaries, self-evaluations of appetite, and satiety. The women were also
receive the other treatment. No dietary restrictions were prescribed asked if they experienced the presence of meat aversion; taste or smell
because the researchers wanted to answer the question, “Does 5-HTP alterations; early satiety; and nausea or vomiting, or both. To verify
reduce appetite and promote weight loss without any conscious effort?” patient compliance, urinary measurement of 5-HIAA was again deter-
To make sure that the women actually took the 5-HTP, researchers mined. As shown in Table 87.9, the women taking the placebo lost 2.28
measured the level of the serotonin breakdown product, 5-HIAA, in lb, whereas the women taking the 5-HTP lost 10.34 lb.
the urine. Table 87.8 lists the results of the study. Like the previous study, 5-HTP appeared to promote weight loss
These results with 5-HTP were achieved without the women making by promoting satiety. Although some women reported some aver-
any conscious effort to reduce food consumption. The average amount sion to meat or altered taste and smell, each woman (100%) reported
of weight loss during the 5-week period of 5-HTP supplementation early satiety (Table 87.10). Most of the women receiving 5-HTP also

experienced mild nausea during the first 6 weeks of the trial, but
during the last 6 weeks, none complained of nausea. The fact that
weight loss was accelerated during the second 6-week period makes
it highly unlikely that 5-HTP promoted weight loss as a result of pro-
ducing nausea.
One study with 5-HTP enrolled overweight women with a BMI
ranging between 30 and 40 kg/m2 and an overactive appetite.39 The
28 subjects of the study were given either 5-HTP (300 mg three times
daily before meals) or a placebo. For the first 6 weeks, there were
no dietary restrictions, and for the second 6 weeks, the women were
placed on a diet of 1200 calories/day. Carbohydrates contributed 53%
of the calories, fats comprised 29%, and proteins provided 18%. No
carbohydrate-rich foods were permitted between meals. Subjects were
examined every 2 weeks to evaluate food intake and body weight.
Routine blood measurements were also performed at the beginning,
at 6 weeks, and at the end of the study. To verify patient compliance,
urinary measurement of 5-HIAA was determined.
The results from this study were even more impressive than the
previous studies, for several reasons. The group receiving the 5-HTP
lost an average of 4.39 lb after the first 6 weeks and an average of 11.63
lb after 12 weeks. In comparison, the placebo group lost an average of
only 0.62 lb after the first 6 weeks and 1.87 lb after 12 weeks. The lack
of weight loss during the second 6-week period in the placebo group
obviously reflected the fact that the women had difficulty adhering to
the diet.
Early satiety was reported by 100% of the subjects during the first
6-week period. During the second 6-week period, even with severe
caloric restriction, 90% of the women taking 5-HTP reported early
satiety. Once again, many of the women receiving the 5-HTP reported
mild nausea during the first 6 weeks of therapy. However, the symp-
tom was never severe enough for any of the women to drop out of the
study. No other side effects were reported.
On the basis of the urinary measurements of 5-HIAA, the women
took their 300 mg of 5-HTP with meals and, as a result, achieved weight
loss. The amount of weight loss was amplified by a better capability
to adhere to a 1200-calorie diet. The structure of the dietary changes
reflected primarily a reduction in pasta, bread, and other carbohy-
drate-rich foods (the study was conducted in Rome).
In the latest study, 25 overweight outpatients with non–insulin-de-
pendent diabetes were enrolled in a double-blind, placebo-controlled
study and randomized to receive either 5-HTP (750 mg/day) or a pla-
cebo for 2 consecutive weeks, during which no dietary restrictions were
prescribed.40 Results again indicated that patients receiving 5-HTP sig-
nificantly decreased their daily energy intake by reducing carbohydrate
and fat intake and reduced their body weight.  trollable and for those who are under close medical supervision.
Insomnia
Several clinical studies showed 5-HTP produced good results in
promoting and maintaining sleep in normal subjects and in those
experiencing insomnia.39–46 One of the key benefits with 5-HTP
in the treatment of insomnia is its ability to increase sleep quality.
This effect is evident by its ability to increase rapid eye movement
(REM) sleep (typically by about 25%) while simultaneously increas-
ing deep sleep stages 3 and 4 without increasing total sleep time.39,42
The sleep stages that are reduced by 5-HTP to compensate for the
increases are non-REM stages 1 and 2, the least important stages of
sleep. In one of the studies, the subjects receiving 200 mg of 5-HTP
increased their amount of REM sleep by 15.5 minutes during the
5-night study.39 Subjects taking 600 mg of 5-HTP increased REM
sleep time by an average of 20 minutes for the 5-night study. These
results indicated that 5-HTP increased the amount of dream time by
about 3 to 4 minutes a night.
CHAPTER 87  5-Hydroxytryptophan 665
Although there was a clear dose-related effect, the lower dosage
is sufficient in most cases. In addition, taking too much 5-HTP may
increase REM sleep to an abnormal level, leading to an increased risk
for nightmares. That said, 5-HTP might prove effective in sleep terrors
in children. To test this hypothesis, an open trial in a group of children
with sleep terrors was compared with a group of children with the same
disorder but without 5-HTP treatment.47 5-HTP was administered
(2 mg/kg per day) at bedtime to 31 randomly selected patients for 20
consecutive days. After 1 month of treatment, 29 of 31 (93.5%) patients
showed a positive response. In the comparison group without drug
therapy, after 1 month, the episodes disappeared in only 4 children
(28.6%), whereas 10 children (71.4%) showed persistence of episodes
with the same frequency as before. After 6 months, 26 of 31 (83.9%)
children treated with 5-HTP were sleep terror–free, whereas in five
children (16.1%), sleep terror episodes persisted. Of the children in
the comparison group, 10 (71.4%) continued to show sleep terrors at
6-month follow-up. These results represent preliminary evidence that
treatment with 5-HTP is able to modulate the arousal level in children
and induce a long-term improvement in sleep terrors. 
Migraine and Tension Headaches
The relationship between serotonin and headaches is fully described in
Chapter 198. Because patients with migraines have low levels of sero-
tonin in their tissues, some researchers refer to migraine headaches as
a “low-serotonin syndrome.”46 Although the primary benefit of 5-HTP
in the prevention of both migraine and tension headaches is related to
its ability to normalize underlying imbalances in the serotonin system,
it also influences the endorphin system in a positive way.
Several clinical studies on the use of 5-HTP for headaches, both
vascular and nonvascular, showed excellent results. In particular, the
use of 5-HTP in the prevention of migraine headaches offers consider-
able advantages over drug therapy. Although a number of drugs were
shown to be useful in the prevention of migraine headaches, all of them
carry significant side effects.
The problem with drug therapy in the prevention of migraine
headaches is perhaps best exemplified by one of the most commonly
used drugs, methysergide (Sansert). Methysergide therapy for the pre-
vention of migraine attacks is effective in about 60% to 80% of cases.
However, this effectiveness is not without a high price because side
effects are quite common and can be severe. Retroperitoneal fibrosis,
pleuropulmonary fibrosis, and fibrotic thickening of cardiac valves
may occur in patients receiving long-term methysergide maleate ther-
apy. Therefore this preparation must be reserved for prophylaxis in
patients whose vascular headaches are frequent or severe and uncon-
Several studies compared 5-HTP with methysergide in the preven-
tion of migraine headaches. In one of the largest double-blind studies,
124 patients received either 5-HTP (600 mg/day) or methysergide (3
mg/day) in identical pills for 6 months.48 Treatment was determined
successful if there was a reduction of greater than 50% in the frequency
of attacks or in the number of severe attacks. Although 75% of the
patients (30 of the remaining 40 patients) taking methysergide demon-
strated significant improvement compared with 71% of the patients
(32 of the 45 patients) taking 5-HTP, this difference was not viewed
as statistically significant (Table 87.11). The advantage of 5-HTP
over methysergide was demonstrated when researchers looked at side
effects. Side effects were more frequent in the group receiving methy-
sergide than in the 5-HTP group. Five patients in the methysergide
group withdrew during the trial because of side effects.
Two other studies comparing 5-HTP with drugs used in the preven-
tion of migraine headaches (pizotifen and propranolol) demonstrated
that 5-HTP compared quite favorably in terms of effectiveness.49,50
666 SECTION 4  Pharmacology of Natural Medicines

TABLE 87.11 5-Hydroxytryptophan TABLE 87.12  Serotonin and β-Endorphin

(5-HTP) Versus Methysergide: Clinical Effects Levels in Juvenile Patients with Headaches
of Treatment in 124 Patients Before and After Administration of
Methysergide 5-HTP
5-Hydroxytryptophan (5-HTP)
No attacks (100% reduction) 35% 25% Beta-Endorphin
Improvement (>50% reduction) 40% 46% (white blood
No improvement 12.5% 29% Serotonin Beta-Endorphin cells, pmol/106
Withdrawal because of side effects 12.5% 0% (serum, mg/L) (plasma, pmol/L) GB/L)
Migraine (13 subjects)
Before 104.6 16.2 110.5
Although these drugs have significant side effects, 5-HTP is extremely After 115.7 19.4 120.3
well tolerated even at dosages as high as 600 mg/day. One of the other Tension-type (7 subjects)
key differences noted in these studies between 5-HTP and the other Before 90.7 14.5 142.3
drugs was 5-HTP’s ability to improve mood and relieve feelings of After 97.2 17.6 152.4
depression. Total (20 subjects)
In a double-blind study of 5-HTP in chronic tension headache, 78
Before 100.5 15.7 129.3
patients with chronic tension-type headaches were treated with 5-HTP
After 108.3 18.4 140.4
(300 mg/day) or a placebo for 8 weeks.48 In comparison with the group
treated with a placebo, there were no statistically significant changes Controls (17 subjects)
in the number of days with headache or in headache intensity in the 96 21.3 359.3
group treated with 5-HTP; however, there was a significant decrease in
the consumption of analgesics.51 During the 2 weeks after treatment,
there was also a significant decrease in the number of days with head-
ache. Subjective opinion during this latter period was also favorable Overall, this study demonstrated very good effects in these chil-
to 5-HTP.  dren. Perhaps the most impressive aspect to consider, however, was
the fact that these benefits were achieved without side effects. Not a
Juvenile Headache single child reported a side effect while taking 5-HTP. Interestingly,
One of the best uses of 5-HTP is in chronic headaches in children. for some reason, children rarely experience even mild nausea from
These headaches are a big problem because of the tremendous risk 5-HTP.
for side effects of the current drugs used to treat, and prevent, them. The possible benefits of using 5-HTP in children with recurrent
Several studies of 5-HTP in the treatment of chronic headaches in chil- headaches or sleep disorders, or both, is far-reaching. Evaluation of the
dren and adolescents showed excellent results.52–54 Given the risks of 48 children in the trial demonstrated inadequate school progress com-
current drugs used in chronic childhood headaches, a trial of 5-HTP pared with their classmates. The children were shown to be of normal
for 2 months certainly seems reasonable. If the headaches are also intellectual capacity but demonstrated inattentiveness similar to that
accompanied by sleep disorders, 5-HTP appears to be especially well observed in depression. Many of the children might have had depres-
suited. sion. The unwillingness of the nine subjects in group C to switch to the
In one study, 48 elementary and junior high students with recurrent other unknown medication (which was the placebo) is a strong indi-
headaches (at least one headache every 2 weeks) and sleep disorders, cator that these children and their parents noted some rather dramatic
including difficulty in getting to sleep, frequent awakenings, sleep- improvements beyond simply a reduction in headaches or improved
walking, nightmares, and bedwetting, were divided into two groups.52 sleep.
Group A was given 5-HTP for 2 months, followed by a placebo for The manner in which 5-HTP may be of benefit in migraine head-
2 months, whereas group B received just the opposite. It was necessary aches may not simply be the overcoming of some defect in serotonin
to divide group A into a nine-patient subgroup, group C. These nine synthesis. As noted previously, part of the clinical benefit of 5-HTP
patients did so well on the 5-HTP that they did not want to switch over may be via an ability to increase the levels of β-endorphin. A decrease
to the other medication, although they had no idea whether they were, in β-endorphin levels in patients with migraine headaches, and tension
in fact, taking 5-HTP or were on a placebo. The dosage of 5-HTP was headaches, was demonstrated by several investigators.55,56
based on the child’s weight (4.5 mg/kg per day). A clinical trial measured the effects of 5-HTP on serotonin and
The headache index was reduced by about 70% when the kids β-endorphin levels in 20 juvenile patients with migraine or ten-
were taking 5-HTP compared with an 11.5% drop when they were sion-type headaches.57 Patients were monitored and evaluated for the
taking the placebo. In the nine patients in group C, there was an frequency and intensity of headache attacks for 3 months before 5-HTP
81.8% decrease in the headache index after the second month. treatment and during 3 months of therapy. The researchers reported
Interestingly, these same patients only exhibited an 18.2% reduc- a statistically significant reduction in the headache score with 5-HTP
tion after the first month. These results indicate that an evaluation treatment in both migraine and tension-type patients. These improve-
of the benefits of 5-HTP in the treatment of headaches requires at ments were likely a result of increased β-endorphin levels, as noted in
least a 2-month trial. The failure to show benefit with 5-HTP in Table 87.12. However, the level of β-endorphins achieved with 5-HTP,
some studies in headaches might be because of the fact that they especially as measured in the white blood cell, was still far less than
lasted less than 2 months. The 25 patients experienced a modest that observed in control patients without recurrent headaches. These
reduction in frequent awakenings, nightmares, sleepwalking, and results imply that longer periods of 5-HTP supplementation may
talking while asleep and no change in difficulty falling asleep or in be required before there is a normalization of β-endorphin levels in
bedwetting. children prone to headaches.
 CHAPTER 87  5-Hydroxytryptophan 667

TABLE 87.13  Patients’ and Physicians’ TABLE 87.14  Effect of 5-Hydroxytryptophan

Opinions on the Effectiveness of (5-HTP) on Depression in Parkinson’s Disease
5-Hydroxytryptophan (5-HTP) Versus Placebo HAM-D
in Fibromyalgia Patient l-Dopa Carbidopa 5-HTP
No. (mg/day) (mg/day) (mg/day) Before After
Response 5-HTP Placebo 1 1000 175 125 22 11
Good 11 1 2 300 75 75 14 3
Fair 8 5 3 400 150 100 21 13
Poor 4 8 4 1000 100 100 12 6
None 0 9 5 500 125 500 18 22
6 1125 112.5 300 18 7
7 500 50 100 17 13
These results may indicate that 5-HTP alone is not able to raise
β-endorphin levels sufficiently to reduce or eliminate headaches, sug- HAM-D, Hamilton Depression Rating Scale.
gesting that other therapies designed to increase β-endorphin levels
should be used along with 5-HTP. Examples of other therapies that rated their present pain at randomly selected times in the morning,
have been shown to raise β-endorphin levels are exercise, acupuncture, afternoon, and evening. The researchers found that a night of poor
and biofeedback.  sleep was followed by a significantly more painful day, and a more
painful day was followed by a night of even poorer sleep. 5-HTP might
Fibromyalgia help break the cycle by addressing the low serotonin level and by pro-
The history of the development of 5-HTP as an effective treatment moting restful sleep. 
for fibromyalgia began with studies on the drug fenclonine.58 This
drug blocks the enzyme that inhibits the conversion of tryptophan to Parkinson’s Disease
5-HTP and, as a result, blocks serotonin production. During the late The use of 5-HTP in Parkinson’s disease provides some benefit but
1960s and early 1970s, it was thought that increased serotonin forma- only if used in combination with the drug Sinemet (the combination
tion might promote migraine headaches (the opposite of what was of l-dopa with the decarboxylase inhibitor carbidopa). Although brain
later proved, i.e., increasing serotonin levels reduced the occurrence levels of serotonin are decreased in Parkinson’s disease, the reduction
of migraine headaches). The researchers discovered that providing in dopamine receptors is more severe. Increasing serotonin levels with
headache patients with fenclonine resulted in severe muscle pain. This 5-HTP in patients not taking Sinemet is associated with worsening of
effect was the exact opposite of what was expected, but it led to some symptoms, especially rigidity.65
important advances in the understanding of fibromyalgia—a way to One of the key benefits of taking 5-HTP in Parkinson’s disease
induce its severe symptoms of (and symptoms nearly identical to) is that it can help counteract the negative effects that the l-dopa in
eosinophilia myalgia syndrome (EMS), the condition caused by con- the Sinemet has on sleep and mood.66–68 In addition, 5-HTP was also
taminated l-tryptophan. The researchers also discovered that migraine shown to improve the physical symptoms of Parkinson’s disease.
patients had a greater reaction to the drug than nonheadache subjects. About 9 of 10 people with Parkinson’s disease have depression.
In most normal subjects, fenclonine produced no fibromyalgia. These The degree of depression in Parkinson’s disease is a reflection of
occurrences highlighted just how sensitive migraine patients are to low the individual’s serotonin levels. The lower the level of serotonin,
serotonin levels. the more severe is the individual’s depression. One study examined
Migraine headaches and fibromyalgia share a common feature: the effect of 5-HTP in seven patients with Parkinson’s disease, all of
both are low-serotonin syndromes.59 After more than 25 years of whom were on Sinemet.65 The initial dosage of 5-HTP was 75 mg,
research, one of the lead researchers stated: “In our experience, as well which was increased by 25 mg every 3 days until the patients reported
as in that of other pain specialists, 5-HTP can largely improve the pain- relief of their depression, or up to a maximum of 500 mg/day for 4
ful picture of primary fibromyalgia.”60 months. The impressive results obtained in these patients are shown
A double-blind study in 50 patients with fibromyalgia found that in Table 87.14.
100 mg of 5-HTP three times per day significantly improved their symp- Six of seven patients responded to 5-HTP. It should be noted that
toms.61 As shown in Table 87.13, 5-HTP was rated substantially better the doses of 5-HTP in five of the six patients who responded ranged
than placebo by subjects and evaluating physicians. Improvements from only 75 to 125 mg. The only patient who did not respond took
were noted in all symptom categories: number of painful areas, morn- 500 mg of 5-HTP. 
ing stiffness, sleep patterns, anxiety, and fatigue. In another study, 100
mg of 5-HTP taken three times a day demonstrated maximum results Seizure Disorders
by day 30 of the 90-day trial.62 Most of the recent research on 5-HTP focused on its use in the treat-
One of the primary benefits with 5-HTP in fibromyalgia may be its ment of several seizure disorders.69–74 5-HTP showed good results in
ability to improve sleep quality. A key finding in patients with fibro- most (but not all) studies in patients with diseases characterized by
myalgia is a reduced REM sleep and an increase in non-REM sleep.63 myoclonus, with the exception of epilepsy, which is not helped by
In addition, the deeper levels (stages III and IV) are not achieved for 5-HTP.
long enough periods. As a result, people with fibromyalgia wake up The best response to 5-HTP for myoclonus occurs in people
feeling fatigued and in pain. The severity of the pain of fibromyalgia who have intention myoclonus, which is most often produced as a
correlates with the rating of sleep quality. For example, a study of 50 result of ischemic damage to the brain. Intention myoclonus can
women with fibromyalgia syndrome recorded their sleep quality, pain be a problem after a stroke or heart attack, overdosage of a drug
intensity, and attention to pain for 30 days, using palm-top computers such as heroin, a severe asthma attack, or an adverse reaction to
programmed as electronic interviewers.64 They described their previ- anesthesia or another chemical. Improvements with 5-HTP were
ous night’s sleep quality within 30 minutes of awakening each day and demonstrated in patients with intention myoclonus. 5-HTP also
668 SECTION 4  Pharmacology of Natural Medicines
produced good results in patients with progressive myoclonus epi-
lepsy, essential myoclonus, palatal myoclonus, and Friedreich’s
ataxia.
In a 1983 article, one researcher of 5-HTP stated: “Some helpless
bedridden patients dramatically improved to the extent that they
could walk again and resume independent living.”74 Because of the
phenomenal results, 5-HTP was the first compound to be evaluated
as an orphan drug by the Pharmaceutical Manufacturing Associations
Commission on Drugs for Rare Diseases.  with EMS. It appeared that either the 5-HTP might have contained a
Irritable Bowel Syndrome and the “Leaky Gut”
Irritable bowel syndrome (IBS) is often accompanied by impaired
intestinal barrier function and “leaky gut” syndrome. Decreased sero-
tonergic function appears to play a part in the intestinal barrier dys-
function. In an interesting double-blind study, 15 patients with IBS
and 15 healthy volunteers ingested either 100 mg 5-HTP or a pla-
cebo.75 Oral 5-HTP administration significantly increased mucosal
levels of 5-HIAA in both healthy controls and patients with IBS, with
the latter group showing a significantly larger increase. Urinary lactu-
lose/L-rhamnose ratios were significantly lower after administration of
5-HTP in healthy controls and were accompanied by redistribution of
zonula occludens-1, pointing to reinforcement of the barrier. In IBS,
expression of the tight-junction proteins was significantly lower com-
pared with healthy controls, and 5-HTP resulted in a further decrease
in occludin expression. These results indicate that in healthy controls,
a reinforcement of the intestinal barrier was seen with 5-HTP intake,
whereas such reaction was absent in patients with IBS. This could
indicate the presence of a serotonin-mediated mechanism aimed to
reinforce the function of the intestinal barrier, which seems to be dys-
functional in patients with IBS.  the 5-HTP, the boys and the father were also evaluated. The older boy
DOSAGE
Enteric-coated preparations are required to avoid nausea. The dosage
should be started at 50 mg three times daily. If the response is inade-
quate after 2 weeks, increase the dosage to 100 mg three times daily.
This recommendation will greatly reduce the mild symptoms of nau-
sea often experienced during the first few weeks of 5-HTP therapy.
Because 5-HTP does not rely on the same transport vehicle as l-tryp-
tophan, it can also be taken with food. Because the half-life of 5-HTP
is relatively short (3–4 hours, with peak serum levels achieved at 1–2
hours), more frequent dosing may be more effective than single higher
doses.
For insomnia, the general recommendation is 100 to 300 mg, 30 to
45 minutes before retiring. Start with the lower dose for at least 3 days
before increasing the dose.  Drug Administration methodology. A minor chromatographic peak
TOXICOLOGY
The major concern with 5-HTP is a possible link to l-tryptophan and
EMS. However, an important distinction must be made in the manu-
facturing process. Although l-tryptophan is produced via bacterial fer-
mentation and filtration, 5-HTP is commercially available through an
extraction process from the seed of Griffonia simplicifolia, an African
plant. 5-HTP extracted from this natural source avoids the contami-
nation problem associated with past manufacturing of l-tryptophan.
Detailed analyses of all evidence by the Centers for Disease Control
and Prevention and other experts led to the conclusion that the cause
of the EMS epidemic could be traced to a single Japanese manufac-
turer, Showa Denko.76,77 Of the six Japanese companies that supplied
l-tryptophan to the United States, Showa Denko was the largest (50%–
60% of all the l-tryptophan). The l-tryptophan was used not only as a
nutritional supplement but also in infant formulas and nutrient mix-
tures for intravenous feeding.
A single case report linked 5-HTP to a condition like EMS in
1980.78 However, this case involved the use of high dosages of 5-HTP
(1400 mg) over a 20-month period. Further examination of the patient
indicated a defect in tryptophan metabolism that resulted in elevations
in kynurenine. Such defects in tryptophan metabolism are common
in patients with scleroderma, which shares many common features
contaminant to which this man was sensitive or that taking such high
doses of 5-HTP over a prolonged period of time aggravated his abnor-
mal handling of l-tryptophan.
There was also a report of a 28-year-old woman, her husband, and
her two sons, 33 and 13 months old, who developed an EMS-like ill-
ness in response to contaminated 5-HTP.76 The young boys inherited
the inability to convert tryptophan to 5-HTP. As a result, they required
daily administration of 5-HTP (5–7 mg/kg). Both boys received the
5-HTP almost from birth.
The mother was not taking 5-HTP, but she prepared it for the
young boys by opening the capsules, mixing the powder in juice or
water, and giving it to them orally with a syringe. She never took the
5-HTP; she only touched it with her hands as she emptied the capsules.
When the second boy was about 9 months old, the mother began
experiencing symptoms of EMS. After consulting a physician in July
1991, it was noted that her eosinophil count was well over 30%. She
continued to worsen and was hospitalized in August 1991 with a ten-
tative diagnosis of EMS. At this time, she was referred to the National
Institutes of Health for further evaluation.
Because of the possible link between the mother’s symptoms and
had an eosinophil count of 9% (normal is 1%–4%), and the younger
boy had a count of 6%. The father had no abnormalities.
The 5-HTP that the boys used was analyzed by high-pressure liq-
uid chromatography and found to contain an impurity not found in
the 5-HTP that the National Institutes of Health used in its studies
for ataxia and myoclonus. Switching the boys to the contaminant-free
5-HTP brought about a normalization of the eosinophil counts.
The mother’s case was interesting because she was the most severely
affected, and skin exposure was the only contact with the contami-
nated 5-HTP.
In 1998, researchers at the Mayo Clinic identified trace levels of a
compound termed “peak X” as the key contaminant using a sensitive
laboratory technique.79 As a result, manufacturers of 5-HTP now screen
for the presence of this compound to ensure that all of the 5-HTP on
the marketplace is free from peak X as outlined in current Food and
(peak X) reported in some 5-HTP samples lacks credibility because
of chromatographic artifacts and infinitesimal concentrations and
has raised undue speculations concerning its chemistry and toxic-
ity. It might also be a moot point because extensive analyses of sev-
eral sources of 5-HTP showed no toxic contaminants similar to those
associated with l-tryptophan, nor the presence of any other significant
impurities.80
There have been no reports of a single person developing EMS from
5-HTP despite its popularity over the past 20 years. Nonetheless, to be
on the safe side, some experts recommend that long-term continual
use of 5-HTP be monitored by regular (every 6 months) eosinophil
determination.
Evidence that uncontaminated 5-HTP does not cause EMS is also
provided by researchers who have been using 5-HTP for more than 25
years. They state: “EMS has never appeared in the patients of ours who
received only uncontaminated l-tryptophan or 5-hydroxytryptophan

(5-HTP).”81 Furthermore, researchers at the National Institutes of
Health studying the effects of uncontaminated 5-HTP on various met-
abolic conditions have not observed a single case of EMS, nor has a
case of elevated eosinophils been attributed to 5-HTP in these stud-
ies.82 In short, there has never been a report of uncontaminated 5-HTP
causing EMS.
Although there has never been a single person developing EMS
from 5-HTP products proven to be free from the contaminants, long-
term continual use of 5-HTP should be monitored by regular (every 6
months) eosinophil determination. For any person with scleroderma
resulting from the problem with tryptophan metabolism noted in
these patients, an eosinophil determination after the first month of
5-HTP use is indicated, especially if dosages are greater than 500 mg/
day. In addition is the following advice:
• Do not use 5-HTP during pregnancy or lactation.
• Do not use 5-HTP in Parkinson’s disease unless the patient is on
Sinemet.
• Do not use 5-HTP in patients with scleroderma.  100 mg and 45.5% at 300 mg 5-HTP.80
DRUG INTERACTIONS
Because 5-HTP is the direct precursor to serotonin, it should not be
used by individuals taking antidepressant drugs without close medical
CHAPTER 87  5-Hydroxytryptophan 669
supervision. Although 5-HTP has been used safely in combination
with prescription antidepressant drugs in clinical studies, taking this
combination could result in too much serotonin in the body. The
result is a condition known as the “serotonin syndrome,” characterized
by confusion, fever, shivering, sweating, diarrhea, and muscle spasms.
5-HTP may antagonize the effects of drugs used in migraine head-
aches like methysergide and cyproheptadine, which block serotonin
effects.
The drug carbidopa greatly enhances the half-life and produces an
apparent clearance at least 14 times smaller, and an area under the curve
that is 15.4 times greater, compared with 5-HTP 100 mg given with-
out carbidopa.83 By combining 5-HTP with carbidopa, increased bio-
availability for brain penetration and decreased peripheral side effects
would be expected because of reduced peripheral decarboxylation of
5-HTP to serotonin. However, in a double-blind study in healthy male
volunteers, nausea and vomiting occurred dose-dependently as the
most frequent side effects, resulting in dose-related dropout of 6.6% at
REFERENCES
See www.expertconsult.com for a complete list of references.
REFERENCES
1. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementa-
tion with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther.
2006;109:325–338.
2. Filippini GA, Costa CVL, Bertazzo A, eds. Recent Advances in Tryptophan
Research, Tryptophan and Serotonin Pathways. New York, NY: Plenum;
1996.
3. Magnussen IE, Nielsen-Kudsk FL. Bioavailability and related pharmacoki-
netics in man of orally administered L-5-hydroxytryptophan in steady state.
Acta Pharmacol Toxicol (Copenh). 1980;46:257–262.
4. Magnussen I, Jensen TS, Rand JH, et al. Plasma accumulation of metab-
olism of orally administered single dose L-5-hydroxytryptophan in man.
Acta Pharmacol Toxicol. 1981;49:184–189.
5. Van Praag HM, Lemus C. Monoamine precursors in the treatment of
psychiatric disorders. In: Wurtman RJ, Wurtman JJ, eds. Nutrition and the
Brain. Vol. 7. New York: Raven Press; 1977:89–139.
6. Van Praag HM. Studies on the mechanism of action of serotonin precursors
in depression. Psychopharmacol Bull. 1984;20:599–602.
7. Das YT, Bagchi M, Bagchi D, et al. Safety of 5-hydroxy-L-tryptophan. Toxi-
col Lett. 2004;150:111–122.
8. Aviram M, Cogan U, Mokady S. Excessive dietary tryptophan enhances
plasma lipid peroxidation in rats. Atherosclerosis. 1991;88:29–43.
9. Simic MG, al-Sheikhly M, Jovanovic SV. Inhibition of free radical processes
by antioxidants—tryptophan and 5-hydroxytryptophan. Bibl Nutr Dieta.
1989;43:288–289.
10. Sano I. L-5-hydroxytryptophan-(L-5-HTP) therapy. Folia Psychiatr Neurol
Japan. 1972;26:7–17. [Japanese].
11. Takahashi S, Kondo H, Kato N. Effect of L-5-hydroxytryptophan on brain
monoamine metabolism and evaluation of its clinical effect in depressed
patients. J Psychiatr Res. 1975;12:177–187.
12. Fujiwara J, Otsuki S. Subtype of affective psychosis classified by response on
amine precursors and monoamine metabolism. J Oral Pathol. 1973;2:93–
100.
13. Nakajima T, Kudo Y, Kaneko Z. Clinical evaluation of 5-hydroxy-L-tryp-
tophan as an antidepressant drug. Folia Psychiatr Neurol Jpn. 1978;32:223–
230.
14. Kaneko M, Kumashiro H, Takahashi Y, et al. L-5-HTP treatment and
serum 5-HTP level after L-5-HTP loading on depressed patients. Neuropsy-
chobiology. 1979;5:232–240.
15. van Praag HM, Korf J, Dols LC, et al. A pilot study of the predictive value
of the probenecid test in application of 5-hydroxytryptophan as antidepres-
sant. Psychopharmacologia. 1972;25:14–21.
16. van Praag HM. Management of depression with serotonin precursors. Biol
Psychiatry. 1981;16:291–310.
17. Robie TR, Flora A. Anti-depressant chemotherapy, 1965. Rapid response to
serotonin precursor potentiated by Ritalin. Psychosomatics. 1965;6:351–354.
18. Nardini M, De Stefano R, Iannuccelli 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.
19. Rousseau JJ. Effects of a levo-5-hydroxytryptophan-dihydroergocristine
combination on depression and neuropsychic performance. A double-blind
placebo-controlled clinical trial in elderly patients. Clin Ther. 1987;9:267–
272.
20. Mendlewicz J, Youdim MB. Antidepressant potentiation of 5-hydroxytryp-
tophan by L-deprenil in affective illness. J Affect Disord. 1980;2:137–146.
21. Alino JJ, Gutierrez JL, Iglesias ML. 5-Hydroxytryptophan (5-HTP) and a
MAOI (nialamide) in the treatment of depressions. A double-blind con-
trolled study. Int Pharmacopsychiatry. 1976;11:8–15.
22. Angst J, Woggon B, Schoepf J. The treatment of depression with L-5-hy-
droxytryptophan versus imipramine. Results of two open and one dou-
ble-blind study. Arch Psychiatr Nervenkr. 1977;224:175–186.
23. Van Praag HM, Korf J. 5-Hydroxytryptophan as an antidepressant. The
predictive value of the probenecid test. J Nerv Ment Dis. 1974;158:331–337.
24. Van Praag HM, Korf J. Serotonin metabolism in depression: clinical appli-
cation of the probenecid test. Int Pharmacopsychiatry. 1974;9:35–51.
25. Van Praag HM. Central monoamine metabolism in depressions. I. Sero-
tonin and related compounds. Compr Psychiatry. 1980;21:30–43.
26. Van Hiele JJ. L-5-hydroxytryptophan in depression. The first substitution
therapy in psychiatry? Neuropsychobiology. 1980;6:230–240.
27. Kielholz P. Treatment for therapy-resistant depression. Psychopathology.
1986;19:194–200.
28. Kious BM, Sabic H, Sung YH, Kondo DG, Renshaw P. An open-label
pilot study of combined augmentation with creatine monohydrate and
5-hydroxytryptophan for selective serotonin reuptake inhibitor- or
serotonin-norepinephrine reuptake inhibitor-resistant depression in adult
women. J Clin Psychopharmacol. 2017;37(5):578–583.
29. Byerley WF, Judd LL, Reimherr FW, et al. 5-Hydroxytryptophan. A review
of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol.
1987;7:127–137.
30. Poldinger W, Calanchini B, Schwarz W. 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.
31. Jangid P, Malik P, Singh P, Sharma M, Gulia AK. Comparative study of ef-
ficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with
first depressive episode. Asian J Psychiatr. 2013;6(1):29–34.
32. Schruers K, van Diest R, Overbeek T, et al. Acute L-5-hydroxytryptophan
administration inhibits carbon dioxide-induced panic in panic disorder
patients. Psychiatry Res. 2002;113:237–243.
33. Weltzin TE, Fernstrom MH, Kaye WH. Serotonin and bulimia nervosa.
Nutr Rev. 1994;52:399–408.
34. Weltzin TE, Fernstrom MH, Fernstrom JD, et al. Acute tryptophan deple-
tion and increased food intake and irritability in bulimia nervosa. Am J
Psychiatry. 1995;152:1668–1671.
35. Goodwin GM, Cowen PJ, Fairburn CG, et al. Plasma concentrations of
tryptophan and dieting. BMJ. 1990;300:1499–1500.
36. Blundel JE, Leshem MB. The effect of 5-HTP on food intake and on the
anorexic action of amphetamine and fenfluramine. J Pharm Pharmacol.
1975;27:31–37.
37. Ceci F, Cangiano C, Cairella M, et al. The effects of oral 5-hydroxytrypto-
phan administration on feeding behavior in obese adult female subjects.
J Neural Transm. 1989;76:109–117.
38. Cangiano C, Ceci F, Cairella M, et al. Effects of 5-hydroxytryptophan on
eating behavior and adherence to dietary prescriptions in obese adult sub-
jects. Adv Exp Med Biol. 1991;294:591–593.
39. Cangiano C, Ceci F, Cascino A, et al. Eating behavior and adherence to
dietary prescriptions in obese adult subjects treated with 5-hydroxytrypto-
phan. Am J Clin Nutr. 1992;56:863–867.
40. Cangiano C, Laviano A, Del Ben M, et al. Effects of oral 5-hydroxy-tryptophan
on energy intake and macronutrient selection in non-insulin dependent diabetic
patients. Int J Obes Relat Metab Disord. 1998;22:648–654.
41. Guilleminault C, Cathala HP, Castaigne P. Effects of 5-HTP on sleep of
a patient with brain stem lesion. Electroencephalog Clin Neurophysiol.
1973;34:177–184.
42. Wyatt RJ, Zarcone J, Engelman K. Effects of 5-hydroxytryptophan on the
sleep of normal human subjects. Electroencephalogr Clin Neurophysiol.
1971;30:505–509.
43. Autret A, Minz M, Bussel B, et al. Human sleep and 5-HTP. Effects of
repeated high doses and of association with benserazide. Electroencephalogr
Clin Neurophysiol. 1976;41:408–413.
44. Zarcone Jr VP, Hoddes E. Effects of 5-hydroxytryptophan on fragmentation
of REM sleep in alcoholics. Am J Psychiatry. 1975;132:74–76.
45. Soulairac A, Lambinet H. Effect of 5-hydroxytryptophan, a serotonin
precursor, on sleep disorders. Ann Med Psychol (Paris). 1977;1:792–798.
[French].
46. Sicuteri F. Hypothesis: migraine, a central biochemical dysnociception.
Headache. 1976;16:145–149.
47. Bruni O, Ferri R, Miano S, et al. L-5-Hydroxytryptophan treatment of sleep
terrors in children. Eur J Pediatr. 2004;163:402–407.
48. Titus F, Davalos A, Alom J, et al. 5-Hydroxytryptophan versus methy-
sergide in the prophylaxis of migraine. Randomized clinical trial. Eur
Neurol. 1986;25:327–329.
669.e1
669.e2 References
49. Bono G, Criscuoli M, Martignoni E, et al. Serotonin precursors in migraine
prophylaxis. Adv Neurol. 1982;33:357–363.
50. Maissen CP, Ludin HP. Comparison of the effect of 5-hydroxytryptophan
and propranolol in the interval treatment of migraine. Schweiz Med Wo-
chenschr. 1991;121:1585–1590. [German].
51. Ribeiro CA. L-5-Hydroxytryptophan in the prophylaxis of chronic ten-
sion-type headache: a double-blind, randomized, placebo-controlled study.
For the Portuguese Head Society. Headache. 2000;40:451–456.
52. De Giorgis G, Miletto R, Iannuccelli M, et al. Headache in association with
sleep disorders in children. A psychodiagnostic evaluation and controlled
clinical study—L-5-HTP versus placebo. Drugs Exp Clin Res. 1987;13:425–433.
53. Santucci M, Cortelli P, Rossi PG, et al. L-5-hydroxytryptophan versus
placebo in childhood migraine prophylaxis: a double-blind crossover study.
Cephalalgia. 1986;6:155–157.
54. Longo G, Rudoi I, Iannuccelli M. Treatment of essential headache in
developmental age with L-5-HTP (cross over double-blind study versus
placebo). Pediatr Med Chir. 1984;6:241–245. [Italian].
55. Fettes, Gawel M, Kuzniak S. Endorphin levels in headache syndromes.
Headache. 1985;25:37–39.
56. Leone M, Sacerdote P, D’Amico, et al. Beta-endorphin levels are reduced
in peripheral mononuclear cells of cluster headache patients. Cephalalgia.
1993;13:413–416.
57. Battistella PA, Bordin A, Cernetti R, et al. Beta-endorphin in plasma and
monocytes in juvenile headache. Headache. 1996;36:91–94.
58. Sicuteri F. The ingestion of serotonin precursors (L-5-hydroxytryptophan
and L-tryptophan) improves migraine. Headache. 1973;13:19–22.
59. Nicolodi M, Sicuteri F. Fibromyalgia and migraine, two faces of the same
mechanism. Serotonin as the common clue for pathogenesis and therapy.
Adv Exp Med Biol. 1996;398:373–379.
60. Nicolodi M, Sicuteri F. Eosinophilia myalgia syndrome. The role of contaminants,
the role of serotonergic metabolism set up. Adv Exp Med Biol. 1996;398:351–357.
61. Caruso I, Sarzi Puttini P, Cazzola M, et al. Double-blind study of 5-hy-
droxytryptophan versus placebo in the treatment of primary fibromyalgia
syndrome. J Int Med Res. 1990;18:201–209.
62. Puttini PS, Caruso I. Primary fibromyalgia syndrome and 5-hy-
droxy-L-tryptophan: 90-day open study. J Int Med Res. 1992;20:182–189.
63. White KP, Harth M. An analytical review of 24 controlled clinical trials for
fibromyalgia syndrome (FMS). Pain. 1996;64:211–219.
64. Affleck G, Urrows S, Tennen H, et al. Sequential daily relations of sleep,
pain intensity, and attention to pain among women with fibromyalgia.
Pain. 1996;68:363–368.
65. Chase TN, Ng LK, Watanabe AM. Parkinson’s disease. Modification by
5-hydroxytryptophan. Neurology. 1972;22:479–484.
66. Mayeux R, Stern Y, Sano M, et al. The relationship of serotonin to depres-
sion in Parkinson’s disease. Mov Disord. 1988;3:237–244.
67. Bastard J, Truelle JL, Emile J. Effectiveness of 5 hydroxytryptophan in
Parkinson’s disease. Nouv Presse Med. 1976;5:1836–1837. [French].
68. Sano I, Taniguchi K. L-5-hydroxytryptophan (L-5-HTP) therapy of Parkin-
son’s disease. Munch Med Wochenschr. 1972;114:1717–1719. [German].
69. Pranzatelli MR, Tate E, Galvan I, et al. A controlled trial of 5-hy-
droxy-L-tryptophan for ataxia in progressive myoclonus epilepsy. Clin
Neurol Neurosurg. 1996;98:161–164.
70. Trouillas P, Serratrice G, Laplane D, et al. Levorotatory form of 5-hydroxy-
tryptophan in Friedreich’s ataxia. Results of a double-blind drug-placebo
cooperative study. Arch Neurol. 1995;52:456–460.
71. Wessel K, Hermsdorfer J, Deger K, et al. Double-blind crossover study
with levorotatory form of hydroxytryptophan in patients with degenerative
cerebellar diseases. Arch Neurol. 1995;52:451–455.
72. Pranzatelli MR, Tate E, Huang Y, et al. Neuropharmacology of progres-
sive myoclonus epilepsy. Response to 5-hydroxy-L-tryptophan. Epilepsia.
1995;36:783–791.
73. Trouillas P, Brudon F, Adeleine P. Improvement of cerebellar ataxia with
levorotatory form of 5-hydroxytryptophan. Arch Neurol. 1988;45:1217–1222.
74. Van Woert MH. Myoclonus and L-5-hydroxytryptophan (L-5-HTP). Prog
Clin Biol Res. 1983;127:43–52.
75. Keszthelyi D, Troost FJ, Jonkers DM, et al. Serotonergic reinforcement of
intestinal barrier function is impaired in irritable bowel syndrome. Aliment
Pharmacol Ther. 2014 August;40(4):392–402.
76. Kilbourne EM. Eosinophilia-myalgia syndrome: coming to grips with a new
illness. Epidemiologic Rev. 1992;14:16–36.
77. Kilbourne EM, Philen RM, Kamb ML. Tryptophan produced by Showa Denko
and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl. 1996;46:81–88.
78. Sternberg EM, Van Woert MH, Young SN, et al. Development of a
scleroderma-like illness during therapy with L-5-hydroxytryptophan and
carbidopa. N Engl J Med. 1980;303:782–787.
79. Klarskov K, Johnson KL, Benson LM, et al. Eosinophilia-myalgia syndrome
case-associated contaminants in commercially available 5-hydroxytrypto-
phan. Adv Exp Med Biol. 1999;467:461–468.
80. Smarius LJ, Jacobs GE, Hoeberechts-Lefrandt DH, et al. Pharmacology of
rising oral doses of 5-hydroxytryptophan with carbidopa. J Psychopharma-
col. 2008;22:426–433.
81. Nicolodi M, Sicuteri F. Eosinophilia myalgia syndrome. The role of con-
taminants, the role of serotonergic metabolism set up. Adv Exp Med Biol.
1996;398:351–357.
82. Michelson D, Page SW, Casey R, et al. An eosinophilia-myalgia syndrome
related disorder associated with exposure to L-5-hydroxytryptophan.
J Rheumatol. 1994;21:2261–2265.
83. Gijsman HJ, van Gerven JM, de Kam ML, et al. Placebo-controlled com-
parison of three dose-regimens of 5-hydroxytryptophan challenge test in
healthy volunteers. J Clin Psychopharmacol. 2002;22:183–189.