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5-Hydroxytryptophan: A Clinically-Effective Serotonin Precursor

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5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behaviour, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.
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Alternative Medicine Review
Volume 3, Number 4 1998 Page 271
5-Hydroxytryptophan: A Clinically-Effective
Serotonin Precursor
by Timothy C. Birdsall, N.D.
5-Hydroxytryptophan (5- HTP) is the intermediate metabolite of the essential
amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of
5-HTP does not require the presence of a transport molecule, and is not affected by the
presence of other amino acids; therefore it may be taken with meals without reducing
its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production.
Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme
tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-
HTP is well absorbed from an oral dose, with about 70 percent ending up in the
bloodstream. It easily crosses the blood-brain barrier and effectively increases central
nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been
implicated in the regulation of sleep, depression, anxiety, aggression, appetite,
temperature, sexual behavior, and pain sensation. Therapeutic administration of 5-HTP
has been shown to be effective in treating a wide variety of conditions, including
depression, fibromyalgia, insomnia, binge eating associated with obesity, chronic
headaches, and insomnia.
Altern Med Rev
5-Hydroxytryptophan (5-HTP) (see Figure 1) is an aromatic amino acid naturally pro-
duced by the body from the essential amino acid L-tryptophan (LT). Produced commercially by
extraction from the seeds of the African plant, Griffonia simplicifolia, 5-HTP has been used
clinically for over 30 years. The clinical efficacy of 5-HTP is due to its ability to increase
production of serotonin in the brain.
Metabolism of Tryptophan and Serotonin
Serotonin (5-hydroxytryptamine), dopamine, and norepinephrine are the three main
“monoamine” neurotransmitters, each produced endogenously from one specific amino acid.
Tryptophan is converted into serotonin, while dopamine and norepinephrine are made from
tyrosine. In the central nervous system (CNS), serotonin has been implicated in regulation of
sleep, depression, anxiety, aggression, appetite, temperature, sexual behavior, and pain sensa-
Timothy C. Birdsall, N.D.
Correspondence address: e-mail: or
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Page 272 Alternative Medicine Review
Volume 3, Number 4 1998
While other cells outside the brain,
such as blood platelets and some enterocytes,
make and/or use serotonin, all serotonin used
by brain cells must be made within the neu-
rons, since serotonin cannot cross the blood-
brain barrier. Therefore, the synthesis of sero-
tonin is heavily dependent upon the availabil-
ity of LT within the CNS. The production and
subsequent transport of LT from the blood-
stream into the CNS can be compromised by
several factors:
1) Stress, elevated cortisol levels, vi-
tamin B6 deficiency, and even high dosages
(above 2,000 mg) of LT, which all stimulate
the conversion of LT to kynurenine, lowering
serum LT levels.
(See Figure 2)
2) Elevated serum levels of kynurenine
inhibit transport of LT into the CNS, and re-
duce CNS serotonin levels.
3) Transport of LT across the blood-
brain barrier requires binding to a transport
molecule, which LT shares with five other
amino acids (tyrosine, phenylalanine, valine,
leucine and isoleucine). Since LT is present in
foods in relatively small amounts in
comparison to these other amino acids, as little
as one percent of dietary LT
may be transported into the
4) LT is used by the
body for other metabolic
purposes in addition to se-
rotonin production, includ-
ing protein synthesis and the
creation of niacin.
Biochemistry and
Metabolism of 5-HTP
5- HTP is the interme-
diate metabolite of LT in the
production of serotonin (see
Figure 2). Therapeutic use
of 5-HTP bypasses the con-
version of LT into 5-HTP by
the enzyme tryptophan hy-
droxylase, which is the rate-limiting step in
the synthesis of serotonin. Tryptophan hy-
droxylase can be inhibited by numerous fac-
tors, including stress, insulin resistance, vita-
min B6 deficiency, and insufficient magne-
sium. In addition, these same factors can in-
crease the conversion of LT to kynurenine via
tryptophan 2,3-dioxygenase, making LT un-
available for serotonin production.
5-HTP is well absorbed from an oral
dose, with about 70 percent ending up in the
Absorption of 5-HTP is not af-
fected by the presence of other amino acids;
therefore, it may be taken with meals without
reducing its effectiveness. Unlike LT, 5-HTP
cannot be shunted into niacin or protein pro-
Serotonin levels in the brain are highly
dependent on levels of 5-HTP and LT in the
central nervous system (CNS). 5-HTP easily
crosses the blood-brain barrier, not requiring
the presence of a transport molecule. LT, on
the other hand, requires use of a transport
molecule to gain access to the CNS. Since LT
shares this transport molecule with several
other amino acids, the presence of these
3- Hydroxyanthranilic acid
carboxymuconic aldehyde intermediate
Xanthurenic acid
Picolinic acid Quinolinic acid
Nicotinic acid (Niacin)
Figure 1. Tryptophan metabolism
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Alternative Medicine Review
Volume 3, Number 4 1998 Page 273
competing amino acids can inhibit LT transport
into the brain.
Mechanisms of Action
5-HTP acts primarily by increasing
levels of serotonin within the central nervous
system. Other neurotransmitters and CNS
chemicals, such as melatonin, dopamine, nor-
epinephrine, and beta-endorphin have also
been shown to increase following oral admin-
istration of 5-HTP.
This ability to increase
not only serotonin levels in the brain, but also
dopamine and norepinephrine, allows 5-HTP
to produce some significant and unique effects
on brain chemistry and on serotonin-related
conditions which other substances, including
LT, cannot duplicate.
Clinical Studies Using 5-HTP
Depression: Much of the published re-
search on 5-HTP has to do with its use in the
treatment of depression. Since the early 1970s,
at least 15 studies have evaluated the clinical
effects of 5-HTP on depression .
These are
summarized in Table 1. Taken together, these
studies examined a total of 511 patients with
different types of depression. Of these 511
subjects, 285 (56%) showed significant im-
provement while taking 5-HTP.
In addition, biochemical studies show
5-HTP is closely involved in depressive
disorders. In a study employing positron-
emission tomography (PET) scanning, eight
healthy volunteers and six people diagnosed
with major depression received infusions of
radiolabelled 5-HTP. The researchers found
significantly less 5-HTP crossed the blood-
brain barrier into the brains of the depressed
subjects than into the brains of the normal
controls. The authors suggested the transport
of 5-HTP across the blood-brain barrier may
be compromised in major depression,
might make the brain dependent on LT to 5-
HTP conversion in the brain.
Some concern has arisen regarding
whether 5-HTP should be used only in con-
junction with a peripheral decarboxylase in-
hibitor (PDI) such as carbidopa. The argument
is essentially that without a PDI, 5-HTP will
be converted into serotonin in the peripheral
circulation, negating any potential CNS bene-
fit from 5-HTP.
However, this argument
ignores scores of clinical studies in which 5-
HTP was given alone and in which significant
clinical benefit was seen, with no significant
adverse effects.
The first large clinical trial using 5-
HTP in depression was conducted by Sano in
1972. Using an open trial design, a total of
107 patients with endogenous unipolar or bi-
polar depression were given daily oral dosages
of 5-HTP from 50 to 300 mg. Significant im-
provement was observed in 74 of the patients
(69%), and no significant side effects were re-
ported. The response rate in most of these pa-
tients was quite rapid (less than two weeks).
The issue of speed of response was
subsequently addressed in a study of 59 pa-
tients with eight different types of depression.
5-HTP was administered orally in dosages
from 150 to 300 mg daily for a period of three
weeks. Thirteen patients (22%) were markedly
improved, and another 27 patients (45.8%)
showed moderate improvement. Of these 40
patients who improved, 20 (50%) began to
show improvement within three days, and 32
patients (80%) improved within two weeks of
beginning treatment with 5-HTP.
In contrast
to many conventional antidepressants which
may take 4 weeks or longer to achieve thera-
peutic response in most patients, those taking
5-HTP appear to have a significantly more
rapid response.
Japanese researchers administered 5-
HTP to 24 patients hospitalized for depression.
After two weeks of treatment, a “marked
amelioration of depressive symptoms” was
observed in seven patients diagnosed with
unipolar depression. The administration of
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Page 274 Alternative Medicine Review
Volume 3, Number 4 1998
Table 1. Clinical trials of 5-HTP use in depression
Reference Number Diagnosis Study Design 5-HTP Duration of Results
of Patients Dosage treatment
(mg/day) (days)
107 Endogenous depression Open Trial 50-300 7-35 74/107 markedly improved
20 Endogenous depression Open Trial 50-200 7-28 10/20 markedly improved
23 Unipolar depression (13); Open Trial 100-300 4-20 7/23 markedly improved
bipolar depression (1);
involutional depression (8);
schizoaffective depression (1)
24 Unipolar depression (20); Open Trial 300 14 7/20 in the unipolar group
involutional depression (2); markedly improved
neurotic depression (1);
psychotic depression (1)
59 Mixed group; 8 different Open Trial 150-300 21+ 13/59 markedly improved;
types of depression 27/59 moderately improved
van Hiele
99 Endogenous depression (44); Open Trial 50-600 a 14+ 37/68 in the endogenous
depression with endogenous group and 6/31 in the personal
features (24); personal group markedly improved
depression (31)
18 Endogenous depression Open Trial 150-300 10-28 10/18 markedly improved
van Praag
5 Endogenous depression Double-blind; 200-3,000 21 3/5 markedly improved
(unipolar and bipolar) 5-HTP vs. placebo
7 Psychotic depression (6); Double-blind; 250-3,250 1-15 1/7 moderately improved
schizoaffective psychosis (1) 5-HTP vs. placebo
25 Melancholia (4); involutional Double-blind; 200-800 10-240 19/25 improved
depression (7); reactive 5-HTP vs. placebo
depression (8); neurotic
depression (6)
14 Endogenous depression Double-blind; 50-300 15-20 12/15 markedly improved
5-HTP vs. nialamide
van Praag
20 Endogenous depression Double-blind; 200
21 11/20 markedly improved; 5-HTP
(unipolar and bipolar) 5-HTP vs. clomipramine and clomipramine equally effective
vs. placebo
van Praag
15 Endogenous depression Double-blind; 200
28 8/15 markedly improved; 5-HTP
(unipolar and bipolar) 5-HTP vs. tryptophan more effective than tryptophan
vs. placebo or plaecbo
39 Bipolar (24); unipolar(15) Double-blind; 300
32 13/21 responded to 5-HTP alone
5-HTP vs. 5-HTP
+deprenyl vs. placebo
36 Endogenous depression (10); Double blind; 300 42 27/36 improved
reactive depression (16); 5-HTP vs. fluvoxamine
situational depression (9);
involutional depression (1);
Total 511 285/511 improved
Total — Double 161 94/161 improved
blind studies
Adapted from van Praag and Lemus.
5-HTP was given in combination with a peripheral decarboxylase inhibitor.
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Alternative Medicine Review
Volume 3, Number 4 1998 Page 275
5-HTP was also associated with a 30 percent
increase in the levels of 5-hydroxyindolacetic
acid, the primary metabolite of serotonin, in
the patients’ cerebrospinal fluid. This
suggested the exogenous 5-HTP was being
converted to serotonin within the CNS.
5-HTP vs. Conventional Anti-depres-
sants: The current conventional therapies of
choice for depression are the selective seroto-
nin reuptake inhibitors (SSRIs). A 1991 Swiss
study evaluated 5-HTP in comparison to an
SSRI drug in a double-blind, multicenter study
design. A total of 36 subjects, all of whom were
diagnosed with some form of depression, re-
ceived either 100 mg of 5-HTP three times per
day, or 150 mg of fluvoxamine (an SSRI) three
times daily. The subjects were evaluated at 0,
2, 4, and 6 weeks, using four evaluation tools:
the Hamilton Rating Scale for Depression
(HRSD), a standard depression rating scale; a
patient-performed self-assessment; the
investigators assessment of severity; and a
global clinical impression.
Both treatment groups showed signifi-
cant and nearly equal reductions in depression
beginning at week two and continuing through
week six. After four weeks, 15 of the 36 pa-
tients treated with 5-HTP, and 18 of the 33
patients treated with fluvoxamine had im-
proved by at least 50 percent, according to the
HRSD scores. By week six, the two groups
had about equal numbers showing 50 percent
improvement. When the numbers were totaled
at the end of the study, the researchers found
the mean percentage improvement from
baseline to the final assessment was slightly
greater for patients treated with 5-HTP. The
number of treatment failures was higher in the
fluvoxamine group (5/29, 17%) than in the 5-
HTP group (2/34, 6%), although neither of
these differences were statistically significant.
All four evaluation tools yielded similar re-
The study also looked at the incidence
of adverse effects from both treatments, which
were found to be rare and generally mild,
usually occurring during the first few days of
treatment and then disappearing. Overall, 5-
HTP appeared to be slightly better tolerated
than fluvoxamine, although the results did not
reach the level of statistical significance.
Tolerance was assessed as being “good to very
good” in 34/36 patients receiving 5-HTP
(94.5%), compared to 28/33 in the
fluvoxamine group (84.8%).
5-HTP has also been compared in a few
studies with conventional tricyclic antidepres-
sants (chloripramine and imipramine) - the
most effective drugs for treating depression
until the development of the SSRIs. The stud-
ies found 5-HTP to be at least as effective as
these drugs in treating severe depression, while
displaying fewer side effects. In severe cases,
5-HTP dosages as high as 1200 mg daily were
Fibromyalgia: Primary fibromyalgia
syndrome is characterized by general musculo-
skeletal aching, multiple tender points, fatigue,
morning stiffness, and sleep disturbances.
Fibromyalgia patients have been found to have
low serotonin
and tryptophan
and some studies have shown symptomatic
improvement with the use of tricyclic and
SSRI antidepressants.
These findings sug-
gest 5-HTP might be useful in the treatment
of fibromyalgia, and three clinical trials have
demonstrated significant improvement in
symptoms, including pain, morning stiffness,
anxiety, and fatigue.
Caruso et al conducted a double-blind,
placebo-controlled study in 50 fibromyalgia
patients, administering 100 mg of 5-HTP three
times daily for a period of 30 days. Signifi-
cant improvements were seen in number of
tender points (p<0.001), subjective pain sever-
ity (p<0.001), morning stiffness (p=0.017),
sleep patterns (p<0.001), anxiety ratings
(p<0.001), and fatigue ratings (p=0.003). The
incidence of side effects in the 5-HTP group
was low (6/25 patients), and no significant
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Page 276 Alternative Medicine Review
Volume 3, Number 4 1998
laboratory abnormalities were reported during
the study.
In a longer-term study, a total of 50
patients diagnosed with primary fibromyalgia
syndrome were given 100 mg 5-HTP three
times per day for 90 days in an open study.
Patients were assessed at the beginning of the
study and after 15, 30, 60, and 90 days of treat-
ment. The clinical variables evaluated in-
cluded: total number of tender points, pain
intensity, sleep quality, morning stiffness, anxi-
ety, and fatigue. All of these measures showed
significant improvement throughout the length
of the study (p<0.001). A total of 15 patients
(30%) reported side effects from the 5-HTP,
but in only one case were they severe enough
for the patient to be withdrawn from the
In a randomized, placebo-controlled
study of 200 fibromyalgia patients who were
also migraine sufferers, 5-HTP (400 mg/day)
was compared to a tricyclic drug (amitrip-
tyline) and a monoamine oxidase inhibitor
(MAOI) drug (pargilyne or phenelzine). The
combination of 5-HTP (200 mg/day) with an
MAOI was also evaluated. Patients were
treated for a total of 12 months and kept a daily
pain diary by means of a visual analogic scale.
At the end of the twelve-month trial period,
all treatment regimens showed significant im-
provement over placebo (p<0.0001), although
the combination of 5-HTP with the MAOI was
the most effective. 5-HTP alone was as effec-
tive as the tricyclic or MAOI drugs. No pa-
tients withdrew from the study due to side ef-
fects; eight percent of the patients taking 5-
HTP alone reported some degree of stomach
Obesity: During dieting, serum
tryptophan levels and CNS serotonin levels
drop dramatically.
These low serotonin
levels in obese patients have been associated
with carbohydrate cravings and resultant binge
eating. It has been theorized that 5-HTP can
help prevent this dieting-associated decline in
serotonin, thus enhancing weight loss. Three
clinical trials in obese patients have
demonstrated decreased food intake and
subsequent weight loss with 5-HTP
Using a placebo-controlled, double-
blind protocol, researchers at the University
of Rome evaluated the effects of 5-HTP (300
mg three times daily) on the eating habits and
weight loss of 20 obese female patients. All
patients had a body mass index between 30
and 40, and were determined to consume an
excess of food daily, based on calculated en-
ergy needs. The twelve-week study period was
divided into two six-week sections. During the
first six weeks, the patients took either 5-HTP
or placebo, but no dietary restrictions were
placed on them. In the second six-week pe-
riod, the patients were placed on a 1200 calo-
rie per day diet, while continuing to take ei-
ther the 5-HTP or placebo. Subjects compiled
detailed 3-day food diaries once every two
Those in the placebo group did not ex-
perience significant weight loss in either of the
two periods (94.3 ± 5.6 kg vs. 93.2 ± 5.3 kg ),
while the subjects in the 5-HTP group showed
significant weight loss in both the first period
(99.7 ± 5.9 kg vs. 98.0 ± 5.0 kg, p<0.03) and
the second period (98.0 ± 5.0 vs. 94.7 ± 5.1
kg, p<0.02). The placebo group also did not
show significant change in their calorie intake,
even in the second period when instructed to
reduce food intake, while the 5-HTP group had
a significant spontaneous dietary intake reduc-
tion during the first period, from 3220 calo-
ries/day to 1879 calories/day (p<0.001), with
carbohydrate intake falling by 50 percent.
During the second period, the calorie intake
of the 5-HTP group decreased further, to 1268
calories/day (p<0.01), with further reductions
in carbohydrates. The researchers interpreted
these findings as supporting the theory that
5-HTP decreased carbohydrate cravings and
binge eating, even in the absence of a struc-
tured diet.
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Alternative Medicine Review
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At this high dosage of 5-HTP (900 mg/
day), about 80 percent of the subjects initially
reported experiencing some nausea. However,
this side effect was not severe enough to cause
any of the subjects to drop out of the study,
and was less frequent during the second six-
week period, suggesting that this symptom
may be a transitory effect of 5-HTP
Chronic Headaches: Chronic head-
aches, especially migraines, are considered by
some researchers to be the result of low sero-
tonin levels, probably as the result of increased
breakdown of serotonin by the enzyme
monoamine oxidase.
Low serotonin levels
are thought to lower pain thresholds in chronic
headache sufferers, allowing other headache
triggers to more easily “set off” a headache.
5-HTP has been used successfully in
the prevention of chronic headaches of vari-
ous types, including migraine, tension head-
aches, and juvenile headaches.
In a large
study of 124 subjects, the ability of 5-HTP to
prevent migraines was compared to
methysergide, one of the most commonly used
migraine drugs. At a dosage of 600 mg daily
for six months, 5-HTP totally prevented or
substantially decreased the number of migraine
attacks in 75 percent of the subjects. However,
this difference was not determined to be sta-
tistically significant.
In a study of 48 elemen-
tary and junior high school students, 5-HTP
(4.5 mg/kg/day) produced a 70 percent de-
crease in headache frequency, compared to an
11 percent decrease in the placebo group.
Insomnia: 5-HTP has been shown to
be beneficial in treating insomnia, especially
in improving sleep quality by increasing REM
Eight normal subjects were
monitored to determine the effect of 5-HTP
on rapid eye movement (REM) sleep. A total
of 600 mg 5-HTP was administered to the
subjects in the following manner: 200 mg at
9:15 pm, followed by 400 mg at 11:15 pm. A
significant increase in the amount of REM
sleep was observed while the subjects were
taking 5-HTP (118 ± 14 mins vs. 98 ± 11 mins,
p<0.005). A smaller study using a 200 mg dose
also showed increases in REM sleep, but to a
lesser degree.
The smaller dose is probably
preferable, since, according to anecdotal
reports, higher doses may have a tendency to
cause very vivid dreams or nightmares.
Initial dosage for 5-HTP is usually 50
mg three times per day with meals. If the clini-
cal response is inadequate after two weeks,
dosage may be increased to 100 mg three times
per day. For insomnia, the dosage is usually
100-300 mg before bedtime. Because some pa-
tients may experience mild nausea when initi-
ating treatment with 5-HTP, it is advisable to
begin with 50 mg doses and titrate upward.
Drug-Nutrient Interactions
Although no specific reports have been
published, it is possible that 5-HTP, when
taken in combination with either a selective
serotonin reuptake inhibitor (SSRI) antidepres-
sant such as fluoxetine (Prozac), paroxetine
(Paxil), sertraline (Zoloft), or fluvoxamine
(Luvox), or an MAOI antidepressant such as
phenelzine (Nardil) or tranylcypromine
(Parnate) may cause a condition known as sero-
tonin syndrome.
This syndrome has been
reported in patients taking LT at doses above
1200 mg/day along with MAOIs, but was not
identified in a 12-month study with 5-HTP
(200 mg/day) taken in conjunction with an
MAOI drug.
Serotonin syndrome is characterized
by agitation, confusion, delirium, tachycardia,
diaphoresis, and blood pressure fluctuations.
Should serotonin syndrome be suspected, 5-
HTP and any other precipitating drug (SSRI
or MAOI) should be discontinued immedi-
ately. Because of the possibility of serotonin
syndrome, 5-HTP should probably not be used
in patients currently being treated with either
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Page 278 Alternative Medicine Review
Volume 3, Number 4 1998
an SSRI or MAOI antidepressant. If it is used
in conjunction with either of these prescrip-
tion drugs, e.g. short-term dual therapy while
changing over from an SSRI to 5-HTP, the
practitioner and patient should be aware of the
potential symptoms of this condition.
One additional concern regarding 5-
HTP is the possibility of an eosinophilia-my-
algia syndrome (EMS) similar to the illness
linked to contaminated LT. The contamination
identified in certain batches of LT has been
related to production methods using bacterial
fermentation and subsequent inadequate fil-
tration. This is unlikely to occur with 5-HTP,
since it is produced by extraction from plant
sources. Two cases of EMS-like symptoms
have been described in patients taking 5-HTP.
One case reported in 1980 involved the use of
very high doses (1400 mg daily).
contamination of LT was not identified as a
factor in EMS until 1990, the product con-
sumed by this patient was not tested for con-
tamination. The second case involved a mother
and two children who were confirmed to have
taken contaminated 5-HTP.
Because of the possibility of seroto-
nin syndrome (see above), 5-HTP should be
used with caution in patients currently being
treated or who have recently been treated with
either an SSRI or an MAOI antidepressant.
There are no adequate, well-controlled
studies on the use of 5-HTP in pregnancy,
therefore, it should not be used while preg-
Side Effects
Some patients may initially experience
mild nausea when taking 5-HTP. This effect
is usually transitory, and is best dealt with by
initiating therapy at low doses (50 mg three
times daily) and increasing the dosage gradu-
ally if necessary.
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... 5-HTP, a precursor of 5-HT, can easily cross the bloodbrain barrier without requiring a transporter and increase the brain 5-HT levels to yield an antidepressant-like effect (Birdsall, 1998). However, the rapid pharmacokinetics of 5-HTP with a half-life of ∼2 h in humans make it impractical as a drug, and the neuropharmacology community turned their attention to the more effective and safe SSRIs (Turner et al., 2006). ...
... In addition to treating depression, 5-HTP also shows positive clinical effects on various neuropsychiatric and metabolic disorders, including insomnia, chronic headaches, fibromyalgia, and obesity (Birdsall, 1998). Despite the capacity to increase the brain and gastrointestinal tract 5-HT levels after oral administration, the basic pharmacology of 5-HTP is still largely unknown. ...
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5-Hydroxytryptophan (5-HTP) has positive clinical effects on various neuropsychiatric and metabiotic disorders, especially depression. Although it increases serotonin levels in the brain and gastrointestinal tract, its pharmacology remains largely unknown. Our goal was to determine the effects of 5-HTP on the mouse gut microbiome, which has a close relationship with depression through the “microbiota-gut-brain axis.” We confirmed that depressive disorder restructures the gut microbial community, and 5-HTP efficiently improves depressive symptoms in mice. Oral administration of 5-HTP significantly restored gut microbiota dysbiosis in mice with depression-like behaviors. The diversity and richness of gut microbial communities and relative abundance of specific microbial taxa at both phylum and genus levels were partially recovered. 5-HTP exhibited some positive effects on restoring the alterations in the concentrations of short-chain fatty acids and brain-derived neurotrophic factors caused by depression in mice. Our results may provide new insights into the pharmacology of 5-HTP in treating depression and other disorders.
... In serotonergic neurons, tryptophan serves as the precursor for 5-HT (Höglund et al., 2019), and 5-hydroxyindoleacetic acid (5-HIAA) is a major metabolite of 5-HT in the central nervous system. Tryptophan hydroxylase (TPH2) is the initial and ratelimiting enzyme of serotonin biosynthesis, which can modulate the concentration of 5-HT in vivo (Sloley and Juorio, 1995;Birdsall, 1998;Walther and Bader, 2003). MAOB is a key enzyme that helps break down serotonin (Bortolato et al., 2010), and the function of SERT is to re-take up serotonin (5-HT) released through the activity of serotonergic neurons (Murphy et al., 2004) while SLC18A2 is a monoamine neurotransmitter transporter, which transports amine neurotransmitters into synaptic vesicles (Kudryavtseva et al., 2017). ...
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Both hypothalamic neurotransmitters and serum steroid hormones are impacted by photoperiod and have effects on physiology and seasonal reproductive. However, the relationship between circulating gonadal steroids and hypothalamic neurotransmitters underlying different photoperiod is still unclear. To further understand the crosstalk of neurotransmitters and steroids in seasonal reproduction, metabolic changes of 27 neurotransmitters concentrated in hypothalamus tissues and 42 steroids hormones in serum were assessed during two artificial photoperiodic programs. The results showed that photoperiod induce testicular atrophy and recrudescence. In L-to-S groups, significantly decreased levels of testosterone concentration were found in serum (P < 0.001) and increased 11-Dehydrocorticosterone (P < 0.05); Testosterone were almost undetectable at SD_14d. In addition, the hypothalamus exhibited significantly increased arginine and 4-aminobutyric acid (GABA) concentration and decreased serotonin and epinephrine content (P < 0.01 or P < 0.05). Accordingly, serum testosterone and androstenedione became detectable at LD_3d in the S-to-L group and were markedly increase at LD_7d. Furthermore, Serum androstenedione showed a significant increase with long light expose (P < 0.01). Additionally, the hypothalamus exhibited both significantly increased L.Tryptophan and phenylalanine concentration, as well as decreased L-glutamine and L-glutamine.acid content (P < 0.01 or P < 0.05). Serotonin metabolism showed significant differences between L-to-S group and S-to-L group. Furthermore, in the correlation analysis, serum testosterone had a positive correlation with 5-Hydroxyindole-3-acetic acid (5-HIAA), while Androstenedione was significantly negative with L.Tryptophan in L-to-S (P < 0.05). However, in S-to-L group, serum testosterone showed strong negative correlation with both serotonin and 5-HIAA (P < 0.05), but positive correlation with L.Tryptophan (P < 0.01), while Androstenedione was significantly negative correlation with both serotonin (P < 0.05) and L-Glutamine (P < 0.01). Photoperiod also had significant effects on the mRNA expression. We found significant differences in gene expression patterns of both serotonin signaling and steroid biosynthesis, while MAOB, NR5A1, and 3β-HSD showed an opposite tendency between two groups. Taken together, our results revealed that circulating gonadal steroids and hypothalamic neurotransmitters were significantly impact quail’s seasonal reproduction. Circulating gonadal steroids have different effects on neurotransmitter at different photoperiodism, which may coordinately influence the seasonal reproduction of quails.
... Supplementation with 5-HTP assists normalization of serotonin synthesis and raises serotonin levels in the brain. Since serotonin aids in regulating mood and behavior, the therapeutic administration of 5-HTP has been effective in treating a wide variety of conditions, including depression and insomnia (Birdsall, 1998;Turner et al., 2006). 5-HTP may also counteract hunger-inducing hormones, working to suppress appetite and helping to lose weight (Cangiano et al., 1998(Cangiano et al., , 1992Ceci et al., 1989). ...
The Ministry of Food and Drug Safety (MFDS) has identified that numerous dietary supplements contain unapproved (hidden, undeclared, and unauthorized) ingredients that could be unsafe. The aim of this study is to summarize the presence of unapproved ingredients in dietary supplements based on the warning dataset released by the MFDS from 2010 to 2019. The warning data were extracted from the alert system on the MFDS’s website. The highest number (ratio) of products found in the dataset were marketed for sexual enhancement [770 (43.3%)], weight-loss [690 (38.8%)], muscular strengthening [243 (13.7%)], or relaxing [76 (4.3%)]. A total of 1,779 products contained one or more unapproved ingredients. The most common unauthorized compounds were icariin, sildenafil, and tadalafil for sexual enhancement, yohimbine, sibutramine, and sennoside for weight loss, and yohimbine and icariin for muscular strengthening, and melatonin and 5-hydroxytryptophan for relaxing products, respectively. Unapproved ingredients continue to be identified in dietary supplements, especially those marketed for sexual enhancement or weight loss, even after warnings by regulatory authorities. The unauthorized compounds in these dietary supplements have potential adverse health effects on consumers owing to accidental misuse, overuse, interaction with other medications, underlying health conditions, or other pharmaceuticals within the supplement. Our study reviewed potential health issues concerning the main unapproved ingredients to contribute to the understanding of adulteration in dietary supplements. The result of this study can be used to elucidate adulteration trends of unapproved ingredients in dietary supplements.
... Moreover, it is an antecedent for serotonin and other beneficial molecules in the brain tissue, including melatonin and niacin, and it guides immune responses in mammals [10,11]. Furthermore, it is a valuable backup for the Kynurenine pathway (KYN) [12,13]. TRP is processed via three diverse biosynthetic paths, i.e., (a) the creation of KYN byproducts, (b) the production of serotonin [14], and (c) the biosynthesis of proteins (Fig. 1). ...
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The amino acid tryptophan (TRP) is critical for the expansion and survival of cells. During the past few years, the manipulation of tryptophan metabolism via indoleamine 2,3 dioxygenase (IDO) has been presented as a significant regulatory mechanism for tolerance stimulation and the regulation of immune responses. Currently, a considerable number of studies suggest that the role of IDO in T helper 2 (Th2) cell regulation may be different from that of T helper 1 (Th1) immune responses. IDO acts as an immunosuppressive tolerogenic enzyme to decrease allergic responses through the stimulation of the Kynurenine-IDO pathway, the subsequent reduction of TRP, and the promotion of Kynurenine products. Kynurenine products motivate T-cell apoptosis and anergy, the propagation of Treg and Th17 cells, and the aberration of the Th1/Th2 response. We suggest that the IDO-kynurenine pathway can function as a negative reaction round for Th1 cells; however, it may play a different role in upregulating principal Th2 immune responses. In this review, we intend to integrate novel results on this pathway in correlation with allergic diseases.
... It is a chemical precursor and metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. It can be effective to treat depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia [48]. ...
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In recent years, the consumption of energy drinks (EDs) has become increasingly popular, especially among adolescents. Caffeine, a psychostimulant, is the main compound of EDs which also contain other substances with pharmacological effects. This review aims to compile current evidence concerning the potential interactions between EDs, medicines, and drugs of abuse as they are frequently consumed in combination. The substances involved are mainly substrates, inductors or inhibitors of CYP1A2, psychostimulants, alcohol and other depressant drugs. Furthermore, intoxications reported with EDs and other substances have also been screened to describe acute toxicity. The results of our review show that the consumption of both EDs alone and in combination is not as safe as previously thought. Health professionals and consumers need to be aware of the potential interactions of these drinks as well as the absence of long-term safety data.
Introduction Understanding the interrelationships between co-occurring chronic health conditions and health behaviors is critical to developing interventions to successfully change multiple health behaviors and related comorbidities. The objective of the present study was to examine the effects of depression, insomnia, and their co-occurrence on risk of obesity and to examine the role of health risk behaviors as potential confounders of these relationships with an emphasis on eating pathologies. Methods Iraq and Afghanistan conflict era veterans (n = 1,094, 51.2% women) who participated in the Women Veterans Cohort Study between July 2014 and September 2019 were categorized as having depression, insomnia, both, or neither condition. Logistic regression models were used to examine group differences in the risk of obesity. Health risk behaviors (i.e., eating pathology, physical activity, smoking, and hazardous drinking) were then assessed as potential confounders of the effects of depression and insomnia on the likelihood of obesity. Results Obesity was most prevalent in individuals with co-occurring insomnia and depression (53.2%), followed by depression only (44.6%), insomnia only (38.5%), and neither condition (30.1%). Importantly, maladaptive eating behaviors confounded the depression–obesity association but not the insomnia–obesity association. There was no evidence that insufficient physical activity, smoking, or hazardous drinking confounded the effects of insomnia or depression on obesity. Conclusions These findings exemplify the complex relationships between multiple health conditions and behaviors that contribute to obesity. Elucidating these associations can enhance the precision with which interventions are tailored to efficiently allocate resources and reduce the severe health impact of obesity among veterans.
5-hydroxytryptophan (5-HTP) is an intermediate molecule in the biosynthesis of serotonin, an important neurotransmitter, regulating a series of metabolic and psychological functions in humans. In this work, we studied the heterologous production of Human Tryptophan Hydroxylase (TPH1) in Escherichia coli, for the synthesis of 5-hydroxytryptophan (5-HTP) from Tryptophan (Trp). To quantify TPH1 activity, a simple fluorescence-based microtiter plate assay was established, based on the changes in fluorescence emission at 340 nm between substrate and product when excited at 310 nm, allowing quick and reliable quantification of released 5-HTP. To increase enzyme production, heterologous TPH1 production was studied in stirred tank bioreactor scale. The effect of rate of aeration (0.25, 0.50 and 0.75 vvm) and agitation (150, 250 and 500 rpm) was evaluated for biomass production, pH, volumetric oxygen transfer coefficient (kLa) and volumetric TPH1 activity. We determined that high agitation and low aeration allowed reaching the maximum measured enzyme activity. Under such conditions, we observed a 90% substrate conversion, obtaining 90 µM (~0.02 g/L) 5-HTP from a 100 µM Tryptophan substrate solution. Finally, we observed that the addition of Tween 20 (0.1%) in the culture broth under production conditions expanded the pH operation range of TPH1. Our results establish a base for a biocatalytic approach as a potential alternative process for the synthesis of 5-HTP using recombinant TPH1.
Background The Office of Disease Prevention and Health Promotion reports that mental health disorders are one of the most "common causes of disability," affecting 18.1% of adults in the United States. This case series examines the use of diet, targeted nutrient supplementation with a focus on amino acids, and lifestyle interventions for the management of mood-related symptoms as a treatment option. Case Presentations The three cases included a personalized amino acid therapy protocol, nutrient cofactor supplementation, and diet and lifestyle recommendations. Clinical assessment questionnaires completed by the clients at intervals during care were used to determine proper amino acid dosing. The first client is a 65-year-old Caucasian male presenting with increased stress, anxiety, depression, and sleep disturbances. A marked decrease in symptoms was experienced three months. The second client is a 24-year-old Caucasian male presenting with concentration and memory impairment, anxiety and depression, food cravings leading to binge eating of carbohydrates, low sleep quality, and unsustainable energy. A substantial decrease in symptoms was achieved in under four months. The third client is a 23-year-old Caucasian male presenting with depression, easy agitation while ruminating on negative thoughts, difficulty focusing and making decisions, poor memory, concentration, and sleep quality, gaming addiction, and low energy and motivation. The client experienced considerable relief from all symptoms in under six months. Conclusion The case series demonstrated marked improvement in mood-related symptoms in as little as 3-6 months for three individuals utilizing amino acid therapy along with dietary, targeted nutrient supplementation, and lifestyle choices.
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Within the general literature on infections and suicidal behavior, studies on Toxoplasma gondii ( T. gondii ) occupy a central position. This is related to the parasite's neurotropism, high prevalence of chronic infection, as well as specific and non-specific behavioral alterations in rodents that lead to increased risk taking, which are recapitulated in humans by T. gondii's associations with suicidal behavior, as well as trait impulsivity and aggression, mental illness and traffic accidents. This paper is a detailed review of the associations between T. gondii serology and suicidal behavior, a field of study that started 15 years ago with our publication of associations between T. gondii IgG serology and suicidal behavior in persons with mood disorders. This “legacy” article presents, chronologically, our primary studies in individuals with mood disorders and schizophrenia in Germany, recent attempters in Sweden, and in a large cohort of mothers in Denmark. Then, it reviews findings from all three meta-analyses published to date, confirming our reported associations and overall consistent in effect size [ranging between 39 and 57% elevation of odds of suicide attempt in T. gondii immunoglobulin (IgG) positives]. Finally, the article introduces certain links between T. gondii and biomarkers previously associated with suicidal behavior (kynurenines, phenylalanine/tyrosine), intermediate phenotypes of suicidal behavior (impulsivity, aggression) and state-dependent suicide risk factors (hopelessness/dysphoria, sleep impairment). In sum, an abundance of evidence supports a positive link between suicide attempts (but not suicidal ideation) and T. gondii IgG (but not IgM) seropositivity and serointensity. Trait impulsivity and aggression, endophenotypes of suicidal behavior have also been positively associated with T. gondii seropositivity in both the psychiatrically healthy as well as in patients with Intermittent Explosive Disorder. Yet, causality has not been demonstrated. Thus, randomized interventional studies are necessary to advance causal inferences and, if causality is confirmed, to provide hope that an etiological treatment for a distinct subgroup of individuals at an increased risk for suicide could emerge.
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In the last few years several open studies supported the hypothesis that L-5-HTP may be an effective antidepressant. Because of the lack of a controlled double-blind trial we started our own investigations to confirm this hypothesis in L-5-HTP. In 1972 we performed two open dose finding trials with L-5-HTP in combination with Benzerazide. These open studies were followed by a double-blind trial comparing L-5-HTP in combination with Benzerazide to Imipramine in 30 patients. Assessments were carried out on day 0, 5, 10, 15 and 20. For data collection we used the Hamilton Rating Scale for Depression, the AMP-system, a Global Rating Scale of Severity of Depression and a Brief Rating Scale for the Behaviour on the ward. In this article we report only a part of the results, mainly on the findings with the AMP-system and the Hamilton Rating Scale for Depression. During our double-blind trial we could not find any significant difference in efficacy of L-5-HTP and Imipramine. The same was found in an open trial. Furthermore the L-5-HTP results showed no difference compared with the results of an Imipramine treatment in 40 patients in earlier double-blind studies. L-5-HTP and Imipramine caused different patterns of side effects. L-5-HTP caused mainly gastrointestinal side effects and Imipramine caused mainly dryness of the mouth and tremor. The gastrointestinal side effects caused by L-5-HTP seemed to be dose dependent.
This chapter presents evidence for a specific indoleamine abnormality in depression and the attempts to correct a suspected deficiency with the serotonin precursor, L-5-hydroxytryptophan (L-5-HTP). L-5-HTP has theoretical advantages compared to L- tryptophan as an agent that could have pharmacological effects. It is metabolized to serotonin whereas 98% of administered L-tryptophan is metabolized to other compounds via the kynurenin pathway. L-5-HTP enters the serotonin synthetic pathway after the apparent rate-limiting step, that is, tryptophan hydroxylation. Therefore, it could increase serotonin more efficiently than L-tryptophan. L-5-HTP crosses the blood–brain barrier. Doses of 600 mg in adult subjects have a rapid-eye-movement (REM) sleep enhancing effect. In addition, L-5-HTP reverses the effects of parachlorophenylalanine (PCPA), which depletes the brain of serotonin. L-5-HTP can be given in doses that have a significant effect on central nervous system activity.
Objective: To study the effect of fluoxetine (FL) and amitriptyline (AM), alone and in combination, in patients with fibromyalgia (FM). Methods: Nineteen patients with FM completed a randomized, double-blind crossover study, which consisted of 4 6-week trials of FL (20 mg), AM (25 mg), a combination of FL and AM, or placebo. Patients were evaluated on the first and last day of each trial period. Outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) scale, and visual analog scales (VAS) for global well-being (1 completed by the physician and 1 by the patient), pain, sleep trouble, fatigue, and feeling refreshed upon awakening. Results: Both FL and AM were associated with significantly improved scores on the FIQ and on the VAS for pain, global well-being, and sleep disturbances. When combined, the 2 treatments worked better than either medication alone. Similar, but nonsignificant, improvement occurred in the BDI scale, the physician global VAS, and the VAS for fatigue and feeling refreshed upon awakening. Trends were less clear for the tender point score. Conclusion: Both FL and AM are effective treatments for FM, and they work better in combination than either medication alone.
Effectiveness of 5-hydroxy-L-trytophan as an antidepressant drug was studied with 59 patients with depressive symptoms using Rating Scale for Depression made by Clinico-Psychopharmacology Research Group in Japan for a preparatory step of a double blind clinical study of 5-hydroxy-L-tryptophan treatment of depression. A daily dose of 150–300 mg of 5-hydroxy-L-tryptophan was administered for three weeks. Favorable responses were observed in 40 patients (67.8%), of whom 13 patients were markedly improved. These effects were noticed in 32 patients (80% of the improved patients) within a week of the treatment. Analysis of General Improvement Rating in the various subtypzs of depressive symptoms indicated that endogenous depression and involutional or senile depression were the preferable indication of 5-hydroxy-L-tryptophan loading. The main side effects of 5-hydroxy-L-trytophan were gastrointestinal disturbances which were minimized by the simultaneous administration of metoclopromide or trihexyphenidyl.
The sleep of a young adult male suffering from hyposomnia following a car accident 6 years ago was studied with the aid of polygraphic recording. The clinical examination found neurological sequels, which showed, among other things, a brain-stem lesion with a third cranial nerve impairment. The lumbar puncture showed an abnormally low level of 5HIAA in the cerebro-spinal fluid. The effects on sleep in this patient of 5-hydroxytryptophan (5HTP), precursor of serotonin, have been studied with polygraphic recording. Two different types of result were observed which may be associated with different doses of 5HTP and the diverse possibilities of metabolic transformation of the precursor. This study has been related to experimental neurophysiologic, neuropharmacologic and neurohistologic work in animals.RésuméLe sommeil d'un adulte jeune présentant une hyposomnie après un accident de voiture survenu 6 ans auparavant a été étudié à l'aide dénregistrements polygraphiques. L'examen clinique retrouve des séquelles neurologiques qui objectivent, entre autres, une atteinte du tronc cérébral au niveau de la 3e paire cranienne. La ponction lombaire révèle un taux anormalement bas de 5HIAA dans le LCR. Les effets, sur le sommeil de ce patient, du 5HTP, précurseur de la sérotonine, ont été étudiés au cours d'enregistrements polygraphiqyes. Deux types différents de résultats ont été observés qui sont peut-être à mettre en relation avec les differences de doses de 5HTP, et les diverses possibilitiés de transformation métabolique de ce précurseur. Cette étude est comparée à divers travaux physiologiques, pharmacologiques et histologiques conduits chez l'animal.
Single oral doses of L-5-hydroxytryptophan (5-HTP) were administered in combination with L-aromatic amino acid decarboxylase inhibitors. The time courses of plasma concentrations of 5-HTP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and the concentrations of 5-HT in blood platelets were measured. Carbidopa enhanced the rise in plasma concentrations of 5-HTP 5-15 fold and counteracted the increase in plasma 5-HIAA levels induced by 5-HTP alone. A single dose of the decarboxylase inhibitor was equipotent to 14 days' pretreatment. Plasma or platelet concentrations of 5-HT failed to reflect the metabolism of 5-HTP. The ratio of 5-HTP to carbidopa influenced the systemic bioavailability of single dose administered 5-HTP indicating dose dependent absorption kinetics. Co-administration of L-dopa with 5-HTP and decarboxylase inhibitors had no effect on gastrointestinal absorption of 5-HTP in six parkinsonian patients.
The response of myoclonus to oral and intravenous L-5-hydroxytryptophan (5-H.T.P.) in combination with a peripheral decarboxylase inhibitor (carbidopa) and to clonazepam has been examined in 9 patients. Moderate improvement or complete cessation of myoclonus followed treatment with one or both of these regimens in 5 patients, 1 of whom also responded to the concurrent administration of L-tryptophan and a monoamineoxidase inhibitor. The remaining 4 patients were at best only slightly improved by either 5-H.T.P. or clonazepam. The responsive group consisted of 3 patients with a history of anoxia, 1 patient with non-history of severe head injury, and 1 patient with non-progressive focal myoclonus and epilepsy. This group had low levels of 5-hydroxyindole acetic acid in the lumbar cerebrospinal fluid. It is suggested that 5-H.T.P. plus carbidopa, L-tryptophan plus a monoamine-oxidase inhibitor, and clonazepam may all act by elevating brain levels of serotonin (5-H.T.) and that some human myoclonic syndromes may be specifically related to a cerebral deficiency of 5-H.T.
Based on 5-HT hypothesis, L-5-HTP (150 or 300 mg/day) was given orally to 18 depressed patients. The global estimates were 2 very much improved; 8 much improved; 3 minimally improved, and 5 unchanged. The action of L-5-HTP was usually rapid. The elevation of the serum 5-HT level 1 week after L-5-HTP administration was relatively lower in the 5-HTP nonresponder group, compared with the responders. The chronological change of the serum 5-HT level in depressed patients after an oral loading dose of 3 mg/kg of L-5-HTP showed a gradual and slight elevation, compared with manic and normal groups. It seemed that the therapeutic effect of L-5-HTP on responders was related to lower 5-HT level in the brain for their pathogenesis, and that there was a metabolic disturbance of L-5-HTP into 5-HT in some depressed patients.