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Modulating central serotonergic function by acute tryptophan depletion (ATD) has provided the fundamental insights into which cognitive functions are influenced by serotonin. It may be expected that serotonergic stimulation by tryptophan (Trp) loading could evoke beneficial behavioural changes that mirror those of ATD. The current review examines the evidence for such effects, notably those on cognition, mood and sleep. Reports vary considerably across different cognitive domains, study designs, and populations. It is hypothesised that the effects of Trp loading on performance may be dependent on the initial state of the serotonergic system of the subject. Memory improvements following Trp loading have generally been shown in clinical and sub-clinical populations where initial serotonergic disturbances are known. Similarly, Trp loading appears to be most effective for improving mood in vulnerable subjects, and improves sleep in adults with some sleep disturbances. Research has consistently shown Trp loading impairs psychomotor and reaction time performance, however, this is likely to be attributed to its mild sedative effects.
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Review
Effects of tryptophan loading on human cognition, mood, and sleep
B.Y. Silber
a,
*, J.A.J. Schmitt
a,b
a
Cognitive Sciences Group, Nestle
´Research Centre, P.O. Box 44, CH-1000 Lausanne, Switzerland
b
Brain Sciences Institute, Swinburne University, P.O. Box 218 (H99), Hawthorn, Victoria 3122, Australia
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
1.1. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
1.2. Modulation of serotonergic function by dietary tryptophan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
1.3. Increasing brain tryptophan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.1. Selection procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.2. Methodological remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. Effects of tryptophan loading on cognitive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1. Tryptophan loading and memory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2. Tryptophan loading and attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.3. Tryptophan loading and executive functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.4. Tryptophan loading and emotional processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.5. Tryptophan loading and psychomotor performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.6. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. Effect of tryptophan loading on mood and alertness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1. Effect of tryptophan loading on mood in clinical populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.2. Effect of tryptophan loading on mood and alertness in healthy and vulnerable volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5. Effect of tryptophan loading on sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.1. Effect of tryptophan loading on sleep parameters in insomniacs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.2. Effect of tryptophan loading on sleep parameters in healthy volunteers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.3. Effect of sub-chronic tryptophan loading on sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.4. Effect of tryptophan loading on sleep and cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.5. Effect of tryptophan loading on sleep in infants and children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.6. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
ARTICLE INFO
Article history:
Received 4 June 2009
Received in revised form 5 August 2009
Accepted 19 August 2009
Keywords:
Tryptophan
Serotonin
Memory
Attention
Cognition
Mood
Sleep
ABSTRACT
Modulating central serotonergic function by acute tryptophan depletion (ATD) has provided the
fundamental insights into which cognitive functions are influenced by serotonin. It may be expected that
serotonergic stimulation by tryptophan (Trp) loading could evoke beneficial behavioural changes that
mirror those of ATD. The current review examines the evidence for such effects, notably those on
cognition, mood and sleep. Reports vary considerably across different cognitive domains, study designs,
and populations. It is hypothesised that the effects of Trp loading on performance may be dependent on
the initial state of the serotonergic system of the subject. Memory improvements following Trp loading
have generally been shown in clinical and sub-clinical populations where initial serotonergic
disturbances are known. Similarly, Trp loading appears to be most effective for improving mood in
vulnerable subjects, and improves sleep in adults with some sleep disturbances. Research has
consistently shown Trp loading impairs psychomotor and reaction time performance, however, this is
likely to be attributed to its mild sedative effects.
ß2009 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +41 21 785 9242; fax: +41 21 785 8544.
E-mail address: beata.silber@rdls.nestle.com (B.Y. Silber).
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Contents lists available at ScienceDirect
Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
0149-7634/$ – see front matter ß2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2009.08.005
1. Introduction
1.1. Serotonin
Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine
neurotransmitter, responsible for neurochemical signal transduc-
tion between neurons. The neurons of the raphe nuclei are the
principal source of 5-HT release in the brain. Although there are
relatively few serotonergic neurons in the brain, these neurons
innervate widespread areas of the brain, such as the forebrain,
hippocampus, cerebellum and spinal cord (Haider et al., 2006), and
are considered important in the modulation of several essential
behavioural and physiological functions, such as mood, sleep and
wakefulness, cognition, sexual behaviour, appetite, aggression,
impulsivity, neurodevelopment, circadian rhythms, body tem-
perature, and neuroendocrine function (Jacob and Fornal, 1995).
Reduced 5-HT function is recognised as a contributing factor in
affective disorders, such as depression, bipolar disorder, anxiety
disorders, and obsessive compulsive disorder (Davis et al., 2002).
Medicinal drugs that stimulate 5-HT activity throughout the brain,
predominantly selective serotonin reuptake inhibitors (SSRIs) and
various tricyclic antidepressants (TCAs), are effective in amelior-
ating the symptoms of these disorders. Furthermore, cognitive
deficits that frequently accompany these disorders have also been
shown to improve with pro-serotonergic pharmacological thera-
pies (Schmitt et al., 2006).
1.2. Modulation of serotonergic function by dietary tryptophan
For a limited number of neurotransmitters, such as serotonin,
dietary precursors can influence the rate of synthesis and function
of the neurotransmitters. The synthesis of 5-HT is dependent on
the brain availability of its precursor, the amino acid
L
-tryptophan
(Trp). The amino acid is converted via a short metabolic pathway
consisting of the two enzymes tryptophan hydroxylase and amino
acid decarboxylase to serotonin. Tryptophan hydroxylase, the rate-
limiting enzyme on the pathway from Trp to 5-HT, is not normally
saturated with Trp. Thus, increasing Trp levels can increase 5-HT
synthesis as much as twofold following 3 g pure Trp load (Young,
1996; Young and Gauthier, 1981), which is significant to modulate
mood, cognition and behaviour (Attenburrow et al., 2003; Cunliffe
et al., 1998; Marsh et al., 2002; Markus et al., 2008; Yuwiler et al.,
1981). While decreasing Trp availability can cause a considerable
decline in 5-HT synthesis and turnover (Nishizawa et al., 1997).
Trp is transported across the blood–brain barrier by a specific
active transport system, which also transports a number of other
large neutral amino acids (LNAAs: leucine, isoleucine, tyrosine,
phenylalanine, and valine) into the brain. As a result, Trp competes
with these other LNAAs for active transport sites. Therefore, the
uptake of Trp does not depend on total concentration of plasma Trp
alone, but primarily on the plasma ratio of Trp to the sum of other
LNAAs (Trp–LNAA ratio) (Fernstrom and Wurtman, 1972). An
increase in the plasma Trp–LNAA ratio can result in an increased
uptake of Trp in the brain. Thus, the relative amount of LNAAs in
the diet has a major impact on the levels of Trp in the brain. A diet
high in Trp, but with a large amount of LNAAs, will not result in
higher brain Trp levels, and may even decrease Trp uptake into the
brain. An intervention rich in Trp relative to other LNAAs is needed
in order to boost uptake of Trp, and consequently serotonin
production, in the brain.
1.3. Increasing brain tryptophan
Increases in plasmaTrp–LNAA ratio can be achieved by giving Trp
the advantage in competition for access to the brain (Fernstrom and
Wurtman, 1971),either through the intakeof pure Trp (Markus et al.,
2008; Sobczak et al., 2002, 2003), increasing carbohydrate intake
(Fernstrom and Wurtman, 1971, 1972; Markus et al., 1998), or
through consumption of tryptophan-rich
a
-lactalbumin protein
(Markus et al., 2000, 2002).Throughout the review these methods of
increasing brain Trp will be referred to as Trp loading.
a
-Lactalbumin is a whey-derived protein with the highest Trp
content and highest Trp–LNAA ratio of all food protein sources
(Heine et al., 1996).
a
-Lactalbumin has been shown to increase
plasma Trp–LNAA ratio up to 130% (Booij et al., 2006; Markus et al.,
2000, 2005; Merens et al., 2005; Scrutton et al., 2007). Ingestion of
normal protein, which also contains Trp, decreases brain Trp. This
is because Trp is the least abundant amino acid in protein, and
therefore the increase in plasma Trp is less than the increase in
plasma LNAAs that compete with Trp for transport into the brain.
Carbohydrates, on the other hand, which contain no Trp, increase
brain Trp and 5-HT, due to a carbohydrate-induced rise in glucose,
which triggers insulin secretion. Insulin stimulates the uptake of
LNAA in skeletal muscles, with the exception of Trp (Fernstrom and
Wurtman, 1971). Consequently, LNAA plasma levels fall, competi-
tion for the transport of Trp decreases, and brain levels of Trp and
5-HT increase. However, a carbohydrate rich/protein poor (CR-PP)
diet increases plasma Trp–LNAA ratio (20–25%; Markus et al.,
1998, 1999) considerably less than
a
-lactalbumin.
For the purpose of the present review, the effects of Trp loading
in humans (clinical populations, vulnerable volunteers, and
healthy volunteers) on cognitive function, mood, and sleep are
considered, to explore the potential benefits of serotonergic
stimulation through Trp loading. As previously mentioned, brain
Trp can be increased through intake of either pure Trp, a
carbohydrate rich/protein poor diet, or
a
-lactalbumin. Therefore,
studies employing these Trp loading manipulations are discussed.
2. Methods
2.1. Selection procedures
An extensive medline search was performed from 1966 to
January 2009 using the search terms: ‘‘tryptophan’’, ‘‘
a
-lactalbu-
min’’, ‘‘cognition’’, ‘‘memory’’, ‘‘attention’’, ‘‘vigilance’’, ‘‘executive
function’’, ‘‘emotional processing’’, ‘‘mood’’, and ‘‘sleep’’. The
search was limited to human studies only. The bibliographies of
the references identified were searched for additional papers that
met the following inclusion criteria: (1) original papers written in
English appearing in a peer-reviewed journal, (2) include a
comparison condition (Trp loading versus placebo or ATD), (3)
specify sample characteristics for the participants, (4) include
cognitive, mood and/or sleep assessments. All studies that assessed
Trp loading on cognition, mood and/or sleep meeting the above
criteria were included in the review.
2.2. Methodological remarks
Forty-three studies were identified for inclusion in the review.
Sixteen studies assessed the effects of Trp loading on cognitive
functioning. Thirteen articles assessed the effects of Trp loading on
mood, and 21 studies assessed the effects of Trp loading on sleep
measures. Twenty-three studies included only healthy subjects, 8
studies assessed healthy volunteers and vulnerable populations
(i.e. mental illness, participants with family history of mental
illness, stress-prone, premenstrual women, individuals with sleep
disturbances), and 12 studies included only vulnerable popula-
tions. Thirty-one studies increased brain Trp with pure Trp. Nine
studies increased brain Trp with
a
-lactalbumin, and three studies
increased brain Trp with a carbohydrate rich/protein poor diet. The
Trp loading studies included in the review are summarized in
Tables 1–3.
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
2
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Table 1
Summary of cognitive findings.
Study Subjects Dose Increase from baseline in
plasma Trp–LNAA ratio
Intervention type Measures Results
Luciana et al.
(2001)
19 healthy adults 10.3 g
L
-Trp Not available; total
plasma Trp levels
increased by tenfold
from 53.22 to
551.4
m
mol/L
Acute, repeated-measures,
double-blind design
(no placebo – Trp loading
or depletion)
Spatial working memory;
affective working memory;
verbal fluency; sustained
attention and short-term
memory span; motor speed
and accuracy
Decrements in working memory for verbal
and affective stimuli relative to Trp
depletion; decrements in motor
performance; improved sustained
attention; no effect on mood
Morgan et al.
(2007)
8 healthy adults 30 mg/kg body
weight
L
-Trp
Not available Acute, repeated-measures,
double-blind, placebo-
controlled design
Executive function No effects found
Attenburrow
et al. (2003)
24 healthy females Nutritionally sourced
pure Trp (1.8 g Trp)
Not available Acute, double-blind, parallel
group, placebo-controlled
design
Emotional processing Trp enhanced perception of fearful and
happy facial expressions relative to placebo
Murphy et al.
(2006)
38 healthy adults 14 days Trp intervention
of 1 g three times a day
Not available Sub-chronic, double-blind,
parallel group, placebo-
controlled design
Emotional processing
(facial expression recognition,
emotion-potentiated startle,
attentional probe, emotional
categorisation and memory);
mood
Trp increased the recognition of happiness
and decreased recognition of disgust in
females; Trp decreased attentional vigilance
towards negative stimuli and reduced
baseline emotional startle response in
females; no effects on mood
Scrutton et al.
(2007) (10)
28 healthy females 40 g
a
-lactalbumin-rich
drink (total Trp
level 1.8 g)
80% Acute, double-blind, parallel
group, placebo-controlled
design
Emotional processing; mood No effects found; increase in subjective
rating of nausea 150 min after
a
-lactalbumin ingestion
Winokur et al.
(1986)
11 healthy males 5, 7.5 and 10 g
L
-tryptophan;
saline administered
intravenously
Acute, repeated-measures,
double-blind, placebo-
controlled design
Psychomotor performance;
subjective ratings of fatigue
L
-Trp produced a dose-dependent
impairment in motor performance;
L
-Trp
increased mental and physical sedation,
but did not alter subjective ratings of
tranquilization
Cunliffe et al.
(1998) (11)
6 healthy adults 30 mg/kg body weight
L
-Trp 41% (peak) Acute, repeated-measures,
double-blind, placebo-controlled
design
Subjective measure of
fatigue (VAS), objective
measure of central fatigue
(Flicker Fusion Frequency
task), simple reaction time,
peripheral fatigue (grip
strength and wrist ergometry)
Trp decreased performance on the Flicker
Fusion Frequency task (measure central
fatigue); Trp slowed reaction time
performance; Trp increased subjective
ratings of fatigue
Dougherty
et al. (2007)
18 healthy adults 5.15 g Trp 127% Acute, repeated-measures,
double-blind, placebo-controlled
design
Sustained attention,
impulsivity
Trp loading produced fewer errors of
omission during a vigilance task in the
Trp loading condition relative to the
Trp depletion condition
Markus et al.
(2005) (7)
Healthy subjects with
(n= 14) or without
(n= 14) mild sleep
complaints
40 g (2 20 g) tryptophan-
enriched
a
-lactalbumin
protein (4.8 g/100 g Trp)
130% increase
from placebo
Repeated-measures, double-blind,
placebo-controlled design
Subjective sleepiness;
vigilance; EEG (ERPs)
a
-Lactalbumin reduced sleepiness in
the morning, improved morning
alertness and attention (P300 ERP) in
both groups;
a
-lactalbumin improved
next morning vigilance performance in
subjects with mild sleep complaints
Markus et al.
(2002) (4)
23 high stress-
vulnerable and 29
low stress-vulnerable
subjects
40 g
a
-lactalbumin-rich
drink (2 20 g containing
12.32 g/kg Trp; Trp/
S
LNAA
ratio of 8.7%)
Not available; Trp–LNAA
ratio was 43% greater
after
a
-lactalbumin
diet than after control
diet
Acute, repeated-measures (diet),
between-subject, double-blind
design
Memory scanning Improved memory scanning in high
stress-vulnerable subjects compared
to placebo; no effect of Trp in low
stress-vulnerable subjects
Markus et al.
(1999)
22 high stress-
vulnerable and 21
low stress-vulnerable
subjects (aged
19–26 yrs)
Carbohydrate rich/protein
poor diet versus protein
rich/carbohydrate poor diet
Not available Acute, repeated-measures (diet),
between-subject, double-blind
design
Memory scanning Improved memory scanning after
experimental stress only in high-stress
volunteers with carbohydrate
rich/protein poor diet
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
3
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Table 1 (Continued )
Study Subjects Dose Increase from baseline in
plasma Trp–LNAA ratio
Intervention type Measures Results
Markus et al.
(1998) (5)
24 high stress-
Vulnerable and 24
low stress-vulnerable
subjects (aged 18–25 yrs)
Carbohydrate rich/protein
poor diet versus protein
rich/carbohydrate poor diet
Not available; Trp–LNAA
ratio increased 48% in
the carbohydrate
rich/protein poor diet
from the protein
rich/carbohydrate poor diet
Acute, repeated-measures (diet),
between-subject, double-blind
design
Memory scanning; mood Failed to demonstrate memory scanning
improvements following a carbohydrate
rich/protein poor diet in stress-prone
subjects following experimental stress
although basic reaction speed was
increased in pooled groups; in high
stress subjects a carbohydrate
rich/protein poor diet prevented
deterioration of feelings of depression
and vigour during stress manifested
after protein rich/carbohydrate
poor diet
Schmitt et al.
(2005) (1)
16 Females with
premenstrual symptoms
40 g
a
-lactalbumin-rich
drink (2 20 g containing
12.32 g/kg Trp; Trp/
S
LNAA
ratio of 8.7%)
6–25% Acute, repeated-measures,
double-blind, placebo-controlled
design
Short- and long-term
memory; executive function
Improved long-term memory for abstract
figures, but not for words; no effect on
executive function
Sayegh et al.
(1995) (2)
24 Premenstrual
females with PMS
Carbohydrate rich drink 29% Acute, repeated-measures,
double-blind, placebo-controlled
design
Verbal recognition memory;
verbal retrieval; mood
Improved verbal recognition memory;
decreased self-report measures of
depression, anger, confusion
Sobczak et al.
(2003, 2002) (9)
30 healthy first-degree
relatives of bipolar
patients and 15
matched controls
7 g Tryptophan intravenous Trp–LNAA ratio increased
1500% as baseline ratio
was 0.11 and 105 min
after Trp ratio was 1.835
Acute, between-group,
repeated-measures, double-blind,
placebo-controlled design
Planning; sustained attention;
focused attention; divided
attention; response inhibition;
psychomotor performance;
short- and long-term memory;
verbal fluency; mood
Trp impaired long-term memory retrieval
and storage and decreased movement time
on a psychomotor task in both groups; Trp
impaired focused attention and planning
in subjects with first-degree relative with
bipolar disorder; Trp increased feelings of
anger, depression,
fatigue, tension, and decreased feelings
of vigour and feelings of alertness in both
groups relative to placebo
Booij et al.
(2006) (3)
23 recovered depressed
patients (21 F and 2 M)
and 20 controls
(17 F and 3 M)
40 g
a
-lactalbumin-rich
drink (2 20 g
containing12.32 g/kg Trp;
Trp/
S
LNAA ratio of 8.7%)
21% Acute, repeated-measures,
double-blind, placebo-controlled
design
Short- and long-term memory;
focused attention and response
inhibition; motor speed;
executive function; mood
Improved abstract visual memory, in
both recovered depressed patients
and healthy controls; slowed motor
response in both groups; no effect on
mood or other cognitive functions
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
4
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NBR-1212; No of Pages 21
Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Table 2
Summary of mood findings.
Study Subjects Dose Increase from baseline in
plasma Trp–LNAA ratio
Intervention type Measures Results
Luciana et al.
(2001)
19 healthy adults 10.3 g
L
-Trp Not available; total plasma
Trp levels increased by
tenfold from 53.22 to
551.4
m
mol/L
Acute, repeated-measures,
double-blind design
(no placebo – Trp loading
or depletion)
Mood; spatial working
memory; affective
working memory; verbal
fluency; short-term
attention and memory
span; motor speed and
accuracy
No effect on mood; decrements
in working memory for verbal
and affective stimuli relative to
rp depletion; decrements in
motor performance; improved
sustained attention
Markus et al.
(2008) (8)
18 healthy subjects 15 g
a
-lactalbumin whey-protein
with 0.8 g Trp and 9.4 g LNAA
(Trp–LNAA ratio 0.1); hydrolysed
protein (Pep2Balance) with 0.8 g
Trp and 4 g LNAA (Trp–LNAA
ratio 1.1); 0.8 g pure Trp; and
1.2 g synthetic peptide containing
0.8 g Trp; 20 g casein protein with
0.4 g Trp and 10 g LNAA (Trp–LNAA
ratio 0.04)
a
-Lactalbumin–67%
Pep2balance–255% pure
Trp–191% synthetic
peptide–263%
Acute, repeated-measures,
double-blind,
placebo-controlled design
Mood and plasma
amino acids
Hydrolysed protein
(Pep2Balance
TM
) produced
faster and greater increases
in plasma Trp–LNAA ratio
compared to
a
-lactalbumin
and pure Trp; Mood improved
60 min after consumption
hydrolysed protein and pure
Trp. Most profound and
durable mood enhancing
effects observed 210 min
after intake of hydrolysed
protein. No mood effects
observed with
a
-lactalbumin
or synthetic Trp peptide
Murphy et al.
(2006)
38 healthy adults 14 days Trp intervention of 1 g 3
times a day
Not available Sub-chronic, double-blind,
parallel group, placebo-controlled
design
Mood; emotional processing
(facial expression recognition,
emotion-potentiated startle,
attentional probe, emotional
categorisation and memory)
No effects on mood; Trp
increased the recognition of
happiness and decreased
recognition of disgust in
females; Trp decreased
attentional vigilance towards
negative stimuli and reduced
baseline emotional startle
response in females
Scrutton et al.
(2007) (10)
28 healthy females 40 g
a
-lactalbumin-rich drink
(total Trp level 1.8 g)
80% Acute, double-blind, parallel
group, placebo-controlled
design
Mood; emotional processing; No effects found; increase in
subjective rating of nausea 150 min
after
a
-lactalbumin ingestion
Beulens et al.
(2004) (12)
18 healthy males 12 g
a
-lactalbumin-enriched
whey-protein (Trp–LNAA ratio
of 0.16) with carbohydrates versus
carbohydrates only
16% Acute, repeated-measures,
double-blind, placebo-controlled
design
Mood No effects
Yuwiler et al.
(1981)
5 healthy males 50 mg/kg
L
-Trp acute; 100 mg/kg
L
-Trp
acute; 50 mg/kg
L
-Trp sub-chronic
for 14 days
Not available Repeated-measures,
double-blind design
Mood and alertness No effect of Trp on valence of mood;
Trp increased lethargy and
drowsiness within 30 min after
50 mg/kg
L
-Trp ingestion
Markus et al.
(1998) (5)
24 high stress-
Vulnerable and
24 low stress-
vulnerable subjects
(aged 18–25 yrs)
Carbohydrate rich/protein poor diet
versus protein rich/carbohydrate
poor diet
Not available; Trp–LNAA ratio
increased 48% in the carbohydrate
rich/protein poor diet from the
protein rich/carbohydrate poor diet
Acute, repeated-measures (diet),
between-subject, double-blind
design
Mood; memory scanning In high stress subjects a
carbohydrate rich/protein
poor diet prevented
deterioration of feelings of
depression and vigour during
stress manifested after
protein rich/carbohydrate poor
diet; failed to demonstrate memory
scanning improvements
following a carbohydrate
rich/protein poor diet in
stress-prone subjects following
experimental stress
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Table 2 (Continued )
Study Subjects Dose Increase from baseline in
plasma Trp–LNAA ratio
Intervention type Measures Results
Markus et al.
(2000) (6)
29 high stress-
Vulnerable and 29
low stress-vulnerable
subjects
40 g
a
-lactalbumin-rich drink
(2 20 g containing12.32 g/kg Trp;
Trp/
S
LNAA ratio of 8.7%)
Not available; Trp–LNAA ratio
increased 48% after
a
-lactalbumin
diet from the control diet
Acute, repeated-measures (diet),
between-subject, double-blind,
placebo-controlled design
Mood
a
-Lactalbumin-rich diet
reduced depressive symptoms
in stress-vulnerable subjects
after experimental stress
Sayegh et al.
(1995) (2)
24 Premenstrual
females with PMS
Carbohydrate rich drink 29% Acute, repeated-measures,
double-blind, placebo-controlled
design
Mood; verbal recognition;
memory; verbal retrieval
Decreased self-report measures
of depression, anger, confusion;
Improved verbal recognition
memory
Steinberg
et al. (1999)
80 females with
premenstrual
dysphoric disorder
6g
L
-Trp (given as 2 g three
times a day) for 17 days
Not available Sub-chronic, between-subject,
randomised, double-blind,
placebo-controlled design
Mood
L
-Trp more effective than
placebo in controlling extreme
mood swings, dysphoria,
irritability, and tension
Sobczak et al.
(2003, 2002) (9)
30 healthy first-degree
relatives of bipolar
patients and 15
matched controls
7 g Tryptophan intravenous Trp–LNAA ratio increased 1500%
as baseline ratio was 0.11 and
105 min after Trp ratio was 1.835
Acute, between-group,
repeated-measures, double-blind,
placebo-controlled design
Mood; planning; sustained
attention; focused attention;
divided attention; response
inhibition; psychomotor
performance; short- and
long-term memory; verbal
fluency
Trp increased feelings of anger,
depression, fatigue, tension,
and decreased feelings of vigour
and feelings of alertness in
both groups relative to placebo;
Trp impaired long-term memory
retrieval and storage and
decreased movement time on
a psychomotor task in both
groups; Trp impaired focused
attention and planning in
subjects with first-degree
relative with bipolar disorder
Merens et al.
(2005) (13)
23 recovered depressed
adults and 20 healthy
adults
40 g
a
-lactalbumin-rich drink
(2 20 g containing12.32 g/kg Trp;
Trp/
S
LNAA ratio of 8.7%)
21% Acute, repeated-measures,
between-subject, double-blind,
placebo-controlled design
Mood
a
-Lactalbumin had no effect in
improving mood after
experimental stress
Booij et al.
(2006) (3)
23 recovered depressed
patients (21 F and 2 M)
and 20 controls
(17 F and 3 M)
40 g
a
-lactalbumin-rich drink
(2 20 g containing 12.32 g/kg Trp;
Trp/
S
LNAA ratio of 8.7%)
21% Acute, repeated-measures,
double-blind, placebo-controlled
design
Mood; short- and long-term
memory; focused attention
and response inhibition;
motor speed; executive
function
No effect on mood; improved
abstract visual memory in both
recovered depressed patients
and healthy controls; slowed
motor response in both groups
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Table 3
Summary of sleep findings.
Study Subjects Dose Increase from baseline
in plasma Trp–LNAA ratio
Intervention type Measures Results
Wyatt et al.
(1970) (1)
Healthy adults 7.5 g Trp Not available Sleep parameters Trp decreased REM sleep and increased non-REM sleep
Nicholson and
Stone (1979) (2)
6 healthy males 2, 4, and 6g
L
-Trp Not available Sleep parameters 4 g
L
-Trp increased percentage of REM sleep and duration
of stage 3 daytime sleep; no modulations to sleep found
during nighttime sleep following 2, 4, and 6 g
L
-Trp
Hartmann et al.
(1974) (3)
Healthy adults 1–15 g Trp (dose–
response study)
Not available Sleep parameters 1–15 g Trp decreased sleep latency, but only in
doses above 5 g modulations to sleep stages
observed, specifically, decreases in desynchronised
sleep % increases in slow-wave sleep
Leatherwood and
Pollet (1984) (19)
Healthy adults 500 mg Trp (5 nights) Sub-chronic, double-blind,
repeated-measures,
placebo-controlled design
Sleep parameters Trp decreased sleep latency, sleep depth increased,
increased sleepiness, and calming effects were reported;
younger females more sensitive to the sedating effects
of Trp than any other group
George et al.
(1989) (6)
10 healthy adults 1.2 or 2.4 g
L
-Trp Not available Acute, repeated-measures,
double-blind,
placebo-controlled design
Objective (sleep latency)
and subjective measures
of sleepiness and their
relationship to blood
L
-Trp levels
Both
L
-Trp doses reduced sleep latency at 1 h, with reduction
persisting at 2 h for 2.4
L
-Trp only; positive correlation
between subjective and objective sleepiness measures
for 2.4 g dose only; correlation between blood Trp and
sleep latency found at 0, 60 min and 120 min for both doses
Spinweber et al.
(1983) (8)
20 healthy adults 4g
L
-Trp Not available; however
plasma total Trp levels
increased 260% and free
Trp 343% relative to
placebo
Acute, repeated-measures,
double-blind,
placebo-controlled design
Waking EEG and
daytime sleep
L
-Trp reduced sleep latency without altering nap sleep
stages; during waking EEG
L
-Trp increased alpha
latency, theta latency, theta amplitude, and decrease
alpha frequency; conclusion
L
-Trp effective sleep hypnotic
Thorleifsdottir
et al. (1989) (15)
20 healthy adults 2g
L
-Trp Not available Acute, repeated-measures,
double-blind,
placebo-controlled design
Daytime arousal
measured with EEG
Trp increased drowsiness reflected by increases in
theta amplitude and decreases in alpha amplitude;
subjective ratings of sleepiness increased with Trp;
psychomotor performance not affected with Trp
Chauffard-Alboucq
et al. (1991) (20)
9 healthy females 500 mg and 1 g
L
-Trp
combined with a
carbohydrate load
200% (500 mg)
300% (1 g)
Acute, double-blind,
repeated-measures,
placebo-controlled design
Perceived sleepiness;
sedative effects
Both Trp doses increased sleepiness and sedative
effects relative to placebo. Effect was observed when
plasma Trp–LNAA ratio increased 200% (500 mg) and
300% (1 g) from baseline, peaking 90 minu after Trp
administration. Peak in perceived sleepiness found
90 min after Trp consumption
Ko
¨rner et al.
(1986) (7)
10 adults with
sleep disturbances
5g
L
-Trp Not available Acute, repeated-measures,
double-blind,
placebo-controlled design
Sleep parameters Trp decreased sleep latency, improved sleep period
time and total sleep time; no effect on slow-wave sleep
Brown et al.
(1979) (5)
18 females with
laboratory sleep-onset
latency greater
than 20 min
1g or 3g
L
-Trp
for 10 nights
Not available Sub-chronic,
repeated-measures,
double-blind,
placebo-controlled design
Sleep parameters Trp had no effect on amount of REM, slow-wave
sleep and wakefulness relative to placebo;
reductions in sleep-onset latency with 3 g Trp
Hartman and
Spinweber
(1979) (9)
15 mild insomniacs 250 mg, 500 mg
and 1 g
L
-Trp
Not available Acute, repeated-measures,
double-blind,
placebo-controlled design
Sleep parameters 1 g Trp reduced sleep latency, whereas the lower
Trp doses produced trends in same direction;
Stage IV sleep increased with 250 mg Trp
Hudson et al.
(2005) (10)
57 chronic
insomniacs
25 mg deoiled butternut
squash seed meal
(contains 22 mg Trp/1 g
protein) mixed with
25 mg dextrose; 250 mg
pharmaceutical Trp
mixed with 25 mg
dextrose and 25 g rolled
oats; rolled oats (placebo)
Not available Acute, between-subjects,
double-blind,
placebo-controlled design
Objective (total sleep
time, sleep efficiency,
total wake time, time
awake-middle of the
night) and subjective
(overall perceived
quality) measures of
sleep
Protein source Trp and pharmaceutical grade Trp
improved subjective and objective sleep measures
Hartman et al.
(1983) (11)
96 chronic
insomniacs
1g
L
-Trp; 100 mg
secobarbital; 30 mg
flurazepam; placebo
for 7 days
Not available Sub-chronic,
between-subjects,
double-blind,
placebo-controlled design
Sleep parameters Trp did not improve sleep during treatment phase (7 days),
however post-treatment Trp improved sleep latency
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Table 3 (Continued )
Study Subjects Dose Increase from baseline
in plasma Trp–LNAA ratio
Intervention type Measures Results
Demisch et al.
(1987a) (13)
39 chronic
insomniacs
2g
L
-Trp and 0.04 g
L
-Trp
(instead of placebo)
Not available Acute, repeated-measures,
double-blind design
Sleep parameters Full
L
-Trp (2 g) dose administered first improved sleep
relative to low Trp dose. However, when low Trp
dose administered first, no difference found between
two treatment conditions. Authors argue that
L
-Trp
seems to be effective in promoting sleep in subjects
with chronic insomnia
Demisch et al.
(1987b) (14)
25 chronic
insomniacs
2g
L
-Trp for 4 weeks
and 4 weeks no
treatment
Not available Sub-chronic,
repeated-measures,
double-blind design
Sleep parameters Trp improved sleep patterns; subjective sleep ratings
improved with Trp; sleep deteriorated in only half of
the patients during the control period (no treatment)
Spinweber
(1986) (4)
20 male chronic
sleep-onset
insomniacs
3g
L
-Trp (6 nights) Not available Sub-chronic,
between-subject,
double-blind,
placebo-controlled design
Sleep; performance;
arousal; brain
electrical activity
No effect of
L
-Trp on sleep latency during first three
nights of administration; nights 4–6 sleep latency
reduced; no effect on sleep stages; Trp did not
impair performance; Trp elevated arousal threshold;
Trp did not alter brain electrical activity
Schneider-Helmert
(1981) (12)
8 severe
insomniacs
2g
L
-Trp (3 nights)
followed by 4 night
placebo period
Not available Sub-chronic, repeated-
measures, double-blind,
placebo-controlled design
Sleep parameters Improvements to sleep found to continue during a
four night placebo period compared to the pre-Trp
baseline, suggesting interval therapy to be useful
method in cases of severe insomnia
Aparicio et al.
(2007) (18)
18 healthy infants Standard infant
commercial milk
(1.5% Trp) administered
during daytime and
nighttime for 1 week;
second condition Trp
enriched milk (3.4% Trp)
given during light-time
(06:00–18:00) and standard
commercial milk given
during nighttime
(18:00–06:00) for 1 week;
experimental condition
infants received the standard
commercial
milk during daytime and Trp
enriched milk during
nighttime for 1 week
Not available Sub-chronic, double-blind,
repeated-measures design
Sleep patterns Infants receiving low Trp formula during the day and high
Trp formula during the night, slept more, manifested
better sleep efficiency, increased immobility time, had
fewer night movements and waking episodes. No
statistical differences found between two control
groups despite the fact that quite different amounts
of Trp were administered (1.5% and 2.72%). Conclusion:
milk formulas with varying Trp contents that are
appropriate to light–dark variations improve the
sleep/wake cycles of infants who are not breast fed
Yogman and Zeisal
(1983) (16)
20 healthy
newborn infants
(2–3 days old)
Trp in 10% glucose or
valine in 5% glucose
Not available Acute, between-subjects
design
Sleep patterns Newborns fed Trp had shorter sleep latencies,
and entered rapid eye movement and quiet sleep
sooner than when fed commercial formula
Steinberg et al.
(1992) (17)
57 healthy infants Formula containing 0, 294,
588, 882
m
mol/L of added Trp;
for comparative purposes
standard human milk and
commercial formula included
Plasma Trp–LNAA ratio
greatest for infants fed
human milk (0.132) and
formula containing highest
level of added Trp (0.129)
Sub-chronic, randomised,
between-subjects design
Sleep patterns Trp–LNAA ratio, not plasma Trp concentrations,
predicted differences in sleep latency across the
different treatment conditions. Sleep latency was
shorter for infants with the highest Trp–LNAA ratios.
Infants consuming formulas with lower Trp loading
had sleep latencies similar to those of infants consuming
commercial formula. Infants consuming highest Trp dose
sleep latencies were shorter than for infants in the human
milk-fed condition. Infants fed high dose of Trp tended to be
less alert, spent less time crying, and more time sleeping than
infants fed lower levels of added Trp
Harada et al. (2007) 1055 infants (0–6
months), 751 young
children (0.6–8 years),
and 473 older children
(9–15 years)
No intervention; index of Trp
calculated at breakfast
Not available Naturalistic study design Sleep habits and
mental symptoms
(e.g. depression,
anger)
Positive correlation between Morning–Evening scores
and Trp index for infants and young elementary
children; lower Trp index scores associated with
increased levels of difficulty in infants falling
asleep at bedtime and waking up in the morning
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
3. Effects of tryptophan loading on cognitive function
In the past decades, animal and human experiments have
provided evidence that central 5-HT can modulate a wide array of
cognitive processes, although the specific actions of 5-HT on
distinct cognitive (sub) domains remains somewhat elusive. Much
of the evidence is derived from psychopharmacological manipula-
tions that increase or decrease 5-HT activity in the brain, either
globally or via specific 5-HT receptors. An overview of the vast
literature on animal studies investigating the role of 5-HT on
cognition is beyond the scope of this paper. Several excellent
reviews have recently been published on this topic (e.g. Monleon
et al., 2008; Meneses, 2007a; Meneses and Perez-Garcia, 2007b;
King et al., 2008; Fone, 2008).
In humans, most data originate from studies that have used
acute tryptophan depletion (ATD) to induce an acute global
reduction in 5-HT synthesis in the brain, or from studies using
acute or sub-chronic administration of pro-serotonergic drugs,
mostly antidepressants. Detailed recent reviews are available on
the effects of ATD on human cognitive functioning (Mendelsohn
et al., 2009) and human brain activation (Anderson et al., 2008;
Evers et al., 2007; Fusar-Poli et al., 2006), as well as on the findings
of pro-serotonergic drug research (Schmitt et al., 2006; Merens
et al., 2007; Harmer, 2008). Studies examining the cognitive effects
of 5-HT stimulation by TRP loading on human cognitive
performance provide additional information on the role of 5-HT
in human cognitive performance and these studies are reviewed
(see Table 1). In the following sections, the TRP loading results for
each of the investigated cognitive domains are discussed in the
context of the relevant findings from human ATD and pro-
serotonergic drug studies.
3.1. Tryptophan loading and memory
Research indicates that 5-HT is involved in specific memory
processes. The most compelling evidence for this in humans has
been obtained from ATD studies showing impaired long-term
memory functioning following ATD. These seem to be specifically
related to disturbed consolidation of new information in the long-
term memory. The effects of ATD are most robustly observed in
visual verbal learning tests, where delayed recall and/or recogni-
tion is impaired (Mendelsohn et al., 2009; Schmitt et al., 2006).
However, a recent pooled analysis of nine ATD studies (Sambeth
et al., 2007) revealed that ATD also impairs immediate recall,
potentially through disruption of early consolidation and/or
impairment of encoding of new information. The impairing effects
were more pronounced in women. No consistent ATD-induced
impairments were found on short-term or working memory
(Mendelsohn et al., 2009). As for serotonergic stimulation, studies
employing acute or sub-chronic administration of serotonergic
drugs (i.e. SSRIs, 5-HT receptor agonists) in healthy volunteers
show an inconsistent pattern of no effects, impairments and
improvements of various memory functions (Schmitt et al., 2006).
Although in depressed patients, successful serotonergic pharma-
cotherapy is generally associated with cognitive enhancement, the
direct effects of 5-HT on memory and other cognitive functions
cannot be easily disentangled from potential cognitive enhance-
ment through alleviation of other depressive symptoms (mood,
motivation and sleep disturbances) (see Schmitt et al., 2006).
A total of eight studies have examined the memory effects of
Trp loading, with four measuring effects on long-term memory
functioning. Sobczak et al. (2003) reported memory deficits
following Trp loading in healthy adults and in healthy first-degree
relatives of bipolar patients. Specifically, impairments in delayed
word recall and recognition were found following an intravenous
7 g Trp challenge. However, the high dose of Trp (which increased
plasma Trp–LNAA ratio by 1500%) also produced significant
sedative effects that were apparent from the subjective rating
scores. Moreover, sedation was positively correlated with memory
decrements, suggesting that the memory impairment may be
attributed to melatonin accumulation, a neuro-hormone that
regulates the circadian cycle by chemically causing drowsiness and
thus promoting sleepiness (Richardson, 2005; Vanecek, 1998, see
Section 6).
During the premenstrual stage, women with premenstrual
complaints manifest serotonergic abnormalities (Halbreich, 2003;
Kouri and Halbreich, 1997), which may underlie, at least partially,
certain symptoms, such as memory deficits (Schmitt et al., 2005).
Interestingly, 40 g
a
-lactalbumin (plasma Trp–LNAA ratios
increased between 6% and 25% from baseline) or a carbohydrate
rich drink (Trp–LNAA increased ratio by 29%) resulted in
improvements in long-term memory for abstract figures and
long-term memory word recognition, respectively, in women with
premenstrual complaints during the premenstrual stage (Sayegh
et al., 1995; Schmitt et al., 2005).
In a more recent study, exploring the effects of Trp loading on
cognitive performance in unmedicated recovered depressed
patients and matched controls, Booij et al. (2006) found that an
a
-lactalbumin-rich diet (two chocolate drinks each containing a
whey-protein fraction rich in
a
-lactalbumin; containing 12.32 g/
kg Trp; Trp/
S
LNAA ratio of 8.7%) improved abstract visual memory
(specifically, recognition and speed of retrieval from short- and
long-term abstract visual memory), without affecting mood, in
healthy controls and in recovered depressed subjects (plasma Trp–
LNAA ratio increased 21% from baseline). These results indicate
that the beneficial effects of Trp loading on memory are not limited
to individuals vulnerable to 5-HT related disorders. Moreover,
these findings are consistent with the ATD literature where
memory consolidation deficits have been observed in healthy
volunteers (Riedel et al., 1999; Schmitt et al., 2000). However, the
beneficial effects of Trp loading on memory performance may be
attributed to impaired memory performance that was observed in
the placebo (casein) condition. Without a non-intervention control
group this possibility cannot be negated. However, the change in
plasma Trp–LNAA ratio in the casein condition is comparable to
previous findings (Merens et al., 2005; Schmitt et al., 2005) and
justifies the use of casein as a placebo.
The other four studies focused on working memory perfor-
mance changes after Trp loading. Luciana et al. (2001) compared
the effects of Trp loading with the effects of Trp depletion on
various cognitive processes in healthy subjects. 10.3 g
L
-Trp
loading increased total plasma Trp by tenfold (53.22 at baseline
to 551.4
m
mol/L), and resulted in decrements to working memory
performance for verbal and affective stimuli relative to Trp
depletion. As both Trp loading and Trp depletion resulted in
decreased levels of positive affect, the authors argue that the
memory impairments in the Trp loading condition are not likely to
be attributed to changes in mood. However, as there was no
placebo condition the results are difficult to interpret and may be
inflated.
Improvements in short-term memory scanning have been
observed in stress-vulnerable subjects following acute Trp loading
(Markus et al., 1999, 2002). Increased serotonergic activity is an
established consequence of stress (Joseph and Kennett, 1983;
Stanford, 1993), and continual stress may lead to a shortage of the
supply of this neurotransmitter. Consequently, serotonin activity
may drop below the functional levels producing stress-related
cognitive disturbances. In accordance with this, it would be
expected that Trp loading would improve cognitive performance in
stress-prone subjects following acute stress as the diminished
serotonergic pools are replenished by Trp loading. Consistent with
this, Markus et al. (1999) found short-term memory scanning
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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improvements, following laboratory acute stress, only in high
stress-prone volunteers after a carbohydrate rich/protein poor
diet. In low stress-vulnerable subjects, Trp loading had no effect on
cognitive performance, as the serotonergic system was not
compromised to begin with. Further support for the beneficial
effects of Trp loading in high stress-prone subjects was found in a
later study where increases in plasma Trp, following an
a
-
lactalbumin-rich diet (two chocolate drinks each containing a 20 g
whey-protein fraction rich in
a
-lactalbumin; containing 12.32 g/
kg Trp; Trp/
S
LNAA ratio of 8.7%), were shown to improve memory
scanning ability in healthy, stress-vulnerable subjects (Markus
et al., 2002). As expected, and consistent with the previous study,
this effect was not observed in the control group (low stress-
vulnerable subjects) (Markus et al. (2002). Interestingly, in an
earlier study Markus et al. (1998) failed to show improvements to
short-term memory following a carbohydrate rich/protein poor
diet in stress-prone subjects following laboratory stress. Although
the diet significantly increased the plasma Trp–LNAA ratio by 42%,
no memory scanning effects were found. The authors suggested
that the lack of effects may be attributable to a higher level of the
subject’s control of the induced stress (Markus et al., 1999).
Hitherto, no studies addressing the chronic effects of Trp on
human cognitive function have been performed. However, animal
studies have produced some interesting results. In a recent study, it
was shown that following 6 weeks of oral Trp administration
(100 mg/kg body weight), spatial working memory was improved
in Trp-treated rats (Haider et al., 2006). Similarly, Khaliq et al.
(2006) reported improved memory following 6 weeks oral
administration of Trp at doses of 50 and 100 mg/kg body weight
in rats. At both doses plasma Trp, brain Trp, and 5-HT levels
increased with Trp. The authors concluded that increases in brain
5-HT synthesis following long-term Trp administration may be
involved in the observed memory enhancement. Haider et al.
(2007) reported improvements in short- and long-term memory
and in learning acquisition following 6 weeks administration of Trp
at doses 50 and 100 mg/kg body weight in rats. These results
further indicate that long-term administration of Trp as a dietary
supplement may be beneficial to memory functioning. Future work
should assess whether chronic consumption of Trp similarly
improves memory function in humans.
In summary, improvements in long-term memory processes,
memory scanning ability, and abstract visual memory following
Trp loading have been shown in vulnerable and clinical popula-
tions where some serotonergic disturbances are known (i.e.
females with premenstrual symptoms, recovered depressed
patients, and in stress-vulnerable subjects following experimental
stress). In contrast, in healthy volunteers the reports are
inconsistent.
3.2. Tryptophan loading and attention
Sustained attention (vigilance) refers to the ability to direct and
focus attention or alertness to a task over a prolonged period of
time. There is consistent evidence from a series of studies with
serotonergic antidepressants that 5-HT stimulation (acute and
sub-chronic) impairs vigilance performance in healthy volunteers
as measured by the Mackworth Clock Test (Riedel et al., 2005;
Wingen et al., 2008; for review see Schmitt et al., 2006). In contrast,
ATD generally does not affect sustained attention (Mendelsohn
et al., 2009) as measured by a variety of tasks (although not the
Mackworth Clock Test). Two studies have assessed the effects of
Trp loading on sustained attention. Both Luciana et al. (2001) and
Dougherty et al. (2007) observed fewer errors of omission during a
vigilance task in the Trp loading condition (10.3 g
L
-Trp; 5.15 g Trp,
respectively) relative to the Trp depletion condition, in healthy
adults. These results suggest that Trp loading may improve
sustained attention. However, as there was no placebo condition
and results were compared only to Trp depletion, the results may
be inflated.
Focused or selective attention refers to the ability to attend to
relevant stimuli while simultaneously ignoring irrelevant informa-
tion. ATD studies have provided evidence for 5-HTs involvement in
focused attention (Mendelsohn et al., 2009; Schmitt et al., 2006).
ATD has been shown to reduce interference on the Stroop test (a
frequently employed measure of focused attention, response
inhibition, and cognitive flexibility) and increase performance on
focused attention components of dichotic listening tasks in healthy
and depressed subjects (Booij et al., 2005; Rowley et al., 1998;
Schmitt et al., 2000). Further substantiation for 5-HTs role in
focused attention is found in ATD studies employing electro-
physiological measures in healthy subjects (Ahveninen et al.,
2002).
The few studies that have explored the effects of 5-HT loading
on focused attention (Go/NoGo Task, Stroop Colour Word Test,
Left/Right Choice Reaction Time, Dichotic Listening Task) have
shown minimal effects. A 7 g intravenous Trp challenge resulted in
performance decrements on the Go/NoGo Task and a Left/Right
Choice Reaction Time task in subjects with a first-degree relative
with bipolar disorder (Sobczak et al., 2003), which is consistent
with the effects of ATD on focused attention. Although the deficit in
focused attention could be explained by a corresponding sedative
effect produced by the high Trp dose, a similar deficit in focused
attention was not observed in the healthy control group. In
addition, the impairment did not extend to other tests of focused
attention (i.e. the Stroop test and dichotic listening). This is
consistent with Booij et al. (2006) who reported no effects of
a
-
lactalbumin (2 20 g whey-protein containing 12.32 g/kg Trp;
Trp–LNAA ratio increase from baseline 21%) on the Stroop task in
both recovered depressed patients and healthy controls.
There is no clear indication that Trp loading affects sustained or
focused attention, although the data on both functions are scarce.
No data are available on Trp loading effects on divided attention.
3.3. Tryptophan loading and executive functions
Executive functions is a general term that refers to a wide
variety of cognitive processes such as planning, decision-making,
monitoring and behavioural adaptation, reasoning, cognitive
flexibility, and response inhibition (Chan et al., 2008). These
functions are considered essential for purposeful, goal-directed,
future-oriented behaviour.
Serotonin’s contribution to executive functioning processes
remains unclear. ATD studies have produced inconsistent results
across most of the executive function domains. Although some
treatment effects have been reported for planning ability, cognitive
flexibility and decision-making (Murphy et al., 2002; Park et al.,
1994; Rogers et al., 1999, 2003; Sobczak et al., 2002; Talbot et al.,
2006), a considerable amount of research has shown no effects of
ATD on planning, cognitive flexibility, decision-making abilities,
response inhibition, and attentional set-shifting or reversal
learning (Anderson et al., 2003; Booij et al., 2005; Evers et al.,
2004, 2005; Gallagher et al., 2003; Hughes et al., 2003;
LeMarquand et al., 1998; Roiser et al., 2007, 2008; Talbot et al.,
2006).
Trp loading has not been shown to modulate planning or
response inhibition in healthy adults (Booij et al., 2006; Morgan
et al., 2007; Sobczak et al., 2003). Furthermore, in sub-group and
clinical populations, Trp loading has similarly not modulated
planning or response inhibition (Booij et al., 2006; Schmitt et al.,
2005). However, Sobczak et al. (2003) observed significant
decrements in planning functions (assessed with the Tower of
London task) in healthy first-degree relatives of bipolar patients
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
following an intravenous 7 g Trp challenge, which was not
observed in the control group. Interestingly, planning deficits
have previously been reported in healthy first-degree relatives of
bipolar patients following acute tryptophan depletion (Sobczak
et al., 2002), which could suggest that these patients may be
sensitive to any modulations to serotonergic functioning.
Overall, Trp loading – as well as ATD studies – has not shown
clear evidence of serotonergic modulation of the various aspects of
executive functioning. Although this may indicate 5-HT does not
exert a meaningful influence on these functions, the inconsisten-
cies may also be partly related to more general issues regarding
executive function test sensitivity and reliability, particularly in
repeated assessments where the level of novelty may confound the
test outcomes (Rabbitt, 1997; Chan et al., 2008).
3.4. Tryptophan loading and emotional processing
Over past years, there has been an increasing interest in the role
of serotonin in processing and classifying emotionally loaded
information. Emotional processing is typically assessed by
measuring response biases to positive or negative stimuli (words,
pictures, reward, punishment) in attention, memory or reaction
time tests, or by measuring perception and classification of
emotionally loaded stimuli, such as emotional face expressions.
Evidence for a serotonergic involvement in such processes has
emerged, as human studies have shown that ATD can decrease
recognition of facial emotions, particularly for fearful expressions,
and leads to a response bias towards negative stimuli in healthy
volunteers and vulnerable populations (Harmer, 2008), although
an absence of ATD effects on facial recognition has also been
reported (Cools et al., 2005; Fusa-Poli et al., 2007; Van der Veen
et al., 2007). Serotonergic stimulation by acute SSRI administration
produces generally opposite effects of those seen with ATD and
enhances positive affective processing (see Harmer, 2008; Merens
et al., 2007 for detailed overviews).
Although the number of studies is limited, the results suggest
that Trp loading can modulate emotional information processing
using facial emotion recognition tasks. Attenburrow et al. (2003)
investigated the acute effects of pure Trp (1.8 g Trp) loading on
facial expression recognition in healthy females. The authors found
that Trp enhanced the perception of fearful and happy facial
expressions relative to placebo. Consistent with this, Murphy et al.
(2006), reported increases in the recognition of happiness and
decreases in the recognition of disgust in healthy females following
14 days Trp intervention (1 g three times a day). Furthermore, Trp
administration decreased attentional vigilance towards negative
stimuli and reduced the baseline emotional startle response. These
effects were not seen in males. Interestingly, modulations of
emotional processing were observed in the absence of any change
in subjective mood ratings. Thus, the authors argue that the
decrease in attentional vigilance towards negative stimuli is a
direct consequence of modulations to 5-HT levels in the brain that
is independent to mood improvement.
In contrast, Scrutton et al. (2007) failed to find an effect of 40 g
a
-lactalbumin-rich drink (total Trp 1.8 g) on recognition of
emotional facial expressions in healthy females. This discrepancy
in results may be attributed to the considerably lower increase in
plasma Trp–LNAA ratio that was achieved following
a
-lactalbumin
(+80%) relative to the Trp–LNAA ratio achieved with pure Trp
(approximately 6-fold increase; Attenburrow et al., 2003). The
increase in Trp–LNAA ratio following
a
-lactalbumin may not have
been sufficient to modulate emotional processing (Scrutton et al.,
2007).
The available reports suggest that Trp loading in females can
induce a positive bias in the processing of emotional stimuli, which
is consistent with the effects of serotonergic antidepressants
(Harmer et al., 2003, 2004, 2006). There is some indication that
these changes occur following higher increases of the Trp–LNAA
ratio, but the current dose–response data are very limited. The
results also suggest that women may be more susceptible to
serotonergic manipulations than men. However, given the small
male sample size it is difficult to draw conclusions regarding the
effect of Trp loading on emotional processing in men.
3.5. Tryptophan loading and psychomotor performance
Trp loading has consistently been shown to impair motor
performance on a range of psychomotor tasks (specifically:
Grooved pegboard test, Left/right choice reaction time task, Motor
choice reaction time task, and the Symbol copying test), in both
healthy adults (Booij et al., 2006; Luciana et al., 2001; Sobczak
et al., 2003; Winokur et al., 1986) and in vulnerable populations
(Booij et al., 2006; Sobczak et al., 2003) following both Trp loading
(range 5–10.3 g) and administration of an
a
-lactalbumin-rich
drink. In line with this, decrements in reaction time performance
following Trp loading have also been consistently reported in
healthy and sub-group volunteers following both Trp and a
carbohydrate rich/protein poor diet (Cunliffe et al., 1998; Markus
et al., 1998; Morgan et al., 2007; Murphy et al., 2006). These
findings suggest that Trp has a mild sedative effect, which is
consistent with previous sleep studies (refer to below Section 5).
Although Cunliffe’s et al. (1998) findings of a decreased Critical
Flicker Fusion threshold (measure of central fatigue) appears to
support Trp’s sedative effects, the putative effects of pupillary
changes were not accounted for. Previous research has shown that
modulations to serotonergic activity through administration of
SSRIs induce an acute and steady increase in pupil diameter
(Schmitt et al., 2002), independently invoking CFF threshold
increases. Nevertheless, the observed increase in subjective ratings
of fatigue reported by Cunliffe et al. (1998) does lend support for
Trp’s sedative effects. Furthermore, the fact that decrements to
psychomotor and reaction time performance have been reported
across different study populations (i.e. healthy, sub-group, clinical
populations), further suggests that psychomotor performance
impairment may be attributed to the proposed sedative effects of
Trp loading, that may be linked to increased melatonin production.
3.6. Conclusion
In summary, the beneficial effects of Trp loading on cognition
are generally modest and not always found. Following Trp loading,
improvements in long-term memory for verbal and abstract
information, as well as memory scanning ability has been shown in
vulnerable and clinical populations. In healthy volunteers the
results are less consistent. However, Trp loading does appear to
induce a positive bias in the processing of emotional stimuli in
healthy women, which is consistent with the SSRI literature. Trp
loading has also consistently been shown to impair psychomotor
and reaction time performance across the different study
populations (i.e. healthy adults and vulnerable populations). There
is no clear indication that Trp loading affects attention or executive
functions, but studies in this field are too limited and hetero-
geneous to allow any firm conclusions.
4. Effect of tryptophan loading on mood and alertness
Since lowered serotonergic functioning has been implicated in
affective disorders (Arango et al., 2002; Deakin, 1998; Delgado,
2000; Mahmood and Silverstone, 2001), the role of 5-HT on mood
has been extensively investigated. ATD studies have shown a
significant, transient reappearance of depressive symptoms
following ATD in both medicated and unmedicated depressed
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
patients in remission (Delgado et al., 1990; Smith et al., 1997), and
in subjects with family histories of depression (Benkelfat et al.,
1994). Although there have been reports of mood-lowering effects
of ATD in healthy subjects (Young et al., 1985), the bulk of the
literature indicates no effects in healthy volunteers (see Ruhe et al.,
2007). Similarly, administration of pro-serotonergic drugs to
healthy volunteers generally does not induce mood changes
(Merens et al., 2007). Based on these results, it is expected that Trp
loading may improve mood in vulnerable populations where
dysfunction of the serotonergic system is known. However, in
healthy subjects, it is likely that the effects of Trp loading on mood
are less clear, with minimal effects expected.
4.1. Effect of tryptophan loading on mood in clinical populations
Over five decades ago Lauer et al. (1958) reported the first
observation that Trp loading improves mood. Some of the earlier
research investigated the use of Trp with other antidepressant
treatments, demonstrating the ability of Trp (doses ranging from
3.5 to 18 g/day) to potentiate the action of monamine oxidase
inhibitors and tricyclic antidepressants in depressed patients
(Ayuso Gutierre and Lopez-Ibor Alino, 1971; Coppen et al., 1963;
Glassman and Platman, 1969; Pare, 1963).
There are a substantial number of studies that have addressed
the efficacy of Trp given alone as an antidepressant (Bowers, 1970;
Chouinard et al., 1979, 1983; Mendels et al., 1975; Murphy et al.,
1974; Steinberg et al., 1999; Thomson et al., 1982), and there are
many reviews available on the topic (Baldessarini, 1984; Carroll,
1971; Cole et al., 1980). However, there is little consensus in terms
of Trp’s efficacy in treating depression as studies vary considerably
in terms of sample size, study populations, dosages, study designs,
and control conditions. For instance, in severely depressed
inpatients, Trp has been shown to have little or no effect when
compared with placebo (Chouinard et al., 1983). In contrast, Trp
has been reported to be an effective antidepressant in mild to
moderately depressed outpatients (Thomson et al., 1982). While in
patients with premenstrual dysphoric disorder, Steinberg et al.
(1999) found that 6 g
L
-Trp (given as 2 g three times a day for 17
days) was more effective than placebo in controlling extreme
mood swings, dysphoria, irritability, and tension.
4.2. Effect of tryptophan loading on mood and alertness in healthy and
vulnerable volunteers
Research investigating the effects of Trp loading on mood in
healthy volunteers and in vulnerable subjects with presumed
dysfunction of the serotonergic system (i.e. stress-vulnerable
subjects, recovered depressed patients, unaffected first-degree
relatives of bipolar disorder patients) has also produced varying
results. Refer to Table 2 for summary of main findings relating to
the effects of Trp loading on mood.
In a recent study in healthy adults, the effects of a hydrolysed
protein on plasma Trp–LNAA ratio and mood was compared to
other sources of Trp (
a
-lactalbumin, hydrolysed protein, pure Trp,
a Trp-containing synthetic peptide), and a placebo protein (Markus
et al., 2008). All of the interventions contained a similar amount of
Trp (0.8 g Trp; excluding placebo), but differed in the content of
other amino acids. The hydrolysed protein produced significantly
faster and greater increases in plasma Trp–LNAA ratio (255%)
compared to
a
-lactalbumin (67%) and pure Trp (191%). Mood (a
total mood disturbance score obtained by summing all six factor
scores of the POMS questionnaire; the six mood factors include:
tension-anxiety, depression-dejection, anger-hostility, vigour-
activity, fatigue-inertia, and confusion-bewilderment) was sig-
nificantly improved 60 min following the hydrolysed protein and
pure Trp. The most profound and durable mood enhancing effects
were observed 210 min after intake of the hydrolysed protein. No
significant mood effects were observed with
a
-lactalbumin or the
synthetic Trp peptide. The lack of a mood effect in the
a
-
lactalbumin condition is consistent with previous research that has
only shown
a
-lactalbumin to reduce feelings of depression
(Markus et al., 1998, 2000) and increase ratings of vigour (Markus
et al., 1998) in stress-vulnerable subjects after acute stress
exposure (Markus et al., 1998, 2000). These results indicate that
larger increases in plasma Trp–LNAA ratio may be more likely to
modulate mood, even in healthy adults.
In contrast, Sobczak et al. (2002, 2003) reported increased
feelings of anger, depression, fatigue, tension, and decreased
feelings of vigour (measured by an abbreviated version of POMS)
and alertness (measured by Bond and Lader Visual Analogue Scale)
in unaffected first-degree relatives of bipolar disorder patients and
healthy controls following a single intravenous 7 g Trp challenge,
when compared to placebo. The intervention led to a 1500%
increase in plasma Trp–LNAA ratio. This increase in plasma ratio
was considerably higher than what was observed by Markus et al.
(2008) and this may have resulted in the opposite mood effect,
specifically negative effects.
A carbohydrate rich/protein poor drink and an
a
-lactalbumin-
rich drink (chocolate drink containing a whey-protein fraction rich
in
a
-lactalbumin; 2 20 g whey-protein containing 12.32 g/kg
Trp; Trp/
S
LNAA ratio of 8.7%) has been shown to reduce feelings of
depression (measured by the depression subscale of the Profile of
Mood States inventory; Markus et al., 1998, 2000) and increase
ratings of vigour (measured by the vigour subscale of the Profile of
Mood States [POMS] inventory; Markus et al., 1998) in high stress-
vulnerable subjects, exposed to experimental stress, relative to a
protein rich/carbohydrate poor drink or a casein diet. In contrast,
no effect of Trp loading was observed on measures of mood and
depressive symptoms in low stress-vulnerable subjects (control)
exposed to experimental stress (Markus et al., 1998, 2000). The
effects of the Trp-rich drink on ratings of depression and vigour
were found when plasma Trp–LNAA ratio increased by only 48%
(Markus et al., 1998, 2000). However, this increase in plasma Trp–
LNAA ratio may not have been high enough to modulate mood in
healthy adults, based on the findings by Markus et al. (2008) and
Sobczak et al. (2002, 2003).
Merens et al. (2005) did not find Trp loading to significantly
modulate ratings of depression, anger, fatigue, tension, and vigour
(measured with the POMS), in stress-induced unmedicated
recovered depressed subjects and healthy controls. Although there
was a trend reduction in depressive ratings following
a
-
lactalbumin (2 20 g whey-protein fraction rich in
a
-lactalbu-
min; containing 12.32 g/kg Trp; Trp/
S
LNAA ratio of 8.7%) in stress-
induced unmedicated recovered depressed subjects, a similar
decrease was also observed in the casein (placebo) condition. The
authors argue that 1-day
a
-lactalbumin intervention may not be
sufficient to prevent a stress-induced deterioration in mood in
unmedicated recovered depressed subjects. Furthermore, plasma
Trp–LNAA ratio increased by only 21%, which may not have been
sufficient to significantly reduce depressive ratings in the
recovered depressed subjects.
These findings are consistent with a later study that reported no
effects of an
a
-lactalbumin-rich diet (two drinks containing a
whey-protein fraction rich in
a
-lactalbumin; containing 12.32 g/
kg Trp) on POMS subscales (i.e. depression, anger, fatigue, tension,
vigour) in recovered unmedicated depressed patients and healthy
controls (Booij et al., 2006), when plasma Trp–LNAA ratio
increased by 21% from baseline.
Similarly, several other studies that have failed to show
modulations to mood following Trp loading in healthy adults also
reported relatively small increases in plasma Trp–LNAA ratio
(relative to the plasma increases noted by Markus et al. (2008) and
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Sobczak et al. (2002, 2003)). Specifically, Beulens et al. (2004)
reported a 16% increase following an
a
-lactalbumin drink and
Scrutton et al. (2007) reported an 80% increase following an
a
-
lactalbumin-rich drink. Murphy et al. (2006) and Luciana et al.
(2001) also did not find Trp loading to modulate mood in healthy
adults. However, plasma Trp–LNAA ratio was not measured.
In conclusion, the effects of Trp loading on mood factors in
healthy volunteers and in vulnerable subjects with presumably
sub-optimal central serotonergic function are rather inconsistent,
with some reports indicating improvements, other reports
showing decreases, yet other studies showing no effect. However,
it is plausible that differences in elevations of the plasma Trp–
LNAA ratio may elucidate some of these inconsistencies. This will
be addressed further in Section 6.
5. Effect of tryptophan loading on sleep
Trp has been shown to have direct effects on the homeostatic
regulation of sleep (Minet-Ringuet et al., 2004), by increasing
availability of brain 5-HT which has been implicated in the
regulation of sleep (Bhatti et al., 1998; Hartmann and Greenwald,
1984). In the pineal gland, 5-HT serves as precursor of melatonin
(Kleine and Moore, 1979), a neuro-hormone secreted during the
night which acts as the signal for darkness in the internal milieu
(Vanecek, 1998).
Nocturnal Trp administration is known to increase physiolo-
gical concentrations of both serotonin and melatonin (Esteban
et al., 2004). Melatonin production in the pineal gland is high
during the night and inhibited by light. Therefore, in the evening
the synthesis of melatonin is activated and serotonin is converted
to melatonin (Richardson, 2005). Administration of Trp during the
night can therefore be useful in facilitating sleep as Trp increases
the release of melatonin (Hajak et al., 1991).
In addition, 5-HT has some direct effects on sleep. Electro-
physiological, neurochemical and neuropharmacological studies
have shown serotonergic activation promotes waking and inhibits
slow-wave sleep and/or rapid eye movement (REM) sleep.
Specifically, serotonergic neurons of the dorsal raphe nucleus fire
at a steady rate during waking, but decrease their firing during
slow-wave sleep, and almost cease activity during REM sleep
(Monti and Jantos, 2008 for review).
The effects of Trp on sleep have been investigated for over four
decades, with several older reviews available on this topic (Cole
et al., 1980; Hartmann and Greenwald, 1984; Young, 1986). The
first study to assess the effects of Trp on sleep, Oswald et al. (1966)
reported that 5–10 g Trp decreased the time before onset of REM
sleep in healthy adults. Since then much research has been
conducted in both healthy and clinical populations, specifically
insomniacs, to explore the effects of Trp loading on sleep
parameters. Refer to Table 3 for summary of the main findings
pertaining to the effects of Trp loading on sleep measures in
healthy adults, vulnerable populations, and infants and children.
5.1. Effect of tryptophan loading on sleep parameters in insomniacs
The bulk of evidence indicates that doses as low as 1 g
L
-Trp
significantly reduce sleep latency and increase subjective ratings of
sleepiness in subjects with insomnia (Brown et al., 1979;
Hartmann et al., 1974; Hartman and Spinweber, 1979; Ko
¨rner
et al., 1986; Spinweber, 1986). Doses below 1 g have shown trends
towards decreased sleep latency in mild insomniacs (Hartman and
Spinweber, 1979). Although in a recent study Hudson et al. (2005)
demonstrated that 250 mg pharmaceutical grade Trp and protein
sourced Trp (25 mg deoiled butternut squash seed meal containing
22 mg Trp/1 g protein mixed with 25 mg dextrose) significantly
improved subjective and objective sleep measures in clinically
diagnosed insomniacs. However, given the small sample size
further research is warranted. Overall, these results indicate that
Trp at doses as low as 1 g improve time to onset of sleep, and doses
below 1 g produce trends in a similar direction.
Few studies have reported modulations to sleep stages in
insomniac subjects following Trp loading. Hartman and Spinweber
(1979) found Stage IV sleep (deep sleep) to be significantly
increased following only 250 mg of
L
-Trp, with no modulations to
sleep observed following 500 mg or 1 g Trp. In a dose–response
study, Hartmann et al. (1974) found that 1–15 g of
L
-Trp decreased
sleep latency, but only doses above 5 g increased slow-wave sleep
and decreased REM sleep. Other studies have failed to demonstrate
modulations to sleep stages (Brown et al., 1979; Spinweber, 1986),
which may, in part, be attributed to varying Trp doses. Spinweber
(1986) found that 3 g
L
-Trp did not alter sleep stages or brain
electrical activity during sleep in chronic sleep-onset insomniacs.
However, significant decreases in sleep latency on nights 4–6 of
Trp administration were found relative to placebo. Similarly,
Brown et al. (1979) did not report modulations to REM and slow-
wave sleep following 1 and 3 g
L
-Trp compared to placebo in
healthy females with mild falling asleep complaints. However,
significant reductions in sleep latency following the 3 g Trp dose
were observed. In summary, doses at low as 1 g
L
-Trp significantly
reduce sleep latency and doses lower than 5 g do not appear to
affect sleep stages.
5.2. Effect of tryptophan loading on sleep parameters in healthy
volunteers
In normal subjects, who fall asleep easily, it would be expected
that Trp loading would produce minimal hypnotic effects as sleep
latency is already short and sleep quality is normal. Nevertheless,
sleep parameters have been shown to improve in healthy subjects
manifesting no sleep problems. Studies have shown that doses of
500 mg, 1 g (Chauffard-Alboucq et al., 1991), 1.2 g, 2.4 g (George
et al., 1989), and 4 g (Spinweber et al., 1983)
L
-Trp significantly
reduced sleep latency and increased subjective ratings of sleepi-
ness in healthy adults during the day (George et al., 1989;
Spinweber et al., 1983; Thorleifsdottir et al., 1989) and during the
night (Chauffard-Alboucq et al., 1991). Interestingly, significant
negative correlations have also been reported between plasma Trp
level and sleep latency at 0, 60 and 120 min following 1.2 g and
2.4 g
L
-Trp administration in healthy adults (George et al., 1989).
Similarly, an intravenous challenge of 3 and 5 g
L
-Trp showed a
dose-dependent increase in the percentage of sleep observed
during Stages I and II (light sleep) during the day compared to
placebo in healthy males (Hajak et al., 1991). During nighttime
sleep, sleep latency for Stages I and II and sleep efficiency improved
following 1, 3, and 5 g
L
-Trp compared to placebo. Interestingly,
during the nighttime condition plasma melatonin increased
considerably higher following 1, 3 and 5 g Trp than during the
daytime condition, lending support to the notion that time of day
may influence melatonin synthesis (Hajak et al., 1991).
Chauffard-Alboucq et al. (1991) reported an increase in
nighttime sleepiness and sedative effects in healthy females
following 500 mg and 1 g
L
-Trp (combined with a carbohydrate
load) relative to placebo. This effect was observed when plasma
Trp–LNAA ratio increased 200% (500 mg) and 300% (1 g) from
baseline, peaking 90 min after Trp administration. Interestingly,
peak in perceived sleepiness was also found 90 min following Trp
consumption. Although previous studies have reported sleepiness
and sedative effects as early as 30 min following Trp administra-
tion (Hartmann et al., 1976; Yuwiler et al., 1981), this difference is
likely attributed to the significantly higher doses consumed,
specifically 4 g (Hartmann et al., 1976) and 50 mg/kg (Yuwiler
et al., 1981) Trp.
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
Few studies have reported modulations to sleep stages
following Trp loading. Furthermore, reports are somewhat
inconsistent. Wyatt et al. (1970) found 7.5 g Trp decreased REM
sleep and increased non-REM sleep in healthy subjects during the
night. Nicholson and Stone (1979) observed an increase in the
duration of Stage III (slow-wave sleep) sleep during the day
following 4 g
L
-Trp in healthy males. However, no modulations to
sleep stages were reported during nighttime sleep following 2, 4,
and 6 g
L
-Trp. In contrast, Spinweber et al. (1983) did not find 4 g
L
-
Trp to modulate sleep stages during the daytime sleep.
It has been argued that
L
-Trp may be an effective daytime
hypnotic for healthy adults, by facilitating sleep onset at times
outside the normal circadian rhythm. Spinweber et al. (1983)
found that during waking EEG, 4 g
L
-Trp significantly increased
alpha latency, theta latency, and theta amplitude, and decreased
alpha frequency, indicating a reduction in wakefulness. However,
no wave bands were modulated during sleep. Similarly, Thorleifs-
dottir et al. (1989) found that during the day, 2 g Trp increased
theta amplitude and decreased alpha amplitude in healthy adults,
characterising the EEG of drowsiness. In addition, increased
subjective ratings of sleepiness were also reported following
morning administration of Trp. Thus, it may be that during the day,
during wakefulness, Trp loading has a relaxing and calming effect
in healthy adults, whereas it has minimal effects on sleep in
healthy adults who fall asleep easily.
5.3. Effect of sub-chronic tryptophan loading on sleep
In patients with severe insomnia, Trp loading seems to either
lack the potency that other hypnotic drugs have, or doses have not
been high enough to modulate sleep. However, reports indicate
that interval and sub-chronic Trp treatment may be an effective
approach for improving sleep in severe cases of insomnia.
Several studies have observed improved sleep quality and
decreased sleep latencies during and several nights following Trp
treatment in chronic insomniacs (Demisch et al., 1987a; Hartman
et al., 1983; Schneider-Helmert, 1981). Interestingly, results are
consistent across different lengths of treatment period. For
example, following three nights of 2 g
L
-Trp administration,
significant improvements to sleep were found to continue during
a four night placebo period compared to the pre-Trp baseline
(Schneider-Helmert, 1981). Reductions to sleep latency have also
been shown 1 week after 1 g
L
-Trp treatment, but surprisingly not
during the 7-day treatment (Hartman et al., 1983). Similarly,
improvements in sleep were found following 4 weeks of 2 g
L
-Trp
treatment in patients with chronic insomnia (Demisch et al.,
1987a,b). During the control period (4 weeks following the 4 week
Trp treatment period), where no Trp was administered, sleep
deteriorated in half of the improved patients, i.e. 10 out of 19
subjects (Demisch et al., 1987a).
In healthy adults, five nights of 500 mg Trp administration has
also been reported to decrease sleep latency and increase sleep
depth, sleepiness, and calming effects, relative to five nights of
placebo (Leatherwood and Pollet, 1984). Interestingly, younger
females were found to be more sensitive to the sedating effects of
Trp than other groups (Leatherwood and Pollet, 1984). These
results suggest that in cases of severe insomnia or even in healthy
adults, Trp loading may be an effective hypnotic when consumed
sub-chronically or intermittently.
5.4. Effect of tryptophan loading on sleep and cognition
A benefit of Trp as a sleep aid is that it does not seem to impair
performance the next day following administration as some more
potent hypnotics have been shown to do (Johnson and Chernik,
1982; Vermeeren, 2004). In a recent study, the cognitive benefits of
evening Trp loading on morning performance were assessed
(Markus et al., 2005). As positive associations between Trp
availability and sleep have previously been shown (see above),
the aim of this study was to ascertain whether evening intake of
a
-
lactalbumin improves morning cognitive performance due to
improved sleep. The authors demonstrated that evening con-
sumption of 2 20 g
a
-lactalbumin protein with an enriched Trp
content of 4.8 g/100 g Trp, increased plasma Trp availability and
the Trp–LNAA ratio by 130%, decreased feelings of sleepiness in the
morning, and improved morning alertness and attention (mea-
sured by the P300 evoked related potential component) in subjects
with and without mild sleep complaints. However, only in subjects
with mild sleep complaints did evening consumption of
a
-
lactalbumin improve vigilance performance the following morn-
ing. These findings provide support for the notion that Trp loading
may improve cognition indirectly by improving sleep.
5.5. Effect of tryptophan loading on sleep in infants and children
The concentration of Trp in human milk varies in relation to the
age of the lactating infant, the duration of the milking episode, and
the time of day, where it has been shown to be higher during dark
time (Cubero et al., 2005). Recently it was shown that oscillations
in Trp concentration in maternal milk parallels oscillations in
infant urinary 6-sulphatoxy-melatonin (Cubero et al., 2005), thus
supporting Trp’s important role in maternal milk as a regulator of
the circadian rhythms of the infant. However, the internal clock
that the oscillating levels of Trp in maternal milk provides,
disappears with the use of commercial milk formulas, as the level
of Trp found in infant formulas always remains constant (i.e. no
difference in Trp level between daytime and nighttime formulas).
Furthermore, maternal milk has been shown to contain higher
levels of Trp than commercial formulas, which result in formula fed
infants manifesting lower plasma Trp concentrations compared to
human milk-fed infants (Heine, 1999).
The effect of Trp loading on sleep latency in newborns was first
investigated by Yogman and Zeisal (1983). The authors found that
newborn infants (2–3 days of age) fed Trp in glucose during an
evening feeding manifested shorter sleep latencies, and entered
rapid eye movement and quiet sleep (defined as quiescent state
with eyes closed, absence of eye movements, little or no motor
activity, and slow, regular respiration) sooner than when fed a
commercial formula containing Trp. A limitation of this study was
that the Trp was ingested in glucose solutions as a single dose,
rather than as a constituent of milk which was chronically fed to
infants.
Thus, in a later study, Steinberg et al. (1992) investigated
whether infant formulas, varying only in Trp content (0, 294, 588
and 882
m
mol/L), result in differences to plasma Trp concentration
and Trp–LNAA ratio, and whether the Trp–LNAA ratio was
predictive of infants’ (gestational age of 37–42 weeks) sleep
latency. Trp–LNAA ratio, and not plasma Trp concentrations,
predicted differences in sleep latency across treatment conditions.
Thus, sleep latency was shorter for infants with the highest Trp–
LNAA ratios. Infants consuming the high Trp dose (882
m
mol/L)
manifested shorter sleep latencies than infants consuming human
milk. Furthermore, infants receiving the high Trp dose tended to be
less alert, spent less time crying, and more time sleeping than the
infants fed lower levels of added Trp (0, 294, 588
m
mol/L). These
findings indicate that infant formula Trp composition can
modulate sleep latency and wakefulness in infants.
In a recent study, Aparicio et al. (2007) demonstrated that milk
formulas with Trp content that is appropriate to the light–dark
variations in Trp level improve the circadian sleep/wake cycles in
infants who are not breast fed. Specifically, infants (aged between
12 and 20 weeks) receiving a low Trp formula during the day and a
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
high Trp formula during the night, slept more, manifested better
sleep efficiency, increased immobility time, had fewer night
movements and waking episodes. No difference was found
between the two control groups (control group 1: low Trp formula
fed throughout the 24 h day; control group 2: low Trp formula fed
from 18:00 to 06:00 h and tryptophan-enriched milk (3.4 g Trp/
100 g protein) fed from 06:00 to 18:00 h) despite that the Trp
content varied considerably (1.5% and 2.72% [note that the latter %
is an average value]). These findings indicate that the use of
different formulas for day and night feeding constitutes an
interesting and novel approach to infant nutrition.
In a large Japanese sample, increased sleep latencies and
difficulties waking up in the morning were shown to be associated
with lower Trp index scores (Trp content consumed during
breakfast) in infants and children (0–8 years; Harada et al., 2007).
This effect was not similarly observed in older children (9–15
years). The authors concluded that Trp consumed at breakfast is
important to sustain a healthy circadian rhythm and improve
quality of sleep. A limitation of this study was that the Trp index
was calculated based only on what was consumed at breakfast.
Therefore, it cannot be excluded that the observed sleep
modulation was due to whole-day or evening dietary Trp intake,
of which breakfast measures may be a proxy.
5.6. Conclusion
Most of the beneficial effects of Trp loading on sleep have been
shown in subjects with some sleep disturbances, such as patients
with mild-moderate insomnia or healthy subjects reporting a
longer than average sleep latency. In these subjects, Trp doses as
low as 1 g have been shown to improve subjective measures of
sleepiness and decrease sleep latency, and doses below 1 g have
produced trends in a similar direction. However, modulations to
sleep stages have only been observed with doses above 5 g Trp (see
Fig. 3).
Interestingly, in healthy subjects who manifest no sleep
disturbances, Trp loading has also been shown to increase
subjective ratings of sleepiness and reduce sleep latency.
Furthermore, Trp appears to be an effective daytime hypnotic
for healthy adults, by facilitating sleep onset at times outside the
normal circadian rhythm, and modulating sleep stages during the
day. Thus, it may be that during wakefulness, Trp loading has a
relaxing and calming effect in healthy adults.
In patients with severe sleep insomnia, Trp loading does not
appear to be effective as a hypnotic. This may be because Trp lacks
the potency that other hypnotic drugs have, or study doses have
not been high enough to produce any sleep benefits. However, the
literature does suggest that Trp loading may be an effective
hypnotic for severe insomniac patients when consumed sub-
chronically or intermittently.
In infants, reports indicate that Trp loading improves sleep.
Moreover, it seems that varying the Trp content in milk formulas
that are appropriate to light–dark variations (i.e. low Trp levels
during daytime feeding and high Trp levels during nighttime
feeding) improves the sleep/wake cycles of infants who are not
breast fed.
6. Discussion
The beneficial effects of Trp loading on cognition are rather
modest and not always found. ATD studies have provided the
fundamental insights into which cognitive functions are suscep-
tible to modulation of 5-HT and the direction of effects. It would be
expected that Trp loading would produce opposite effects to that of
ATD. However, this has not generally been the case. Reports vary
considerably across the different cognitive domains, study designs,
and populations. There are several possible explanations for this.
Given the few Trp loading studies that have been performed,
there are considerable differences in methodology, such as, Trp
doses, method of administration, treatment regimes, and variances
in study populations, which all affect the central 5-HT effects that
are achieved, and thus the behavioural outcome of the manipula-
tion.
Variations in Trp dose will inevitably produce different results.
However, in addition, variations in Trp found in plasma may also
modulate the outcome. As metabolism differs across individuals
and populations, the level of plasma Trp would seem to be an
important aspect to be taken into consideration. However, only a
limited number of studies address this point. It may be that
variance in performance is dependent on the level of Trp found in
blood rather than as a function of dose administered. Furthermore,
plasma Trp–LNAA should also be considered as a means to identify
that a specific amount of Trp has been transported to the brain in
order to better understand the outcome. This notion is illustrated
in Figs. 1 and 2. In healthy subjects, plasma Trp–LNAA increases up
to 80% have not been found to modulate mood and memory (with
Fig. 1. Summary of the cognitive changes by increase in tryptophan versus large neutral amino acid (TRP–LNAA) ratios after tryptophan loading. Reference numbers are linked
to the symbols in order of appearance in the rows and refer to the studies described in Table 1.
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
exception of one study). However, larger increases in plasma Trp–
LNAA ratio (191–255%) have been shown to improve mood and
attention (Markus et al., 2005, 2008). While, considerably large
increases in Trp–LNAA ratio (up to 1500%) have been shown to
impair memory performance and produce negative mood effects
(Luciana et al., 2001; Sobczak et al., 2002, 2003). In vulnerable
subjects, it appears that the most beneficial effects of Trp loading
on memory, mood and alertness are attained when plasma Trp–
LNAA ratio increases 20–60% from baseline. Significant increases in
plasma Trp–LNAA ratio (i.e. above 151%) produce negative effects
across the different cognitive domains. Note that psychomotor
performance has consistently been shown to be impaired across all
populations irrespective of the plasma Trp–LNAA ratio. This will be
addressed later in the discussion. Future research should report
changes in the plasma Trp–LNAA ratio as this may help elucidate
the variance in Trp loading effects on cognitive functions in both
normal and vulnerable individuals.
The effects of Trp loading may also be dependent on the initial
state of the serotonergic system of the subject. Trp loading may
either move serotonin towards the optimal level (if the subject has
a hypo-serotonergic state to begin with (i.e. depressed, stress-
vulnerable, women with premenstrual complaints), thus improv-
ing performance, or move serotonin beyond the optimal level if the
subject is already at the optimal level to begin with (healthy
subjects), thus decreasing performance or producing no effects. Trp
loading seems to improve memory performance in vulnerable
subjects (i.e. premenstrual symptoms, recovered depressed
patients, stress-vulnerable subjects following experimental stress,
mild insomniacs), whereas, minimal modulations to memory
performance have been shown in healthy subjects. Moreover,
based on the ATD and Trp loading literature, it appears to be easier
to induce cognitive decrements than to enhance performance in
healthy subjects who already have a close to optimal performance
level. ATD always move 5-HT activity away from its optimum, thus
it is relatively easy to find decrements. However, it seems rather
difficult to improve already optimal function. These differences in
the initial state of the serotonin system may explain the variance in
reported effects, and the lack of mirrored behavioural effects of
opposite 5-HT manipulations. Comparing the effects of Trp loading
in individuals with low versus normal serotonergic states in the
same study could provide a clearer picture as to the influence of
initial serotonergic state on the effects of Trp loading. Only few
studies have implemented such a design and the general pattern of
results is rather inconsistent. Markus et al. (1999, 2002) found
improvements in memory scanning ability and mood (Markus
et al., 1998, 2000) in high stress-vulnerable individuals with no
effects in low stress-vulnerable subjects. In contrast, Booij et al.
(2006) reported improvements in abstract visual memory in both
vulnerable and control populations. Sobczak et al. (2002, 2003)
reported decrements in memory and psychomotor performance
and mood in both unaffected first-degree relatives of bipolar
disorder patients and healthy controls. Finally, Merens et al. (2005)
found no effect on mood in either recovered depressed patients or
healthy controls. Taken together, these comparative studies do not
indicate that initial state serotonergic function is a strong general
determinant of the effects of Trp loading. However, the large
heterogeneity in Trp loading methodology and dose, outcome
measures and ‘vulnerable’ study populations hampers a clear cut
comparison between studies. Furthermore, the actual presence
and extent of a lowered serotonergic state in the investigated
populations’ remains an assumption as 5-HT activity or vulner-
ability is not actually measured in the studies.
An important question that therefore needs to be addressed is
how we define serotonergic vulnerability. In the scientific
literature it generally refers to a vulnerability or sensitivity to
natural or experimental modulations or dysregulations to the
serotonergic system (Jans et al., 2007). There are a range of factors
that can modulate the serotonergic system which subsequently
may produce a hypo-serotonergic state. These include innate
factors, such as genetics, gender, personality characteristics,
prenatal stress; and environmental factors, such as stress and
drug use. It has been proposed that the serotonergic functioning of
an individual will determine the individual’s vulnerability to
develop a 5-HT related disorder (Jans et al., 2007). Specifically, the
model suggests that as long as the number of innate and
environmental factors that disrupt serotonergic functioning are
Fig. 2. Summary of the mood changes by increase in tryptophan versus large neutral amino acid (TRP–LNAA) ratios after tryptophan loading. Reference numbers are linked to
the symbols in order of appearance in the rows and refer to the studies described in Table 2.
B.Y. Silber, J.A.J. Schmitt / Neuroscience and Biobehavioral Reviews xxx (2009) xxx–xxx
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
limited, the disturbances they cause to the serotonergic system
will be compensated for, and thus no overt behavioural changes
should be observed. However, if several of these vulnerability
factors occur, a threshold will be reached and the system will no
longer be able to compensate (Jans et al., 2007). This is when overt
behavioural changes will be observed and pathologies surface. The
variance in performance following Trp loading may be related to
what is proposed by this model and may also elucidate the lack of
any mirror-behavioural effects with ATD reports. It is also
important to note that studies implementing manipulations to
the serotonergic system establish serotonergic vulnerability only
as an outcome, an endpoint. Therefore, there will always be
variations in the degree of serotonergic vulnerability within the
study population (even if the population is seemingly homogenous
i.e. depressed, stress-prone, healthy, etc.), and thus modulations in
performance in response to 5-HT challenges will vary across
subjects making interpretation of results difficult. Furthermore,
differences in the form that serotonergic vulnerability presents
itself, for example state or trait, may further complicate
interpretation of the effects of various manipulations of the
serotonergic system. Specifically, premenstrual syndrome in
women or stress may be defined as a state level of serotonergic
vulnerability as it is transient. Whereas, depression, a more stable
and permanent form of hypo-serotonergic state, can be seen as
trait. Thus, manipulations to the serotonergic system (5-HT
challenges or ATD) may modulate serotonergic functioning
differently for state or trait cases of serotonergic vulnerability,
thus producing variance in behavioural outcomes.
It is unclear whether the relationship between serotonergic
activity and cognitive function is a linear one or follows an
inverted-U curve, where either too little or too much serotonin can
impair performance. This may be true irrespective of the initial
state of the serotonergic system of the individual. In vulnerable
subjects, it seems that Trp loading improves performance when
plasma Trp–LNAA ratio increases up to 150% from baseline.
However, increases above this have been shown to negatively
impact performance across various cognitive domains (Fig. 1).
Similarly, in healthy subjects, the effects of Trp loading on memory
and mood appear to follow the inverted-U curve hypothesis.
Specifically, low doses of Trp attained from
a
-lactalbumin drinks
have been shown to produce minimal effects on memory
performance. Similarly, studies that have reported plasma Trp–
LNAA increases up to 80%, have not reported mood to be
modulated. However, large increases in plasma Trp–LNAA ratio
(191–255%) have been shown to improve mood (Markus et al.,
2008). Whereas, high doses of Trp (i.e. 7 g IV and 10.3 g) producing
increases in Trp–LNAA ratio up to 1500% have been shown to
impair memory performance and produce negative mood effects
(Luciana et al., 2001; Sobczak et al., 2002, 2003). This could be
related to both the initial serotonergic system of the individual (i.e.
high serotonin function) or to the Trp dose administered (i.e. high
doses). Independent of the positive association of 5-HT activity and
function or the inverted-U curve hypothesis, ATD will always move
5-HT activity away from good functioning and thus it is easy to
produce decrements. Currently there is insufficient evidence to
either support or dismiss an inverted-U curve hypothesis.
However, further research investigating this dose–response effect
could provide insight into an optimal plasma Trp–LNAA ratio that
may improve cognitive performance in healthy adults.
The effects of Trp loading differ across the cognitive domains.
Specifically, Trp loading has quite consistently been shown to
improve aspects of memory functioning in vulnerable subjects, yet
impair motor and reaction time performance within the same
population. This does not seem to be attributed to a dose effect as
Fig. 3. Summary of the changes in sleep measures by dose of tryptophan administered acutely or sub-chronically. Reference numbers are linked to the symbols in order of
appearance in the rows and refer to the studies described in Table 3.
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Please cite this article in press as: Silber, B.Y., Schmitt, J.A.J., Effects of tryptophan loading on human cognition, mood, and sleep.
Neurosci. Biobehav. Rev. (2009), doi:10.1016/j.neubiorev.2009.08.005
the same doses and populations were employed across the
cognitive domains. It may be that these cognitive functions are
related to different neuroanatomical serotonergic pathways. The
hippocampus has long been associated with learning and memory
processes (van Strien et al., 2009) and serotonergic projections
from the raphe nuclei innervate various hippocampal subregions
(King et al., 2008). Long-term memory improvements observed
following Trp loading may therefore be linked to increased
serotonergic activity in the hippocampus. Animal studies have
provided some evidence for memory enhancing effects of
augmentation of 5-HT neurotransmission in the hippocampus
(e.g. Haider et al., 2006, 2007) although other findings do not
support this notion (e.g. Farr et al., 2000; Adams et al., 2008).
Delineating the effects of global serotonergic manipulations on the
hippocampus is difficult due to the complexity of serotonin
receptor sub-types distribution on the different cell types in this
region (Meneses, 1999). For example, agonist as well as antagonist
5-HT6 receptors in the hippocampus can improve cognition, and
may be related to stimulation or inhibition (via GABAergic
interneurons) actions on cholinergic and/or glutaminergic activity,
depending on the localisation of the 5-HT6 receptors (King et al.,
2008). In humans, decreased activation in the right hippocampus
has been observed after ATD, but only during acquisition and not
during retrieval of verbal information, and this has been
hypothesised to reflect encoding and/or early consolidation
deficits (Van der Veen et al., 2006). However, it must be noted
that the serotonergic system also innervates other brain areas that
are considered to be important for learning and memory, including
the medial septum, entorhinal cortex and prefrontal cortext (King
et al., 2008) and memory effects of serotonin may therefore result
from a complex interplay of 5-HT actions on these as well as other
brain areas.
In addition, part of the cognitive effects of Trp loading may be
related to non-serotonergic mechanisms, particularly through
melatonin. Melatonin production in the pineal gland varies
dramatically in a circadian fashion that is internally controlled
by the suprachiasmatic nuclei of the anterior hypothalamus with
high levels of melatonin being synthesized and secreted during the
dark phase and virtually no production during the light phase
(Blask, 2009). Melatonin production is also inhibited by exposure
to light of sufficient intensity (>200 lux) (Brzezinski, 1997).
Nevertheless, Trp loading (3–5 g i.v.) has been shown to markedly
and dose dependently increase circulating melatonin in humans
during the day, albeit less pronounced as during the night (Hajak
et al., 1991). The enterochromaffin cells of the gastrointestinal tract
have been proposed as a significant source of circulating melatonin
during the day (Bubenik, 2002) and particularly after Trp loading
(see Huether, 1994). Interestingly, the melatonin production in the
gastrointestinal tract appears to be regulated by food intake rather
than photoperiodicity (Bubenik, 2002). Daytime conversion of Trp
into melatonin may underlie mild sedating effects of Trp loading,
especially at higher dosages, which may be most sensitively
detected by psychomotor tasks. Finally, alteration of glutaminergic
neurotransmission following Trp loading should be considered as
potential mechanism of cognitive effects, as Trp may be
metabolised via the kynurenine pathway, yielding quinolinic acid
and kynurenic acid that can activate and antagonise the NMDA
receptor, respectively (Ruddick et al., 2006).
Few studies have investigated the chronic effects of Trp loading
on cognitive functioning in humans. This is an interesting avenue
that should be explored further as it can provide insight into the
potential long-term benefits of Trp loading. Animal studies have
demonstrated that increases in brain 5-HT metabolism following
long-term Trp administration enhance memory processes. In
addition, human clinical trials assessing the effects of chronic Trp
administration in the treatment of depression have demonstrated
improvements to mood and a decrease in depressive symptoms.
These results suggest that chronic administration of Trp does not
necessarily decrease tolerance and desensitise the effects. It may
be that Trp loading has more of an accumulative effect, and thus
more robust cognitive effects may be seen following chronic
administration in healthy adults.
Over the past decades, a role of the central serotonergic system
in cognitive functioning has been revealed. In humans, these
insights stem largely from experiments describing the conse-
quences of reduced brain serotonergic function, often by means of
tryptophan depletion. Now the challenge is to identify under
which conditions an augmentation of serotonergic function can
exert beneficial effects, particularly in ‘healthy’ individuals, i.e.
without neuropsychiatric diseases, who nevertheless experience
sub-optimal mental states (as discussed above). Optimizing
mental health through restoration of state or trait serotonergic
hypofunction in such individuals is obviously a compelling notion.
In non-clinical populations a milder, non-pharmaceutical inter-
vention such as oral Trp loading may be the preferred manner to
achieve this. The current data seems to indicate that such an
approach may be feasible and valuable, although the research has
been rather fragmented and inconsistent in terms of methodol-
ogies. A structured approach, including investigations of dose–
response relationships, chronic studies and comparative effects in
well-characterised (presumably) serotonergically vulnerable
populations will not only provide deeper fundamental insights
into the role of serotonin in cognition and mood, but will also lead
to evidence-based recommendations for the use of Trp to
counteract cognitive and affective disturbances, particularly in
non-clinical populations.
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... Unauthorized reproduction of this article is prohibited. 13), tryptophan (14), tart cherries (15,16), glycine (17), magnesium (18) and L-theanine (19). ...
... Dietary tryptophan (Trp) is a well-established sleep active ingredient, which has over four decades of research within this area (14). Trp crosses the blood brain barrier by active transport, therefore acting to release the monoamine neurotransmitter serotonin, a precursor of melatonin (38). ...
... Trp crosses the blood brain barrier by active transport, therefore acting to release the monoamine neurotransmitter serotonin, a precursor of melatonin (38). However, given other large neutral amino acids (LNAAs) also compete to cross the blood brain active barrier system, it is the addition of an adequate dose of dietary Trp (1000-3000 mg), alongside an optimal Trp:LNAA ratio which increases brain bioavailability and can subsequently lead to enhanced sleep through the upregulation of melatonin (14,39). In comparison to our study, Hartmann and Spinweber (40) found that a dose of 1000 mg of Copyright © 2022 by the American College of Sports Medicine. ...
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Purpose: To test the hypothesis that a novel nutritional blend comprised of tryptophan, glycine, magnesium, tart cherry powder and L-theanine, enhances subjective and objective measures of sleep during free living conditions. Methods: In a randomised, repeated measures crossover and double blind deception design, participants (n = 9 male and 7 female; age: 24 ± 3 years; body mass: 69.8 ± 11.6 kg; stature: 170.8 ± 9.1 cm) completed a 3 day familiarisation period, followed by 3 day intervention and placebo trials. Subjective Pittsburgh Quality Sleep Index, Core Consensus Sleep Diary and Karolinska Sleepiness Scale survey tools, alongside objective actigraphy measures of sleep were assessed, with daily nutritional intake, activity and light exposure standardised between trials. Participants provided daily urine samples for assessment of targeted and untargeted metabolomes. Results: The intervention trial reduced sleep onset latency (-24 ± 25 mins; p = 0.002), increased total sleep time (22 ± 32 mins; p = 0.01) and sleep efficiency (2.4 ± 3.9 %; p = 0.03), whilst also reducing morning sleepiness (p = 0.02). Throughout the study, 75 % of participants remained blinded to sleep assessment as a primary outcome measure, with 56 % subjectively indicating improved sleep during the intervention trial. Metabolomic analysis highlighted several significantly altered metabolomes related to sleep regulation between trials, inclusive of 6-sulfatoxymelatonin, D-serine and L-glutamic acid. Conclusions: Data demonstrate that employing the proposed blend of novel nutritional ingredients during free living conditions reduced sleep onset latency, increased total sleep duration and increased sleep efficiency, leading to reduced perceptions of morning sleepiness. These effects may be mediated by the upregulation of key metabolites involved in the neurophysiological modulation of the sleep/wake cycle.
... Adequate tryptophan improves 5HT metabolism which improves mood, sleep and even cognition [108,109]. Acetylcholine plays an important role in attention and cognition. Even cholinergic signalling in sept hippocampal system improve the memory process [110] Drumstick ...
... It has also seen GLP-1 influences the dopamine levels in Parkinson's diseases. In animal models it inhibits oxidative stress and inflammation and reduces hippocampal neurodegeneration [107,108] ...
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Foods not only supply energy but also help in growth, development and maintenance of health including cognitive functions. It has also been observed that specific nutrients can affect cognitive abilities at different ages. Diverse nutrients present in the food play a crucial role in the maintenance of cognitive functions and deficiencies of such nutrients might lead to neurodegenerative diseases such as Alzheimer disease, Parkinson’s disease and other neuronal dysfunction including dementia. The purpose of the present study is to determine the existing data available in different science literature regarding food items available in India that have potent action on brain function. Searched in PubMed, Google Search, Google Scholar, Research Gate. Using the keywords “Foods for Brain”,Diet influence on cognition'', “Micronutrients on cognition “, “Diets in Cognition”. The direct connection between nutrition, brain function and behaviour exist in several research. Traditional Indian diet consists of many phytochemicals/phytonutrients which have shown one pivotal role in reducing inflammation. There are hundreds of different spices that are specifically used in traditional Indian food which are rich in many phytonutrients that proves to play an important role in better nerve health like turmeric prevents brain damage due to oxidative stress even saffron has neuroprotective properties that protects the hippocampus against age related damage. Many studies proved that specific nutrients can affect our brain development. Phytonutrients present in the Indian food does improves alertness, concentration and performance of brain by reducing oxidative stress, high inflammation, stress induced neurotoxicity and it also impacted on the nerve functionality,however how much portion of such specific food we need to include in diet for best cognitive performance is yet to get disclosed, further research is still needed in this field. Furthermore, traditional Indian foods are having bright future in improving neurological health of an individual.
... In healthy normo-serotonergic subjects, it has no effect or a negative effect. 27,28 The serotonergic system's sensitivity is likewise affected by genetic, environmental, and psychological factors. 16 In this study, the initial condition of the respondent's serotonergic system was not known. ...
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Introduction. Offshore and onshore workers have a higher risk of psychological stress related to their job. Stress reactions vary depending on the type of stressor, the duration or severity of the stressor, their genetics, their coping styles, and their nutrition. Tryptophan is an essential amino acid precursor of serotonin and melatonin, which have an antidepressant effect and roles in stress perception and management. This study assessed the correlation of daily tryptophan intake and occupational factors with stress outcome scores based on the Indonesian Short Version New Brief Job Stress Questionnaire (SV-NBJSQ) among offshore and onshore workers.
... Previously, the consumption of different proteins with different tryptophan content has shown to modify plasmatic levels of tryptophan and the tryptophan ratio, which directly correlates to levels of serotonin production within the central nervous system in rats and humans (Williams et al. 1999;Fernstrom et al. 2013;Orosco et al. 2004;Choi et al. 2009). Variations in serotoninmediated systems such as changes in mood (Markus et al. 2000;Steenbergen et al. 2016), sleep (Bravo et al. 2013;Binks et al. 2020), and cognitive performances (Luciana et al. 2001;Silber and Schmitt 2010) have been reported after tryptophan loading strategies in humans. Specifically, α-lactalbumin has already shown to increase the tryptophan ratio levels between 50 and 130%, 60-240-min post consumption in young healthy humans (Markus et al. 2005(Markus et al. , 2008Fernstrom et al. 2013;Oikawa et al. 2019). ...