Much of the evidence is derived from investigations that increase or decrease 5-HT activity in the brain, either globally or via specific 5-HT receptors. Several reviews have been published on this topic (1-5).
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 reviews are available on the effects of ATD on human cognitive functioning (6) and human brain activation (7-9), as well as on the findings of pro-serotonergic drug research (10-12).
Tryptophan 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 Much of the evidence is derived from investigations that increase or decrease 5-HT activity in the brain, either globally or via specific 5-HT receptors. Several reviews have been published on this topic (1-5). 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 reviews are available on the effects of ATD on human cognitive functioning (6) and human brain activation (7-9), as well as on the findings of pro-serotonergic drug research (10-12). Tryptophan 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 recognition is impaired (8,10).
However, a pooled analysis of nine ATD studies revealed that ATD also impairs immediate recall, potentially through disruption of early consolidation and/or impairment of encoding of new information (13). The impairing effects were more pronounced in women. No consistent ATD-induced impairments were found on short-term or working memory (10). 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 (12).
Although in depressed patients, successful serotonergic pharmacotherapy 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 enhancement through alleviation of other depressive symptoms (mood, motivation and sleep disturbances) (12).
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. reported memory deficits following Trp loading in healthy adults and in healthy first-degree relatives of bipolar patients (14). Specifically, impairments in delayed word recall and recognition were found following an intravenous 7 g Trp challenge. However, the high dose of Trp 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. (15,16).
During the premenstrual stage, women with premenstrual complaints manifest serotonergic abnormalities (17,18), which may underlie, at least partially, certain symptoms, such as memory deficits (12). In a study exploring the effects of Trp loading on cognitive performance in unmedicated recovered depressed patients and matched controls, Booij et al. found that an Trp enriched chocolate drink 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 ratio increased 21% from baseline) (17). 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 (9,12).
The other four studies focused on working memory performance changes after Trp loading. Luciana et al. 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, and resulted in decrements to working memory performance for verbal and affective stimuli relative to Trp depletion (19). 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.
Improvements in short-term memory scanning have been observed in stress-vulnerable subjects following acute Trp loading (20,21). Increased serotonergic activity is an established consequence of stress (22), 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. found short-term memory scanning 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, were shown to improve memory scanning ability in healthy, stress-vulnerable subjects (23). In an earlier study Markus et al. (22) 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 (20).
No studies addressing the chronic effects of Trp on human cognitive function have been performed. However, animal studies have produced some interesting results. In one 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 (24). Similarly, Khaliq et al. (25) 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.(24) 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.
Tryptophan 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 (7,9,12).
Two studies have assessed the effects of Trp loading on sustained attention. Both Luciana et al. (26) and Dougherty et al. (27) observed fewer errors of omission during a vigilance task in the Trp loading condition relative to the Trp depletion condition, in healthy adults. These results suggest that Trp loading may improve sustained attention.
Focused or selective attention refers to the ability to attend to relevant stimuli while simultaneously ignoring irrelevant information. ATD studies have provided evidence for 5-HTs involvement in focused attention (9,12). ATD has been shown to increase performance on focused attention in healthy and depressed subjects (12,15,18). Further substantiation for 5-HTs role in focused attention is found in ATD studies in healthy subjects (28). The few studies that have explored the effects of 5-HT loading on focused attention have shown minimal effects. (24,25)
Tryptophan 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 (29). 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 (30, 31), 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 (32-37).
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 inconsistencies may also be partly related to more general issues regarding executive function test sensitivity and reliability. (25,28).
Tryptophan and emotional processing
Over past years, there has been an increasing interest in the role of serotonin in processing and classifying emotionally loaded information. 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 (16), although an absence of ATD effects on facial recognition has making abilities, response inhibition, and attentional set-shifting or reversal also been reported (38-40). Serotonergic stimulation by acute SSRI administration produces generally opposite effects of those seen with ATD and enhances positive affective processing (36,38).
Attenburrow et al. (41) 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. (42), 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 is a direct consequence of modulations to 5-HT levels in the brain that is independent to mood improvement.
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 (38,41,42). The results also suggest that women may be more susceptible to serotonergic manipulations than men.
Tryptophan and psychomotor performance
Trp loading has consistently been shown to impair motor performance on a range of psychomotor tasks in both healthy adults (19, 22,25,26) and in vulnerable populations (19,22) following Trp loading. 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 (28,29,32,33).
These findings suggest that Trp has a mild sedative effect, which is consistent with previous sleep studies. Previous research has shown that modulations to serotonergic activity through administration of SSRIs induce an acute and steady increase in pupil diameter (27). 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.
Tryptophan and mood
Over five decades ago Lauer et al. (43) 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 (44-47).
There are a substantial number of studies that have addressed the efficacy of Trp given alone as an antidepressant (48-51), and there are many reviews available on the topic (52-54). 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 (52). In contrast, Trp has been reported to be an effective antidepressant in mild to moderately depressed outpatients (51). While in patients with premenstrual dysphoric disorder, Steinberg et al. (50) 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.
Effect of tryptophan 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.
In a study in healthy adults, (27). mood (a total mood disturbance score obtained by summing 6 mood factors: tension-anxiety, depression-dejection, anger-hostility, vigour, activity, fatigue-inertia, and confusion-bewilderment) was significantly improved 60 min following pure Trp. 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. (55,56) reported increased feelings of anger, depression, fatigue, tension, and decreased feelings of vigour and alertness 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. (55) and this may have resulted in the opposite mood effect, specifically negative effects.
A Trp chocolate drink has been shown to reduce feelings of depression (21,22) and increase ratings of vigour in high stress vulnerable subjects.
Merens et al. (57) did not find Trp loading to significantly modulate ratings of depression, anger, fatigue, tension, and vigour in stress-induced unmedicated recovered depressed subjects and healthy controls. Although there was a trend reduction in depressive ratings in stress induced unmedicated recovered depressed subjects, a similar decrease was also observed in the placebo condition. The authors argue that since plasma Trp–LNAA ratio increased by only 21%, it 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 on depression, anger, fatigue, tension, and vigour in recovered unmedicated depressed patients and healthy controls (46), 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. (58) and Sobczak et al. (59,60).
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 be the cause of some of these inconsistencies
Tryptophan and sleep
Trp has been shown to have direct effects on the homeostatic regulation of sleep (61), by increasing availability of brain 5-HT which has been implicated in the regulation of sleep (62,63). In the pineal gland, 5-HT serves as precursor of melatonin , a neuro-hormone secreted during the night which acts as the signal for darkness in the internal milieu. Nocturnal Trp administration is known to increase physiological concentrations of both serotonin and melatonin (64). 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. Administration of Trp during the night can therefore be useful in facilitating sleep as Trp increases the release of melatonin. In addition, 5-HT has some direct effects on sleep. Electrophysiological, neurochemical and neuropharmacological studies have shown serotonergic activation promotes waking and inhibits slow-wave sleep and/or rapid eye movement (REM) sleep.
The effects of Trp on sleep have been investigated for over four decades. The first study to assess the effects of Trp on sleep, (65) 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.
Effect of tryptophan 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 (66-70). Doses below 1 g have shown trends towards decreased sleep latency in mild insomniacs (68). Although in a recent study (69) 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.
Hartman and Spinweber 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,(68) 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.
Effect of tryptophan 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 (72), 1.2 g, 2.4 g, and 4 g (L-Trp significantly reduced sleep latency and increased subjective ratings of sleepiness in healthy adults during the day (72,73) and during the night. Chauffard-Alboucq et al. 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 administration (74,75).
Wyatt et al. found 7.5 g Trp decreased REM sleep and increased non-REM sleep in healthy subjects during the night (76). Nicholson and Stone observed an increase in the duration of Stage III (slow-wave sleep) sleep during the day following 4 g L-Trp in healthy males (77).
Effect of sub-chronic tryptophan on sleep In patients with severe insomnia
Several studies have observed improved sleep quality and decreased sleep latencies during and several nights following Trp treatment in chronic insomniacs (78-80). 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 (77). Reductions to sleep latency have also been shown 1 week after 1 g L-Trp treatment, but surprisingly not during the 7-day treatment (78). Similarly, improvements in sleep were found following 4 weeks of 2 g L-Trp treatment in patients with chronic insomnia (79,80). 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 (79).
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 (81). Interestingly, younger females were found to be more sensitive to the sedating effects of Trp than other groups (81). 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.
Effect of tryptophan 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 (82,83). In a recent study, the cognitive benefits of evening Trp loading on morning performance were assessed (84). 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 alactalbumin improves morning cognitive performance due to improved sleep. These findings provide support for the notion that Trp loading may improve cognition indirectly by improving sleep.
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