L-Tyrosine Profile

This supplement has been proposed for the following purposes or treating the following conditions. Also given is the current scientific support for use (on a scale of 0-10). Note that a low rating does not necessarily indicate that a supplement does not work, just that research is either unavailable or has not demonstrated a benefit.

• Cognitive performance – 9
• Stress – 9
• Athletic performance – 7
• Depression – 7
• Narcolepsy - 7
• Phenylketonuria – 7
• Appetite suppression* - 6
• Drug dependence - 6
• Parkinson's – 6
• Vascular dementia – 6
• Vitiligo - 3
*In conjunction with stimulants

Side effects
• Tyrosine supplements should not be taken by those with conditions associated with increased dopamine levels such as mania and schizophrenia.
• Tyrosine should be avoided in patients with melanoma.
• This supplement may increase sensitivity to the effects of CNS stimulants. Caution is advised when taking tyrosine along with stimulants and dosages should be lowered accordingly.
• Other drugs which tyrosine may interact with include monoamine oxidase inhibitors (MAOIs), opiates, and L-DOPA.

Introduction

L-tyrosine is an amino acid found in the diet that is a precursor to numerous important substances in the body, most notably the catecholamines dopamine (DA) and norepinephrine (NE). It is also a precursor to both melanin and thyroxine. Tyrosine is considered to be conditionally essential because it can be synthesized from phenylalanine when there is sufficient dietary phenylalanine [1]. People with phenylketonuria lack the enzyme necessary to convert phenylalanine to tyrosine, and for them tyrosine is an essential amino acid [2]. It is also an essential amino acid in infants, uremic patients, and some malnourished patients [3].

Supplementation with tyrosine results in increased plasma and brain levels of the amino acid [4]. The rate-limiting enzyme for the creation of DA is tyrosine hydroxylase, which converts tyrosine to DOPA [5]. In rats, this enzyme is around 75% saturated, meaning that increasing tyrosine availability should have the ability to increase DA synthesis by approximately 1/3rd [6]. This makes increasing tyrosine availability less effective at increasing DA levels than increasing tryptophan availability is at increasing serotonin levels, but it is still enough to exert measurable effects [7].

Tyrosine depletion through dietary means reliably produces the symptoms of decreased dopamine and norepinephrine levels in both humans and animals. These include reduced response to amphetamines, endocrine changes, decreased mood and spatial memory abilities, and other psychological changes [8-10]. In animals, tyrosine depletion results in lower brain levels of dopamine, and this effect has also been found in humans in a positron emission tomography (PET) study [9].

Studies on the opposite effect, increasing DA and NE by increasing tyrosine availability, produce less reliable results. This may be a function of the dose-response curve and the conditions of the study. Many studies indirectly indicate that tyrosine increases catecholamine levels in humans because of the behavioral changes it produces (see below). Tyrosine supplementation also increases plasma neurotransmitter levels [11]. In the brain, changes in neurotransmitter levels from increased tyrosine availability vary based on brain region and conditions. Some neurons become more sensitive to tyrosine availability when their activity increases [12]. One source indicates increased activation of DA neurons, increased DA synthesis, or rapid or chronic depletion of intraneuronal DA as the most likely situations in which tyrosine availability will have a significant effect in humans [13].

Athletic Performance

Tyrosine supplementation has the potential to increase athletic performance in multiple ways. One of the mechanisms possibly contributing to fatigue during exercise is an increase in central serotonin levels and an increase in the ratio of serotonin to dopamine. Tyrosine may help decrease this ratio and compete with tryptophan (the amino acid precursor to serotonin) at the blood-brain barrier [14-15]. Increased dopaminergic activity may decrease the perception of fatigue. Also, during highly stressful conditions, catecholamine levels can become depleted, and tyrosine may be particularly useful under these conditions [14].

There have only been a few studies examing the effect of tyrosine on exercise performance. One study compared the effects of placebo, tyrosine (25 mg/kg), carbohydrates, and tyrosine plus carbohydrates on a cycling time trial after 90 minutes of submaximal cycling. The tyrosine group performed better than the placebo group (32.64 minutes vs. 34.44 minutes), and the tyrosine plus carbohydrate group completed the time trial sooner than the carbohydrate only group (26.11 minutes vs. 27.17 minutes), but neither of these differences were statistically significant. However, tyrosine did significantly decrease the rating of perceived exertion relative to placebo. The authors also found a different metabolic response to exercise in the tyrosine and carbohydrate group than the carbohydrate group, and suggested that a difference in study design, such as conditions resulting in greater catecholamine depletion, may have demonstrated a significant difference in performance [14].

Another study was conducted by Struder et al. [16]. In this study, subjects were given either placebo, paroxetine (an SSRI), BCAAs, or 20 grams of tyrosine and cycling performance was measured. Tyrosine did not improve performance on any measure. However, the hormonal profile in the subjects consuming tyrosine was indicative of a decrease, rather than an increase in central dopamine levels. This is consistent with animal studies, which indicate that excessive quantities of tyrosine decrease dopamine levels [14].

Supporting the idea that the lack of effect in these studies is due to study design is the fact that tyrosine improves physical performance in animals subjected to stressful conditions. For example, when administered prior to cold stress, tyrosine increased swimming performance in rats, an effect which was further increased by coadministration of amphetamine. This was associated with increased NE in the hippocampus [17].

Cognitive Performance And Stress

Tyrosine is particularly useful at combatting the decrements in cognitive performance associated with stress and fatigue. Various stressors result in increased catecholamine synthesis and release and consequently increased precursor demand, and many stress-related changes in behavior and cognition are associated with catecholamine depletion [18]. Norepinephrine depletion is associated with behavioral depression and decreased exploration and motor behavior in animals and lowered attention span in humans, and dopamine is important for learning and memory processes [19]. Since stress results in increased catecholamine synthesis and depletion, it is likely that the impact of tyrosine supplementation will become more pronounced in this state.

In a number of experimental paradigms, tyrosine reduces or prevents impairments in cognition and other negative effects caused by stressors. One study found tyrosine restored maze performance to normal in mice fed a 40% restricted diet [15]. In other rodent studies, tyrosine has protected from behavioral and neurochemical changes associated with hypoxia, restraint stress, and tail-shock. Some of the effects prevented were an increase in corticosterone and NE depletion [17]. Treatment of sheep subjected to stress with large amounts of tyrosine reduced many of the physiological changes, including the increase in cortisol [20]. Tyrosine has also been reported to increase the survival rate in rats stressed by sepsis and acute hemmorhagic shock [7].

In humans subjected to stressful conditions, tyrosine not only improves working memory and attention but may also improve mood and well-being [14, 18]. Tyrosine has been reported to alleviate some of the negative consequences of cold, high altitudes, fatigue, military training, and sleep deprivation [21-22]. It has also been postulated to decrease stress under conditions of aging, anorexia, and obesity [21].

One study in healthy young men compared the effects of 150 mg/kg tyrosine, caffeine, phentermine, and D-amphetamine on cognitive performance in sleep deprived subjects. Tyrosine improved performance on several tests, but was not as effective as D-amphetamine [22]. Another study found that tyrosine did not affect sleep related measures such as sleep quantity and quality after sleep deprivation, while the other psychostimulants did [23]. In subjects exposed to cold and hypoxia, tyrosine reduced the incidence of headache, tension, fatigue, and psychomotor impairments. In another study in healthy subjects subjected to 90 dB noise, tyrosine improved mental performance and reduced blood pressure relative to placebo [19].

Because most of the research has focused on highly stressful conditions that are not commonly encountered in real life, a study was conducted to see if tyrosine was still effective under conditions of relatively mild stress. This was measured by the ability to perform multiple simple tasks simultaneously. When subjects were given simple tasks, such as arithmetic, auditory monitoring, visual monitoring, and a memory task, tyrosine did not improve performance. When asked to perform multiple simple tasks at the same time, performance on the memory task was significantly better in subjects receiving tyrosine. This study demonstrated that tyrosine can improve cognitive performance even in the absence of significant stress-related biological changes [18].

Other Benefits

As a precursor to DA and NE, tyrosine holds some promise in the treatment of depression. Early case reports were promising, and some small studies indicated that tyrosine potentiated the effect of 5-HTP [7]. However, a study in the 80's compared L-tyrosine, imipramine, and placebo and found no benefit from tyrosine supplementation [6]. In another study, researchers classified some cases of depression as dopamine-dependent based on polygraphic sleep recordings, and tyrosine was useful in this subset of patients [7]. Thus, tyrosine may be useful in some cases of depression or in conjunction with some other antidepressant drugs, but further research is needed to fully clarify its usefulness.

Tyrosine has also been explored in the treatment of Parkinson's and dementia. It was reported to elevate DA production in patients with Parkinson's, as measured by the levels of a DA metabolite in cerebrospinal fluid [7]. A small study reported benefits in some Parkinson's patients receiving tyrosine for three years with less side effects than traditional treatments [24]. One study associated combined administration of tyrosine, 5-HTP, and carbidopa with improvement in a small number of patients with vascular dementia [25]. At this point, the evidence of a use for tyrosine in the treatment of these conditions is still weak.

As covered above, tyrosine can combat some of the effects of sleep deprivation. It has also been studied in the treatment of narcolepsy. In a double-blind, placebo-controlled trial, tyrosine treatment for four weeks caused some improvements on some measures (tiredness, drowsiness, alertness) but not others, and the effect was described as a mild stimulant action that was not clinically significant [26]. Still, this does provide evidence that tyrosine may be of some benefit in patients with narcolepsy, and its utility in conjunction with other treatments has yet to be explored.

Tyrosine can potentiate the effects of various drugs, allowing a lower dose to be equally effective. In animals, tyrosine potentiated the appetite suppressing effect of ephedrine, amphetamine, and phenylpropanolamine, although in another study it failed to potentiate their peripheral effects [27-28]. Tyrosine has been reported to potentiate DA release from methylphenidate (Ritalin) [29]. It also potentiated the analgesic effect of morphine and codeine in rats [30].

A benefit in treating drug dependence has also been hypothesized [31-32]. Withdrawal from addictive drugs is often associated with catecholamine depletion. However, in cocaine-dependent subjects, one study did not find a benefit from tyrosine, and another found alleviation of only one symptom from tyrosine and tryptophan supplementation [32-33]. In rats, tyrosine reduced amphetamine self-administration in animals that had been exposed to amphetamines for 4-6 months, but not 35 days or less. The authors hypothesized that tyrosine may be useful in certain subjects depending on their history of drug use [34].

Another potential use for tyrosine is normalization of blood pressure. In addition to decreasing blood pressure in humans subjected to stress, tyrosine can increase blood pressure in hypotensive animals and lower blood pressure in hypertensive animals. However, tyrosine did not cause improvements in patients with mild hypertension [7]. Tyrosine should not be used for this purpose until further information is available.

Because tyrosine is used in the synthesis of melanin, it is reputed to be beneficial in darkening skin and hair pigmentation or treating vitiligo. Also, oral and topical phenylalanine (the amino acid precursor to tyrosine) combined with UV light has been successfully used to treat vitiligo [35]. Changing the tyrosine concentration does change the pigmentation of some tissues in vitro, and cats fed low amounts of tyrosine (but still adequate for good health) are unable to maintain hair color and growth [5]. However, research has not established a change in pigmentation from tyrosine supplements in humans.

In the secondary literature, other proposed uses of tyrosine include weight loss, appetite suppression, and sexual enhancement. All of these uses have theoretical support, but research is needed before it can be established that tyrosine is useful for these purposes.

Dosage and Side Effects

Toxicological studies indicate that tyrosine is quite safe. In mice and rats, no toxic signs were observed after both IM and subcutaneous injection of up to 2500 mg/kg, at which point some edema was noted in rats. The LD50 is not established, but is greater than 5000 mg/kg. After 28 days of 10, 25, or 50 mg/kg injections to rats, the primary noted effect was some immune system stimulation at 25 mg/kg or more. In beagle dogs, the effects were similar. Also, in vitro studies indicated no mutagenic effect. A review of the studies from 1976-2001 found that they reflected "a lack of toxicity" [36].

Because tyrosine primarily increases DA and NE levels in situations of increased demand or depletion, side effects are less common and severe than with most stimulants. Taken before bed, it may result in insomnia. It should also be noted that, although animal toxicology studies indicate a high degree of safety, long-term safety of tyrosine supplements has yet to be established in humans.

The daily dosage of tyrosine supported in the majority of the literature is 100 mg/kg [4, 19]. 3.2 g had antidepressant activity, and 9 g improved the symptoms of narcolepsy [7, 26]. Doses as high as 150 mg/kg have been reported to be of benefit, while 20 g daily may be too much, as it may have reduced DA levels [14, 22]. Therefore, the daily dosage for most will probably fall in the 3-12 g range. Exceeding this amount is not recommended, and the dosage should be started on the lower end of this range to determine personal tolerance, especially if one is taking stimulants or antidepressants. The dosage should be divided among 3 or more doses daily. Around 2 g prior to exercise may be used to improve athletic performance.

N-acetyl-L-tyrosine has been proposed as a "better" form of tyrosine. While the present research is limited, it indicates that if anything N-acetyl-L-tyrosine is inferior. When orally administered to mice, N-acetyl-L-tyrosine was less bioavailable than tyrosine and two other prodrugs [37]. When given parentally, N-acetyl-tyrosine has inferior bioavailability compared to tyrosine in piglets and human newborns [38].

Certain supplements may improve the results from tyrosine supplementation, depending on the purpose it is being used for. Vitamin B6 is sometimes recommended because it is involved in the conversion of tyrosine into dopamine, although there is not yet scientific support for the contention that it will increase the effects of tyrosine supplementation. Tyrosine is commonly used along with D,L-phenylalanine for a stimulant and antidepressant effect. The combination of tyrosine with 5-HTP may also be useful for relieving depression. Finally, tyrosine may also be used to potentiate the appetite suppressing effects of ephedrine or other stimulants.

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