L-Tyrosine

The catecholamine metabolic pathway in vivo starts with the amino acid L-phenylalanine, which gets converted into L-tyrosine by the enzyme phenylalanine hydroxylase. L-tyrosine then gets converted into the compound L-DOPA via tyrosine hydroxylase. L-DOPA is then decarboxylated via aromatic L-amino acid decarboxylase into Dopamine, which later turns into noradrenaline via oxidation from the enzyme dopamine-beta-hydroxylase and then finally converted to adrenaline via Phenylethanolamine-N-methyl-transferase. The last three compounds (Dopamine, NA, Adrenaline) are collectively referred to as 'Catecholamines'; the rate limiting step in this formula is the enzyme tyrosine hydroxylase.^[1]

Supplementing with any of the prior substrates has the ability to increase adrenaline levels, given that the enzyme between said substrate and adrenalines are not maxed out.

Supplemental L-tyrosine is converted into L-DOPA and then into active catecholamines (adrenaline/epinephdrine, noradrenaline/norepinephrine, and dopamine). L-Tyrosine forms a pool of substrate that this group of catecholamine neurotransmitters can get substrate from when their production is needed.

Phenylketonuria (PKU) is a genetic disease in which the body fails to properly metabolize the amino acid Phenylalanine, and said amino acid can build up to toxic levels.

Tyrosine has been looked at for possibly alleviating symptoms of PKU (as a reduction of phenylalanine may reduce catecholamines, but this can be attenuated with L-tyrosine which is what Phenylalanine turns into in order to create catecholamines). Results, however, are preliminary.^[2][3]

L-tyrosine can go through three types of metabolisms: the amino acid can be taken up in the tissues and incorporated into peptides and proteins, small amounts can be converted into thyroxine, melanin and catecholamines, or it can be deaminated to form p-hydroxy phenylpyruvic acid (a substrate for gluconeogenesis). The enzyme that catalyzes tyrosine to form the substrate for gluconeogenesis is most active in the day in in vivo rat livers with lower tyrosine concentrations; in humans, tyrosine concentration in plasma is the lowest between 1:30- 2:30 am and rises to a peak at 10:30 am.^[4]

Tyrosine is usually metabolized into L-dopa via hydroxylation, but another pathway involving its decarboxylation can lead to build-up of trace amines such as tyramine.^[5] The hydroxylation of tyrosine by the enzyme tyrosine hydroxylase is the rate-limiting step in the synthesis of catecholamines like norepinephrine and epinephrine.^[6]

There is some concern that tyrosine may decrease the effectiveness of L-dopa. Tyrosine and levodopa compete for absorption in the proximal duodenum by the large neutral amino acid (LNAA) transport system. L-tyrosine should not be taken at the same time as L-dopa. Additionally, tyrosine is a precursor to thyroid hormones and might boost levels of thyroid hormone medication like levothyroxine and liothyronine.^[7][8] Tyrosine is also contraindicated with MAOI like isocarboxazid, phenelzine, tranylcypromine, and selegiline. Monoamine oxidase is the enzyme responsible for the breakdown and inactivation of the catecholamines. A buildup of the catecholamines, including tyramine, which can be found in certain foods and formed from exogenous tyrosine in the gut by certain bacteria in some foods, can result in dangerous increases in blood pressure.^[9]

There are drug interactions between L-tyrosine and MAOI medications, thyroid medications, and levodopa.

150mg/kg L-tyrosine taken in a vessel of apple sauce can elevated plasma tyrosine concentrations from 56.3nmol/L (baseline and similar to control values) to the range of 140-168nmol/L within 90 minutes, which remained within that concentration until measurements stopped at 150 minutes; a significant difference from placebo existed within 30 minutes and was measured at approximately 80nmol/L.^[10] These changes in plasma tyrosine concentrations were not matched with increases in plasma noradrenaline, which were similar between groups.^[10] Plasma tyrosine concentrations increased to a mean of 203 mmol/L in response to large doses (about 10 g) of extra tyrosine in healthy individuals.^[11] Reference values of tyrosine concentrations in plasma vary between 35-102 mmol/L for different age groups and sexes (including children and adults) after an overnight fast.^[12] In nonfasting healthy young adults, plasma tyrosine concentrations vary between 61-99 mmol/L. ^{[13] [14]}

A similar spike in serum tyrosine levels is noted in rats (serum norepinephrine untested) and the increase in serum tyrosine appears to return to baseline 4 hours after oral administration.^[15]

L-tyrosine levels peak in the blood within 1-2 hrs after ingestion, but stay elevated for up to 8 hours.

Most mechanisms related to L-Tyrosine are due to it being a precursor to catecholamine synthesis, and catecholamine synthesis being somewhat sensitive to a localized substrate pool.^[16][17]

L-Tyrosine (200-400mg/kg) can acutely increase noradrenaline (aka. norepinephrine or NE) concentrations in the hippocampus and prevent an acute stress-induced reduction of NE concentrations in rats subject to cold stress.^[18] This may precede the ability of L-Tyrosine administration to reverse losses of memory induced by cold stress in humans.^[10] This study (n=8) noted that 150mg/kg L-Tyrosine (dissolved in apple sauce that placebo ingested solely) taken before cognitive testing in a room where the temperature was reduced from 22°C to 4°C was able to reduce the time taken to answer a delayed Matching-to-Sample test and increase the amount of correct answers relative to cold placebo, but was unable to fully preserve performance seen in warm control periods (where L-Tyrosine did not appear to further improve performance).^[10]

Currently no evidence that L-Tyrosine supplementation can improve memory function from baseline, but may be able to attenuate a decrease in memory formation associated with acute stressors

One study has combined supplemental L-Tyrosine and 'extended wakefulness' and noted that 150mg/kg of L-Tyrosine was able to attenuate the decrease in cognitive performance that was associated with sleep deprivation.^[19]

May improve cognitive performance during sleep deprivation without significantly affecting sleep function

Acute uncontrollable stress is a phenomena that is able to deplete norepinephrine (NE) concentrations in neural tissue, particularly the hypothalamus and brainstem (containing the locus coeruleus)^[20] and behavioural alterations associated with NE depletion in research animals have been shown to be avoidance/escape,^[21] spontaneous motor activity,^[22] aggressive behaviors,^[23] and swimming.^[24] Ingestion of L-Tyrosine can attenuate the development of behavioural abnormalities associated with acute uncontrollable stressors in research animals in the range of 200-400mg/kg (oral or intravenous) 30-60 minutes prior to the acute stressor.^{[20][25][26][18]}

Appears to mitigate some overt symptoms of acute and uncontrollable stress (this is in contrast to the adaptogen class of molecules, which may be effective against chronic and manageable stress); the two stress respones being mediated by different mechanisms

Some studies have been conducted specifically as it applies to cold stress (the goal of cold exposure therapy) have noted decrease immobility time in a dose-dependent manner in mice given 200-400mg/kg L-Tyrosine injections to a similar magnitude of 5-20mg/kg Phenylpropanolamine; Tyrosine appeared to synergistically reduce immobility time when paired with either Phenylpropanolamine or Amphetamines.^[18] These effects correlated with hippocampal noradrenaline concentrations, which were preserved with L-Tyrosine.^[18] These protective effects have been noted in human subjects, albeit a small sample size.^[10]

May reduce the adverse effects of cold stress, has some human evidence of doing so (as it pertains to memory function)

One study in humans subjected to high altitudes has noted protective effects against acute stress due to lessened symptoms of acute stress, where 100mg/kg L-tyrosine (divided into two doses taken an hour apart) was associated with less headaches, stress, fatigue, distress, sleepiness, muscular soreness, and coldness due to the acute stressor as assessed by the Environmental Symptoms Questionnaire.^[27] This study also noted improvements (relative to placebo) on global ratings of mood and happiness (assessed by Clyde Mood Scale and Profile of Mood states) and cognitive function (various cognitive tests).^[27] Similar results are noted with the same oral dose after acute noise stressor^[28] and some of these effects are noted after acute physical lower body stressors.^[29]

Protection against acute stress has also been noted during a week-long combat training session, where 42g of protein (of which 2g were Tyrosine) was compared to placebo and associated with a preservation of cognitive performance, although this study failed to find significant improvements in mood between groups.^[30]

Increasing levels of L-tyrosine in the brain is being looked at as a pharmaceutical method of alleviating neurological decline as catecholamines are typically decreased in states of dementia.

Surprisingly, catecholamines may act as anti-oxidants in the brain and be neuroprotective.^[31]

150mg/kg L-Tyrosine taken prior to a cognitive test (with acute stressor) failed to significnatly influence blood pressure inherently or the spike in blood pressure induced by the acute stressor (which L-Tyrosine did not modify, spiking in both control and L-Tyrosine condition).^[10]

One study conducted in cadets undergoing combat training who consumed 42g protein (2g tyrosine, confounded with other amino acids) noted that supplementation was associated with a decrease in systolic blood pressure by 10.4% from baseline, with placebo experiencing a lesser and nonsignificant decrease in blood pressure; no significant change noted in diastolic in this study although a trend towards reduction was noted^[30] and another study under acute noise stress noted that L-Tyrosine ingestion was associated with a reduction in diastolic blood pressure within 15 minutes of ingestion of 100mg/kg.^[28] This reduction in diastolic blood pressure has been noted previously in research animals.^[32][33]

Although there isn't much reliability in the evidence currently, supplemental L-Tyrosine appears to either be ineffective or slightly reduce blood pressure; studies are confounded with the inclusion of stressors (which increase blood pressure) and effects of L-Tyrosine per se cannot be easily separated from the effects of an L-Tyrosine and stress interactions

N-Acetyl-L-Tyrosine is a more soluble form of L-Tyrosine that appears to be relatively heat stable in solution^[35] that can be deacetylated to L-Tyrosine in the kidneys.^[35]

N-Acetyl-L-Tyrosine appears to be able to contribute free L-Tyrosine in vivo after IV administration, but only able to increase L-Tyrosine concentrated 20% despite much larger increases in serum NALT.^[35] 56% of the adminstered dose of NALT is excreted in 4 hours^[35] and another study suggests that, overall, 35% of the total NALT dose (administered parentally) is excreted via the urine as NALT and not L-Tyrosine.^[36]

Limited practical evidence on NALT as an alternative to L-Tyrosine

Rats were given doses of 0, 200, 600, or 2000 mg/kg a day to examine toxicity of L-tyrosine. Edema of the cornified layer of the forestomach was seen in 600 mg/kg supplementation in female rats and in both sexes at 2000 mg/kg day. There was increased weight and hypertrophy of hepatocytes in the liver associated with an increase in ALT and AST in both sexes when given 2000mg/kg/day of L-tyrosine. An increase of kidney weight and urinary protein was also seen at 2000 mg/kg/day. Lastly, an increase in triglycerides, total cholesterol, phospholipids, potassium ions, calcium, total protein, and alpha one globulin were seen in both sexes at 2000 mg/kg/day.^[37]

While the etiology of chronic migraine headaches is not well-understood, one hypothesis for its genesis involves abnormal metabolism of tyrosine.^[5] Tyrosine is usually metabolized into L-dopa via hydroxylation, but another pathway involving its decarboxylation can lead to build-up of trace amines such as tyramine. It is this abnormal build-up of trace amines which is suspected by some researchers to play a role in migraines.^[5] Some research has found that chronic migraine sufferers have elevated plasma levels of major products of tyrosine, including the neurotransmitters dopamine and norepinephrine, along with the trace amine tyramine.^[38] This is consistent with the hypothesis that abnormal tyrosine metabolism favoring trace amine synthesis leads to high release of these neurotransmitters, which contributes to migraines.^[38] It is possible that increased intake of L-tyrosine in migraine sufferers may fuel this process and make migraines worse, although there is currently no direct evidence substantiating this claim.

L-tyrosine is Generally Recognized as Safe (GRAS) in the USA. ^[39] When L-tyrosine is used orally and short term at a dose of ≤150 mg/kg or ≤12 g per day for up to three months is generally safe.^{[40][41][42][43]}

Mothers with PKU could be taking tyrosine supplementation due to the hypothesis that low fetal tyrosine concentration in blood can cause mental retardation. However, this hypothesis has not been proven in any trial with a treatment based on tyrosine supplementation without phenylalanine restriction.^[7]

A toxic effect of a combination of mildly increased phenylalanine and tyrosine was shown in offsprings of rats after taking tyrosine supplementation. The offsprings of the rats showed difficulties in learning. However, there have been no studies showing this toxic effects in humans. ^[44]

There has been hypotheses that tyrosine may be bad to the fetus. However, no human studies can prove this hypothesis.

Patients with hereditary tyrosinemia or persistent hypertyrosinemia may develop skin and eye lesions when the plasma level is 10 times of that found in clinical trials administering a tyrosine dose of 150 mg/kg to humans.^[11]

In patients with hereditary tyrosinemia, it may cause skin and eye lesions at doses above the recommended intake.

When 100 mg/kg of tyrosine is administered to humans, tyrosine decreased diastolic blood pressure.^[45][46] However, in another human study, tyrosine increased heart rate and blood pressure after 150 mg/kg tyrosine supplementation.^[47]

Following tyrosine supplementation of 12 g in 113 g of applesauce in adults with normal thyroid function in Antarctica during the summer, thyroid-stimulating hormone decreased by 30%. In the winter, there was a 47% improvement in mood and TSH decreased by 28% along with an increase of 6% in serum-free triiodothyronine.^[48] Additionally, 10g/day of L-tyrosine was given to patients with schizophrenia and resulted in increased saccadic intrusions.^[49]

In children with nemaline myopathy (a condition which causes chewing and swallowing difficulties, recurrent aspiration, and poor control of oral secretions), 250-3000 mg/day L-tyrosine supplementation caused an initial decrease in sialorrhea and an increase in energy levels.^[50] Patients with severe dementia due to Alzheimer’s disease received a combination treatment of 5-hydroxy-tryptophan, carbidopa, and tyrosine (4 g) which caused diarrhea, drowsiness, nausea, vomiting, and agitation. However, it is not clear if these side effects were due to tyrosine alone.^[51]

L-tyrosine can have an effect on blood pressure, heart rate, and mood. It may cause gastrointestinal upset, drowsiness, and agitation.