Does L-tyrosine improve cognitive function?

Comment by InpharmD Researcher

Limited data is available describing the impact of L-tyrosine on cognition. While some data suggests improvement in working memory and inhibitory control in stressful and cognitively demanding situations, conflicting data also exists showing detrimental effects on cognition. Overall, the effect of tyrosine supplementation on cognitive performance improvements is largely unknown.

Background

A 2015 review evaluated the available cognitive and behavioral studies on tyrosine to determine whether and when tyrosine supplementation can be beneficial for performance. A number of studies have shown an effect on tyrosine to improve cognitive performance in healthy humans prior to stress exposure. Typically in these studies, hypothermia is used as the stressor, and tyrosine has repeatedly been shown to reverse cognitive impairments. Tyrosine has also been shown to improve working memory while participants were exposed to an auditory stressor. Additionally, two studies showed enhancement of working memory performance with tyrosine in the absence of stress exposure. Improvement has also been shown in inhibitory control without influencing response execution. Doses ranged significantly from 500 mg to 12 g per day. For depressed, schizophrenic, and phenylketonuria patients, tyrosine alone was not found to be effective. Patients with ADHD and Parkinson’s disease had mixed results, with some studies showing benefit and others showing no effect. It is hypothesized that tyrosine supplementation seems to replete neurotransmitter levels in the brain and reverse the stress-induced degradation of a variety of cognitive functions. Of note, most literature reports results on short-term rather than long-term settings. [1]

A 1984 article reviewed the few trials observing tyrosine with mixed results. One study did not find benefit for depression but was limited in descriptions. A case report mentioned of a 30-year-old woman with unipolar depression who could not tolerate antidepressants benefitting from tyrosine 100 mg/kg/day divided into 3 daily doses. Further non-blinded trials found tyrosine same dose to double tyrosine plasma and cerebrospinal fluid concentration. At the time this article was written, tyrosine and its effects on human pathology was still vaguely understood. [2]

An animal study conducted in 1980 found that tyrosine administration increased brain neuron synthesis of both dopamine and adrenaline. A single dose of 100 to 150 mg/kg in healthy volunteers found a dose-related increase in plasma tyrosine concentration and ratio of concentration of tyrosine. [3]

A small 2018 study (N= 24) investigated the effects of tyrosine on reactive and proactive response inhibition and signaling in dopaminergically innervated fronto-striatal regions. The study incorporated a double-blind, counterbalanced, placebo-controlled, within-subject design. Patients received a dose of 150 mg/kg tyrosine or placebo, adjusted to body weight. Effects were measured based on various neurological measures (e.g., verbal IQ, Baratt impulsiveness scale, hospital anxiety, and depression scale), as well as tasks to be performed during test sessions.Tyrosine was not found to alter reactive (stopping response inhibition) or proactive (anticipatory response slowing) inhibition behaviorally. However, it did increase fronto-parietal proactive inhibition-related activation. Ultimately, it was suggested that tyrosine resulted in detrimental effects on brain and cognition, with impact becoming worse with increasing age. [4]

References:

[1] Jongkees BJ, Hommel B, Kühn S, Colzato LS. Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands--A review. J Psychiatr Res. 2015;70:50-57.
[2] Gelenberg AJ, Gibson CJ. Tyrosine for the treatment of depression. Nutr Health. 1984;3(3):163-173. doi:10.1177/026010618400300305
[3] Gelenberg AJ, Wurtman RJ. L-tyrosine in depression. Lancet. 1980;2(8199):863-864. doi:10.1016/s0140-6736(80)90213-5
[4] Bloemendaal M, Froböse MI, Wegman J, et al. Neuro-Cognitive Effects of Acute Tyrosine Administration on Reactive and Proactive Response Inhibition in Healthy Older Adults. eNeuro. 2018;5(2):ENEURO.0035-17.2018. Published 2018 Apr 30. doi:10.1523/ENEURO.0035-17.2018

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Does L-tyrosine improve cognitive function?

Please see Tables 1-3 for your response.


 

Tyrosine for depression: a double-blind trial

Design

Randomized, prospective, double-blind trial

N= 65

Objective

To compare the effects of L-tyrosine, imipramine, and placebo on depression 

Study Groups

Tyrosine (n= 21)

Imipramine (n= 22)

Placebo (n= 22)

Inclusion Criteria

Ages 18-75 years without childbearing potential, diagnosis of major depressive disorder, entry score of ≥ 20 on a modified Hamilton Depression Rating Scale (HAM-D) 

Exclusion Criteria

History of mania, psychosis, schizophrenia, alcoholism, illicit drug use/addiction, epilepsy, serious suicidal risk with poor response to antidepressant therapy  

Methods

Depression was diagnosed per the Research Diagnostic Criteria and patients underwent a strict 24-hour urine collection period along with baseline blood draws. Patients were randomized to receive L-tyrosine 500 mg, imipramine hydrochloride 12.5 mg, or lactose placebo and were slowly titrated by 9 days to a target dose of L-tyrosine 100 mg/kg/day or imipramine 2.5 mg/kg/day in 3 divided doses. Urine samples were collected over 3 days before and after treatment and blood samples were taken at baseline and throughout treatment. 

Duration

Intervention: 4 weeks 

Outcome Measures

HAM-D score after treatment, change in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), change in fasting plasma tyrosine levels

Baseline Characteristics

 

Tyrosine 

(n= 21)

Imipramine

(n= 22)

Placebo 

(n= 22)

Age, years

36.2 41.6 40.5

Male 

16  16  14 

Baseline HAM-D score

24.3 24.3 24.5

HAM-D= Hamilton Depression Rating Scale

Results

Endpoint

Tyrosine

(n= 21)

Imipramine

(n= 22)

Placebo

(n= 22)

Approximate HAM-D score after treatment, ± SEM

~ 13

~ 12

~ 16

Approximate change in MHPG excretion, ± SEM

~ 0.19  ~ -0.27 ~ -0.03

Approximate change in tyrosine plasma levels, ± SEM

~ 20 ~ -2.5 ± 4 ~ 2.7

Note: Data was presented as a graph without exact numerical markers. These numbers are estimates provided to the best of our abilities.

SEM= standard error of the mean; MHPG= 3-methoxy-4-hydroxyphenylglycol

Adverse Events

Common Adverse Events: dry mouth, nausea, vomiting, 

Serious Adverse Events: over sedation, loss of impulse control

Percentage that Discontinued due to Adverse Events: Tyrosine (1 [4.8%]), Imipramine (5 [22.7%]), Placebo (1 [4.5%])

Study Author Conclusions

Although this study found no hazard from tyrosine therapy, and while it is conceivable that somewhere there are patients with major depressive disorder who will benefit from tyrosine treatment, this trial lends no support to that line of thinking.

InpharmD Researcher Critique

The study is relatively old (1990) and the criteria for diagnosing depression may have been different compared to today. The study had a small sample size in each treatment arm and was primarily dominated by male patients. Seventeen patients dropped out of the study before completion and were excluded from efficacy analyses. Finally, the data was presented primarily as figures and graphs.



References:

Gelenberg AJ, Wojcik JD, Falk WE, et al. Tyrosine for depression: a double-blind trial. J Affect Disord. 1990;19(2):125-132. doi:10.1016/0165-0327(90)90017-3

 

L-tyrosine pharmacotherapy of schizophrenia: preliminary data

Design

Placebo-controlled, double-blind, crossover study 

N= 11

Objective

To increase dopaminergic neural transmission along with mesocortical projections in patients by increasing the precursor availability of L-tyrosine for dopamine biosynthesis.

Study Groups

Tyrosine (n= 11)

Placebo (n= 11)

Inclusion Criteria

Male patients, diagnosis of schizophrenia 

Exclusion Criteria

N/A

Methods

Schizophrenia was diagnosed based on the Schedule of Affective Disorders and Schizophrenia (SADS) interview and chart review.

All patients were placed on molindone at 150 mg/day for 1 week before being randomly assigned to either L-tyrosine at 10 g/day in four divided does in addition to molindone or placebo in addition to molindone for 3 weeks. Patients were then crossed over to the other group for another 3 weeks. Molindone 150 mg/day was administered for the duration of the study. 

Duration

Each intervention: 3 weeks 

Total duration: 6 weeks

Outcome Measures

Brief Psychiatric Rating Scale (BPRS), Schedule for the Assessment of Negative Symptoms (SANS), Clinical Global Impressions (CGI) scale, Simpson-Angus scale, Abnormal Involuntary Movement Scale (AIMS), Wisconsin Card Sorting Test (WCST), memory measures, and smooth-pursuit eye movement (SPEM) task

Baseline Characteristics

 

Tyrosine/placebo

(n= 22)

 

 

Age, years

37.8 ± 6.8    

Male

11 (100%)    

Duration of illness, years

16.4 ± 6.7    

Results

Endpoint

L-tyrosine

(n= 11)

Placebo

(n= 11)

p-Value

Total BPRS, mean

44.7 45.2 0.89

Total SANS, mean

44 48  0.64 

CGI, mean

4.5 4.5 0.82

Simpson-Angus Scale, mean

6.8 7.1 0.88

AIMS, mean

9.6 9.5 0.46

WCST

Number of preservative errors

Number of categories completed

 

36.1 ± 17.6

2.1 ± 2.1

 

34.4 ± 20.1

2.2 ± 2.5

 

0.85

0.92

Memory measure

Source memory

Recognition memory

Temporal ordering

 

0.59 ± 0.13

26.7 ± 7.6

0.76 ± 0.15

 

0.62 ± 0.1 

27.9 ± 8.2

0.79 ± 0.18

 

0.52

0.73

0.69

SPEM measures

Shagass score

3-6º saccades

6-10° saccades

>10° saccades

& error

Gain

 

3.7 ± 0.89

14.3 ± 6.8

8.4 ± 5.7

6.9 ± 6.8

7.4 ± 5.4

0.76 ± 0.06

 

2.9 ± 0.7

11 ± 4.2

1.6 ± 1.4 

3 ± 6.1

3.13 ± 1.3

0.77 ± 0.02

 

0.06

0.27

0.006

0.25

0.05

0.53

BPRS= Brief Psychiatric Rating Scale; SANS= Schedule for the Assessment of Negative Symptoms; CGI= Clinical Global Impressions; AIMS= Abnormal Involuntary Movement Scale; WCST= Wisconsin Card Sorting Test; SPEM= smooth-pursuit eye movement task

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

The results of the study show that plasma tyrosine levels can be significantly elevated by the supplemental oral administration of 10 g L-tyrosine in patients with schizophrenia. However, except for an adverse effect on SPEM performance, no significant treatment effect for L-tyrosine supplementation is evident when the data from this crossover study are analyzed using the patients as their own controls. 

InpharmD Researcher Critique

This is an older study (1994) that only included male patients. The inclusion and exclusion criteria were not explained in detail if they were present at all which further introduces heterogeneity into this small population of patients. Overall, the data is exploratory at best.



References:

Deutsch SI, Rosse RB, Schwartz BL, Banay-Schwartz M, McCarthy MF, Johri SK. L-tyrosine pharmacotherapy of schizophrenia: preliminary data. Clin Neuropharmacol. 1994;17(1):53-62. doi:10.1097/00002826-199402000-00006

 

An open trial of L-tyrosine in the treatment of attention deficit disorder, residual type

Design

Open-label trial

N=12

Objective

To investigate L-tyrosine's effect in patients with attention deficit disorder, residual type (ADHD-RT)

Study Groups

L-tyrosine (n= 12)

Placebo (n= 12)

Inclusion Criteria

Diagnosed with ADHD-RT, ages 21-45, no history of alcohol or substance abuse in previous 6 months, and taking birth control medication if female

Exclusion Criteria

Not diagnosed with ADHD-RT

Methods

Patients were diagnosed with ADHD-RT using the Utah criteria. Patients had to have attention deficits and hyperactivity beginning in childhood carrying over to adulthood and had at least 2 of the following characteristics: 1) affective lability, 2) poor organization and an inability to complete tasks, 3) excessive or explosive temper, 4) impulsivity, and 5) low tolerance for stress. 

All patients were single-blinded to receive placebo for 1 week for washout. Patients with no improvement were then given an open trial of tyrosine at a dose of 50 mg/kg per day and titrated to a maximum of 150 mg/kg per day in three divided doses as tolerated.

Duration

Intervention: 8 weeks 

Outcome Measures

Change in targeted ADHD symptoms scale 

Baseline Characteristics

 

Tyrosine/placebo

(n= 12)

 

Age, years

30.2 ± 7.5  

Female

6 (50%)  

Baseline targeted ADHD symptoms scale 

27.3 ± 3.9  

ADHD= attention-deficit/hyperactivity disorder

Results

Endpoint

Tyrosine/placebo

(n= 12)

p-Value

Targeted ADHD symptoms scale 

Week 4

Week 8

 

11.5 ± 8.3

17.4 ± 9.3

p<0.1

ADHD= attention-deficit/hyperactivity disorder

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

L-tyrosine was therapeutically effective after 2 or more weeks but those who responded became tolerant to its therapeutic effects by week 6 and regressed. These findings suggest L-tyrosine is not useful in and appears to have no clinical utility in the treatment of attention deficit disorder, residual type. 

InpharmD Researcher Critique

The study is relatively old (1987) with only 12 patients in total who completed the trial. Neither the patients nor experimenters were blinded after the washout period.  



References:

Reimherr FW, Wender PH, Wood DR, Ward M. An open trial of L-tyrosine in the treatment of attention deficit disorder, residual type. Am J Psychiatry. 1987;144(8):1071-1073. doi:10.1176/ajp.144.8.1071