Effects of Tyrosine on Parkinson's Disease: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Abstract

Individuals with Parkinson's disease (PD) can suffer from orthostatic hypotension (OH) resulting from reduced levels of norepinephrine (NE), which inhibits the sympathetic nervous system. Levodopa reduces NE levels even further, leading to a greater decrease in blood pressure (BP) and increased OH. Tyrosine is a nonessential amino acid that is the major precursor to NE. Reduced levels of tyrosine have been shown after administration of l‐dopa. This study was a single‐center, randomized, double‐blind, placebo‐controlled trial to test the effects of supplementing l‐tyrosine on BP, plasma tyrosine, NE levels, and autonomic responses to exercise in PD. Thirty‐six subjects with PD receiving l‐dopa medication that suffer from OH participated. Random assignment was to a placebo group or l‐tyrosine 1,000 mg (500 mg of 2× daily) group for 7 days. OH testing and exercise testing was performed pre‐ and postsupplementation. There was no effect of tyrosine on BP after OH testing postsupplementation (tyrosine, n = 17; placebo, n = 19). There was an increase in plasma tyrosine in the tyrosine group (P > 0.05). There were no significant changes in any of the secondary outcome measures. l‐tyrosine at 1,000 mg (500 mg/2× day) for 7 days is safe and well tolerated in PD. Our results were inconclusive as to whether an increase in plasma tyrosine has an effect on OH in subjects with PD. An increase in plasma tyrosine had no effect on BP or autonomic responses in subjects with PD during acute exercise stress. (Trial registration: http://ClinicalTrials.gov.; identifier: NCT01676103)

Parkinson's disease (PD) is a degenerative neurological disease that affects over 1 million people in the United States.1 Cardinal motor features of PD include abnormal gait and balance, bradykinesia, freezing, and tremor.2 However, nonmotor complications of the autonomic nervous system can be just as disabling and can affect quality of life. One of the most debilitating nonmotor symptoms is orthostatic hypotension (OH). OH is defined as upon standing for 3 minutes, there is a reduction in systolic blood pressure (SBP) of at least 20 mm Hg or a reduction in diastolic blood pressure (DBP) of at least 10 mm Hg.3, 4 OH can cause dizziness, chronic fatigue, decreased quality of life, and increased falls.5 OH affects over 50% of all people with PD.6 One of the pathophysiological reasons for autonomic abnormalities is denervation of the sympathetic nervous system (SNS) and reduced levels of the neurotransmitter catecholamine, norepinephrine (NE).7, 8, 9 SNS abnormalities and reduced levels of NE are observed before PD medication is introduced.6 However, levodopa and dopamine agonists that are commonly used to treat PD cause further inhibition of the SNS, which reduces NE levels and blood pressure (BP) further.6 l‐dopa increases inhibition of the SNS. This inhibition of the SNS by l‐dopa further decreases NE production and increases OH, primarily through venous and arterial dilation.6 This inhibition of the SNS not only affects positional BP responses, but also affects acute responses to external stress. For example, NE typically increases during exercise, which increases heart rate (HR) and BP to meet the demands of the body.10 PD suppresses NE, BP, and HR responses during exercise stress.8

Tyrosine is a nonessential amino acid that is the major precursor to tyrosine hydroxylase (TH), which is the first rate‐limiting step in the synthesis of NE.11 Individuals with PD have decreased activity of the enzyme TH.12 A reduction in TH expression is connected to PD pathogenesis and is one of the early signs of PD.12, 13 Animal models have demonstrated that elevating levels of plasma tyrosine prevented NE depletion and raised BP in hypotensive rats by saturating the TH enzyme.14 The amount of tyrosine that crosses the blood–brain barrier (BBB) is dependent upon the ratio of tyrosine to other competing amino acids.11, 15 Previous work has demonstrated that when tyrosine is taken orally, the plasma tyrosine concentration was raised high enough to cross the BBB, increasing its availability for catecholamine synthesis.15 It has been suggested that supplementing tyrosine may increase NE production and minimize OH in PD.14, 16, 17 Reduced levels of tyrosine have been shown after administration of l‐dopa in PD.18 Currently, there are no clinical trials examining the effect of tyrosine supplementation on OH in a PD population. The current experiment was a double‐blind, placebo‐controlled, randomized clinical trial to test the effect of oral l‐tyrosine supplementation in individuals with PD that suffer from OH. We hypothesized that oral l‐tyrosine will increase plasma tyrosine and plasma NE. Furthermore, we hypothesized that l‐tyrosine will improve OH as well as SNS responses during acute exercise stress.

Patients and Methods

The proposed study was organized and conducted at the Adele Smithers Parkinson's Disease Treatment Center of the New York Institute of Technology's College of Osteopathic Medicine (Old Westbury, NY). All subjects were enrolled between September 2012 and November 2013. The study was approved by the institutional review board at the conducting site, and all participants signed a written informed consent.

Subjects

All subjects had a diagnosis of PD by a licensed neurologist according to the UK Parkinson's Disease Society Brain Bank (UKPDBB) Clinical Diagnostic Criteria.19 The UKPDBB is a three‐step diagnostic tool that defines inclusion and exclusion criteria for diagnosing PD.19 Subjects were between 45 and 79 years of age and mentally were able to participate in the study. The International Parkinson and Movement Disorder Society (MDS)‐UPDRS20 section III motor test was administered on all subjects on medication by a certified MDS professional who was blinded to group assignment. The criteria for eligibility were currently taking anti‐Parkinson's medication, as well as taking l‐dopa for at least 4 weeks preceding participation. All participants were prescreened by a medical professional and were diagnosed with OH as defined by the American Academy of Neurology (AAN).5 Patients were excluded if they were taking medication to treat hypertension, hypotension, or any medication or condition that would affect BP or HR. Forty subjects were enrolled and randomized by the study coordinator. The study coordinator generated treatment assignments through a random number generator computer program using a 1:1 ratio to either the tyrosine or the placebo group. Only the study coordinator had access to the assignment of treatment groups. Outcome measures were performed by medical professionals blinded to participants’ treatment group. The same medical professional obtained BP for all subjects to minimize inter‐rater variability.

Outcomes

Subjects were randomly assigned to one of two groups that received supplementation: (1) tyrosine oral supplement group (500 mg 2× daily)21 or (2) control oral placebo group (2× daily, similar capsule). Every subject underwent two testing sessions (presupplementation and 7 days postsupplementation). Both groups were instructed to take the supplement 1 hour after l‐dopa medication was ingested. A food journal was kept the week during supplementation. Subjects were asked to maintain a similar diet and similar fluid intake as the week before testing in order to minimize the dietary effect on BP.

Orthostatic BP Testing

Subjects were asked to lie supine with their arms at their side and feet uncrossed. BP was taken manually (Baumanometer; WA Baum Co., Inc., Copiague, NY) in this position after 10 minutes of rest. Subjects were then asked to stand upright and BP was taken every minute for 3 minutes. Any symptoms (dizziness, and so on) reported by subjects were recorded. A drop in SBP of 20 mm Hg or a 10‐mm Hg drop in DBP within these 3 minutes indicates OH according to the AAN.3

Exercise Testing

After OH testing, subjects had a 15‐minute rest and were symptom free before undergoing an exercise stress test. A Modified Bruce Protocol,22 which consists of five 3‐minute stages on a treadmill, was used to implement acute stress. During the test, HR, oxygen consumption (VO₂), and 12 lead electrocardiogram tracings were recorded at 1‐minute intervals. BP was recorded within the third minute of each stage. The treadmill test was concluded when subjects attained peak exercise. Peak exercise was determined when a subject attained any one of the following: (1) 85% of target HR; (2) a rate of perceived exertion of 9; (3) inability to maintain the pace of the treadmill; or (4) a respiratory exchange ratio of over 1.3. The American College of Sports Medicine guidelines for terminating exercise testing were followed.22 The same procedures were followed exactly 7 days after intervention. One subject was tested on day 8 because of poor weather conditions, but had maintained the supplement schedule for the extra day. During postsupplementation testing, each subject was brought to the same exercise intensity level that they achieved on the treadmill during presupplementation testing.

Plasma Samples

Fasting blood samples were taken twice during each pre‐ and postsupplementation testing session. One plasma sample was taken at rest (before exercise) and used to analyze tyrosine and NE. A second sample was taken after peak exercise and used to analyze NE. Plasma was collected in tubes that contained sodium heparin anticoagulant. Samples were immediately put in an ice bath and then placed in a centrifuge within 10 minutes to separate serum from plasma. Once separated, the plasma was transferred to a neutral transport tube, frozen, and processed within 48 hours using the methodology of liquid chromatography mass spectrometry by Quest Diagnostics (Nichols Institute, San Capistrano, CA).

Sample‐Size Rationale and Statistical Analyses

A power analysis was performed on HR, BP, and NE based upon previous work by DiFrancisco‐Donoghue.8 To yield a minimum 0.80 power with an alpha level set at 0.05 would require 34 subjects. Taking into account an estimated 15% subject dropout, we proposed a sample size of 40.

A repeated‐measures analysis of variance (ANOVA) that investigated whether the groups were different over time was used to test the hypothesis that l‐tyrosine will increase plasma tyrosine and plasma NE, from pre‐ to postsupplementation, and to test the hypothesis that l‐tyrosine will decrease OH. Furthermore, we also used a repeated‐measures ANOVA to compare all secondary outcome measures (HR, SBP, DBP, and NE) during the exercise testing. If the results from the ANOVA were significant (P < 0.05), then we used t tests with a Bonferroni's correction to explore where the differences were. Results are presented as mean ± standard deviation (SD). Statistical significance was set at P < 0.05 (Table 2).

Table 2.

Measurement values of study participants change from pre‐ to postintervention (mean ± SD)

	Tyrosine Group				Control Group				Pre‐ vs. Postsupplementation P
	Presupplement	95% CI	Postsupplement	95% CI	Presupplement	95% CI	Postsupplement	95% CI
OH testing
SBP change supine to stand	28.9 ± 12.4	22.5–35.3	13.9 ± 22.4	2.4–25.4	27.9 ± 9.2	23.5–32.3	11.8 ± 17.7	3.3–20.3	0.001a
DBP change supine to stand	9.5 ± 10.7	4.0–15.0	6.5 ± 11.2	0.74–12.3	4.2 ± 5.0	1.8–6.6	4.3 ± 6.8	1.0–7.6	0.21
Symptomatic No. (%)	9 (52)		3 (18)		8 (42)		2 (11)		0.88b
Exercise stress test change from rest to peak
HR	38.4 ± 22.5	26.8–50.0	37.4 ± 19.3	27.5–47.3	35.7 ± 18.5	16.8–34.6	34.6 ± 15.2	27.3–41.9	0.61
SBP	18.8 ± 20.2	8.4–29.2	16.2 ± 24.7	3.5–28.9	26 ± 22.2	15.3–36.7	21.1 ± 20.1	11.4–30.8	0.32
DBP	4.4 ± 9.2	−0.33 to 9.2	5.8 ± 12.6	−0.68 to 12.3	1.0 ± 7.5	−2.6 to 4.6	0.0 ± 6.0	−2.9 to 2.9	0.9
VO2 mL/kg/min	13.0 ± 5.3	10.3–15.7	12.1 ± 4.6	9.7–14.5	11.9 ± 5.0	9.5–14.3	11.7 ± 3.5	10.0–13.4	0.25
NE pg/mL	369 ± 348.6	190–548	472.7 ± 381.9	277–669	500 ± 286.7	362–638	560 ± 509.3	315–805	0.32
Plasma tyrosine
Tyrosine μmol/L	56.2 ± 15.1	48.5–64	73.1 ± 22.4	61.6–85	61.4 ± 12.8	55.2–67.6	59.2 ± 13.2	52.8–65.6	0.009a

^aSignificance.

^bChi‐square (χ²) test.

CI, confidence interval.

Results

Of the 40 subjects, 36 (85%) completed the protocol (17 subjects in the tyrosine and 19 in the placebo group; Fig. 1). The number of subjects that dropped out was as follows: 1 subject from the control group because he started fludrocortisone acetate to increase his BP and 3 from the tyrosine group after changing their decision to participate. There were no adverse events and there were no changes to antiparkinsonian medications for the duration of the study. Baseline characteristics are summarized in Table 1. There were no significant differences in baseline characteristics between the two groups (Table 1).

Figure 1.

Study flow chart.

Table 1.

Subject characteristics

	Control Group (n = 19)	Tyrosine Group (n = 17)
Male sex, no. (%)	11 (59)	12 (70)
Age (years), mean ± SD	67.2 ± 9.6	66.5 ± 12.3
Years diagnosed, mean ± SD	7.2 ± 5.3	7.4 ± 5.4
UPDRS motor score	25.7 ± 11.9	24.9 ± 15.2
Anti‐Parkinson's medication no. (%)
l‐dopa therapy	19 (100)	17 (100)
Dopamine agonists
Ropinirole, pramipexole, amantadine	9 (47)	6 (35)
Other antiparkinsonian agents
Tolcapone, rasagiline, ensam	14 (74)	14 (82)

Efficacy of Tyrosine

Primary Outcome

Orthostatic Hypotension Test (Supine to Stand)

On average, the change (drop) that occurred in SBP after moving from supine to stand was significantly less (P < 0.001), regardless of group (tyrosine or placebo) at postsupplementation testing, as compared to presupplementation testing. There were no significant differences found when comparing the groups (P = 0.73) nor were any significant interaction effects found (P = 0.87). The DBP did not significantly change (P > 0.05 for all). Table 2 displays the change in SBP and DBP for each group. Furthermore, of the 17 subjects in the tyrosine group, 9 (52%) were symptomatic after OH testing at presupplementation, and of the 19 subjects in the placebo group, 8 (42%) were symptomatic presupplementation (Table 2).

Secondary Outcomes

Exercise Stress Test

As displayed in Table 2, there were no significant changes in any outcome measures for the change from rest to peak exercise in (HR, SBP, DBP, VO₂, or NE), when comparing pre‐ to postsupplementation testing (P > 0.05 for all).

Plasma Tyrosine

A significant interaction effect (P = 0.001) was identified for plasma tyrosine, meaning that groups performed differently than one another at postsupplementation when compared to presupplementation. As displayed in Table 2, through use of post‐hoc t tests, it was revealed that tyrosine concentrations were similar between the groups at presupplementation; however, as expected, at postsupplementation, plasma tyrosine was elevated, when compared to the placebo group (P = 0.013) and when comparing to presupplementation values (P < 0.001). Tyrosine was well tolerated in all of our subjects. There were no adverse reactions reported.

Discussion

Previous research suggests that supplementing tyrosine may improve BP in PD.14, 16, 17 We demonstrated a significant increase in plasma levels of tyrosine in the tyrosine group; however, we failed to show any effect on BP using an OH test. Furthermore, our study demonstrated that supplementing 1,000 mg/day (500 mg 2× daily) of l‐tyrosine for 7 days was well tolerated and safe in individuals with PD taking l‐dopa and other anti‐Parkinson's medication, but had no effect on the change in plasma NE, BP, or HR from resting values to peak during acute exercise stress.

Tyrosine hydroxylase deficiency usually manifests within the first 3 years of PD.13 Side effects of TH dysfunction have been suggested to affect other aspects of PD. We focused on OH and autonomic responses because previous research demonstrated that low NE is a major reason for abnormal BP and HR in PD.8, 23

During an acute exercise stress test, individuals with PD present with lower BP, lower HR, and lower plasma NE levels than age‐matched healthy controls.8 NE levels are reflective of how intense an individual is working. NE is partly responsible for the increases in BP and HR and typically will spike after 65% to 70% of maximum VO₂.8, 23 Although previous research demonstrated that the increase in NE and exercise intensity was linear in PD subjects, HR and BP never reached the level that non‐PD subjects attained (as a result of starting at a lower baseline NE).8 In the current study, the intensity of exercise our subjects achieved on the first visit was the same intensity level postsupplementation (measured by vo ₂) to avoid any inadvertent increase in NE. Supplementing l‐tyrosine did not affect any of these autonomic responses during acute exercise.

Growdon et al. examined oral l‐tyrosine in subjects with PD at 100  and 150 mg/kg.15 They found that plasma tyrosine levels peaked 2 hours after ingestion. However, those that took a 150‐mg/kg dosage had plasma tyrosine levels stay significantly elevated after 8 hours, whereas the 100‐mg/kg dose group was approaching their fasting tyrosine plasma levels after 8 hours. In our current study, the subjects’ baseline tyrosine levels were within a normal reference range (33–160 μmol/L; Quest Diagnostics, Nichols Institute). Although we demonstrated, at a dose of 500 mg 2× daily, a significant increase in plasma tyrosine, our subjects were still within the normal reference range. Normal reference ranges are usually determined by taking either the lowest and highest values (range) of results obtained on a normal healthy large population.24 It is reasonable to question whether a normal reference range is an appropriate guideline for a diseased population and what the appropriate concentration of tyrosine is required to show a clinical effect.24

Interestingly, 63% of people with PD use nutritional supplements, and less than 50% report this use to physicians.25 To our knowledge this is the first clinical trial to examine the effects of oral tyrosine supplementation in a PD population for safety and for SNS efficacy. The changes observed in SBP could possibly be a placebo effect, which is not uncommon in clinical trials with PD20; however, given the short duration of this trial, it is difficult to determine whether this was a placebo effect. Additionally, the confidence interval for SBP (after OH testing) yields the results as inconclusive. Future studies should use a larger cohort of subjects to determine more definitively whether or not supplementing l‐tyrosine for treatment of OH is effective.

Given that we did not find changes in NE or autonomic responses, our study does not support our secondary hypothesis that oral l‐tyrosine can improve NE, BP, or HR under acute exercise stress.

Limitations of our study would be the short time frame for supplementation. We used an average recommended dose of tyrosine under a high‐stress condition. Furthermore, we failed to administer a patient‐rated outcome measure. Future assessment can perhaps use more than one OH test, use a valid patient‐rated outcome tool, and do continuous BP monitoring that could assess the fluctuations of BP throughout the day during the cycle of l‐dopa. The level that plasma tyrosine was increased to was not sufficient enough to affect plasma NE production. Dosage and the resulting plasma and brain levels of tyrosine are important determinants of its clinical effectiveness. Future studies may investigate a higher dose of l‐tyrosine to increase circulating concentrations of tyrosine over a longer period of time in a larger cohort of subjects.

l‐tyrosine at a dosage of 1,000 mg daily (500 mg 2× daily) for 7 days is safe and well tolerated in subjects receiving dopamine therapy and other anti‐Parkinson's medication. l‐tyrosine at 1,000 mg daily was enough to increase plasma tyrosine in PD. Supplementing 1,000 mg/day of l‐tyrosine to individuals with PD does not affect OH or autonomic responses during acute exercise stress.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

J.D.D.: 1A, 1B, 1C, 2C, 3A, 3B

E.R.: 2A, 2B, 2C, 3B

E.M.L.: 2A, 2B, 2C, 3B

W.G.W.: 1B, 1C, 2C, 3B

Disclosures

Funding Sources and Conflicts of Interest: This study was funded by the Michael J. Fox Foundation Rapid Response Innovation Award.

Financial Disclosures for previous 12 months: J.D.D. has received a Michael J. Fox Foundation Rapid Response Innovation Award: The Effects of Tyrosine on Orthostatic Hypotension in Parkinson's Disease ($75,000; August–December 2013; role: principle investigator). E.R. has received a Michael J. Fox Foundation Rapid Response Innovation Award: The Effects of Tyrosine on Orthostatic Hypotension in Parkinson's disease ($75,000; August–December 2013; role: coinvestigator). E.M.L. has been supported by Townsend Design: Evaluation of the Townsend Design Rebel Reliever Knee Brace for Individuals with Knee Osteoarthritis ($75,000; 16 April 2013–30 June 2014; role: principal investigator); the Hartman Foundation for Parkinson's Disease (grant awarded to Stony Brook University to transition to Thomas Hartman Center for Parkinson's Disease Stony Brook): Improving gait and cognition in PD: a dual‐task intervention study (Amount, $2,000,000; subaward, $100,000; 1 April 2013–30 March 2015; role: coinvestigator); and the Foundation for Physical Medicine and Rehabilitation: Measurement of Medial Collapse During Bilateral and Unilateral Squat ($10,000; 1 June 2013–30 May 2014; role: co–principal investigator). W.G.W. has received a Michael J. Fox Foundation Rapid Response Innovation Award: The Effects of Tyrosine on Orthostatic Hypotension in Parkinson's disease ($75,000; August–December 2013; Role: coinvestigator).