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: ClinicalTrials.gov.; identifier: NCT01676103)
Parkinson's disease (PD) is a degenerative neurological disease that affects over 1 million people in the United States. Cardinal motor features of PD include abnormal gait and balance, bradykinesia, freezing, and tremor. 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. OH affects over 50% of all people with PD. 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).[7-9] SNS abnormalities and reduced levels of NE are observed before PD medication is introduced. 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. 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. 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. PD suppresses NE, BP, and HR responses during exercise stress.
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. Individuals with PD have decreased activity of the enzyme TH. 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. 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. 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. 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.
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. 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. 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). In the current study, the intensity of exercise our subjects achieved on the first visit was the same intensity level postsupplementation (measured by VO2) 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. 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. 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.
Interestingly, 63% of people with PD use nutritional supplements, and less than 50% report this use to physicians. 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 PD; 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.