Low Dose Niacin Versus Placebo Treatment for Parkinson's Disease: A Randomized Controlled Trial

Parkinson's Disease (PD) patients have lower niacin levels compared to their spouses. The main objective was to study low-dose daily niacin supplementation on motor symptoms in Parkinson's disease subjects. Forty-Seven PD patients were randomly assigned to receive low-dose niacin or placebo in a randomized, double-blind study for the rst six months. After the double-blind phase, all participants received open-label niacin for the next six months. All patients were evaluated at baseline, six months, and one year of treatment. The main outcome measure was the Unied Parkinson's Disease Rating Scale III (UPDRS III) scores. Secondary outcome measures were depression, sleep quality, mental exibility and cognition, and physical fatigue. six-month randomized, double-blind, placebo-controlled (wait-listed) over-the-counter study of 250mg daily slow-release niacin with a subsequent six-month open-label portion. The study was a single-center trial conducted at Charlie Norwood Veterans Affairs Medical Center (CNVAMC, GA, USA) neurology clinic and Augusta University Medical Center (AUMC, GA, USA) tertiary movement disorders center (clinicaltrials.gov identier: NCT03462680). Supplements (placebo and niacin), a room for performing outcome measures, and blood level measurements (amino acids and serotonin) were provided by the CNVAMC. Patients were tested at baseline, after six months of daily 250mg niacin or placebo, and then again after six months of open-label 250mg daily niacin. All measurements were taken by a single assessor to eliminate interrater differences. The protocol was approved by the institutional review boards at CNVAMC and AUMC. All participants gave written informed consent prior to any study procedures.

Parkinson's disease (PD) is one of the most common movement disorders a icting about 1% of the population above 60 and reaches 4% by age 80. A de nitive diagnosis for PD requires an autopsy, and there is no cure or de nitive disease-slowing therapy despite extensive investigation [1]. Sinemet (carbidopa/levodopa) remains the cornerstone of PD therapy but can lead to signi cant motor complications (wearing off and dyskinesia) over time [2].
Numerous pathophysiological processes interplay in PD, but neuroin ammation and mitochondrial dysfunction remain at the core of PD pathology. Niacin is, therefore, a proper choice as an adjunct therapy in PD because it is anti-in ammatory and boosts mitochondrial function, providing NAD [3][4][5].
Our previous data, including a recently published three-month effectiveness trial, support this nding and indicate that niacin may in uence outcomes in PD [3,[6][7][8]. Moreover, carbidopa in Sinemet is known to deplete niacin levels in treated PD patients [9]. Despite the above-mentioned reasons and strong indications from animal models in PD, there have been no prior randomized clinical trials for supplementation of niacin in PD.
We hypothesized that niacin might improve tremor, rigidity, and overall UPDRS III scores in PD. At the end of the 6-month double-blind controlled trial, all participants enrolled received an open-label niacin supplementation for another six months (total 12 months), and then the randomization code was opened. This study reports the nal analysis of 39 randomized PD patients who completed six months of

Study Design and Participants
The trial was a six-month randomized, double-blind, placebo-controlled (wait-listed) over-the-counter study of 250mg daily slow-release niacin with a subsequent six-month open-label portion. The study was a single-center trial conducted at Charlie Norwood Veterans Affairs Medical Center (CNVAMC, GA, USA) neurology clinic and Augusta University Medical Center (AUMC, GA, USA) tertiary movement disorders center (clinicaltrials.gov identi er: NCT03462680). Supplements (placebo and niacin), a room for performing outcome measures, and blood level measurements (amino acids and serotonin) were provided by the CNVAMC. Patients were tested at baseline, after six months of daily 250mg niacin or placebo, and then again after six months of open-label 250mg daily niacin. All measurements were taken by a single assessor to eliminate interrater differences. The protocol was approved by the institutional review boards at CNVAMC and AUMC. All participants gave written informed consent prior to any study procedures.
Mild to moderately severe Parkinson's Disease patients with H&Y scores between 0.5-4 were enrolled in the study. The UK Parkinson's Disease Society Brain Bank Diagnostic Criteria [10] were used for the inclusion criteria. Subjects were previously stabilized on all Parkinson's Disease medications prior to enrollment with expected medication stability for at least six months. To be quali ed for the study, subjects had scores above 24 on the mini mental state exam (MMSE), indicating no signi cant evidence of dementia that may confound the study. Those with other severe neurological problems, previous brain surgery, functional blindness, inability to participate in visuomotor or gait assessments, an allergy to niacin, or other severe illnesses were excluded from the study. An attending expert neurologist used clinical judgment to determine if a patient was suitable for the study, which included an optional spinal tap.

Intervention
Forty-seven patients were enrolled in the study. Patients were randomized and blinded to receive either 250 mg of niacin once daily or a placebo, in accordance with the sequestered xed randomization schedule ( Fig. 1), using balanced blocks to ensure an approximate 1:1 ratio of the two treatment arms for early-stage or late-stage patients. The Veterans Affair pharmacy generated the randomized sequence for the trial. The PI, all study personnel, and study subjects were blinded to this randomization. The code was not revealed to the investigators until the study was completed in April 2020.

Outcomes of the study
The primary outcome of the study was a change in the UPDRS III scores from baseline to six months and then one year. Rejection of the null hypothesis occurs when the mean score at twelve months is less than baseline. Based on pilot data, the margin of superiority representing the minimal clinically meaningful change in score, δ, is 5. This value is consistent with the expected median annual rate of decline in the UPDRS III score of + 5.5 points [11,12]. Secondary outcomes included depression rating by the GDS, fatigue rating by the FSS and VAFS, mental resilience measured by TMT A and B, the difference between TMT-B and TMT-A was considered as a measurement of cognitive exibility [13], cognitive ability, and mental fatigue through the Stroop Test, overall cognitive function by MMSE (which excluded those who displayed dementia as a score < 24), amino acid and serotonin levels, and physical strength and fatigue through a grip strength test. There were no changes made during the course of the trial period.

Statistical Analysis
The sample size of 39 patients was determined by power analysis to give 80% power (α = 0.05) to detect a reduction of 2.5 points in UPDRS III scores after six-month treatment [11,12]. For a signi cance level (α) of 5%, and a power (1-β) of 80%, an expected standard deviation of the difference between pairs of data is 3.9, and the minimum sample size was 13 participants per group. Our study sample was substantially increased to take into account potential dropouts or unexpected increase in variability.
Data for all participants was captured into an Excel sheet (Microsoft Excel v2016) for subsequent analysis. Outcomes of all 39 participants who completed the 6-month trial were analyzed according to their randomization groups, comparing differences between treatments and differences between time points of baseline, six months, and one year.
One outlier was removed from UPDRS III scores based on the ordinary least-squares regression test (Q = 10%). All other outcome data had no outliers removed by the robust regression and outlier removal test [14]. Mean, standard deviations or standard error, and ranges were calculated for all numerical data. Categorical data were presented as counts and percentages. Statistical differences were tested between the treatment groups and time points by ANOVA with Tukey's posthoc corrections for primary outcomes. P-values were not corrected for the multiple comparisons between placebo and niacin for the secondary outcomes.
Differences were considered signi cant when p ≤ 0.05; all p values were two-sided. All analyses were performed using Prism (v8.0, Graphpad, San Deigo, CA, USA).

Participant Characteristics
Between 2015-2019, 47 participants were enrolled at the Charlie Norwood VA medical center; and randomly assigned to the placebo (n = 26) or 250 mg daily niacin (n = 21) group (Fig. 1). The mean age was 68.4, with a mean duration of the disease being 5.8 years (Table 1). Forty-four were Caucasian, three were African American, and eight of the 47 were women. The H&Y score of all patients ranged between 0.5-4.0. Thirty-four subjects were rated early-stage (H&Y < 2.5), while thirteen were classi ed as late-stage (H&Y ≥ 2.5). Twenty-ve (64.1%) subjects were Veterans (Table 1). *Medication information on two subjects in the niacin group was not available.
The 6-month follow-up was completed by 39 of the 47 enrolled patients. Eight of the 39 patients did not complete the optional 6-month open-label portion of the study (Fig. 1). Those who discontinued the study did so due to the ushing effect of niacin (n = 2), voluntary discontinuation (n = 7), or the SARS-CoV-2 shut-down of clinical research (n = 7). Although both groups took niacin from six to twelve months, the group who took the placebo for the rst six months will continue to be referred to as the placebo group for this study.    The study personnel were blinded to the group assignment, the randomization code was revealed at the completion of the study.
Values presented are Mean (95% CI). *p < 0.05 A signi cant decrease occurred across both groups over a treatment period of one year (p = 0.012), but no signi cant differences were found between treatments at any time point (Fig. 2D and Table 2).

Secondary Outcomes
Six months of 250mg niacin vs placebo Of all the secondary outcomes, no signi cant differences were observed for FSS, VAFS, GDS, Stroop test, or walk and turn time ( Table 2). Serum levels of amino acids valine, tyrosine, tryptophan, phenylalanine, leucine, and isoleucine were also not different between the treatment groups. Sleep e ciency or percentage of light sleep, deep sleep, or awake time also did not show any signi cant differences for this portion of the study ( Table 2).
The difference between TMT-B and TMT-A is a measurement of cognitive exibility while removing the factors of motor and visuoperceptual de cits. The change in cognitive exibility between baseline and six months was not signi cant between treatment groups. The difference between the treatment groups at six months was 2.44 [95% CI, -47.02 to 51.91] ( Table 2).
Grip strength, a measure of motor function and muscle energetics, did not show signi cance (

Adverse Events
Adverse events were similar between the niacin and placebo groups. Out of 47 recruited patients, Eight patients dropped out during the rst six months, and eight more dropped out before the one-year time point. The ushing effect of niacin occurred in and caused discontinuation for two patients, one in each group. Unrelated injuries occurred in one patient in the niacin group and one in the placebo group, although neither resulted in discontinuation of the study. One patient complained of leg cramps at the end of the study but was likely due to dehydration rather than supplement intake as assessed by the neurologist. No other adverse events were reported. Seven patients could not complete the study due to the SARS-CoV-2 shut-down, and all other dropouts voluntarily discontinued the study.

Discussion
In this single-center, double-blind, placebo-controlled, randomized clinical trial comprising of patients with early-and late-stage PD, supplementation of a single daily dose of niacin for twelve months improved the rigidity, bradykinesia, and overall UPDRS III scores. To our knowledge, this is the rst trial where niacin (a form of vitamin B3) is tested at a low dose for PD in a randomized, placebo-controlled, double-blind, prospective trial. A 250mg daily dose of niacin produced negligible or no ushing symptoms when consumed after meals as instructed. Our previous preliminary studies helped us decide the low dose for niacin [7,8]. Different low-dose regimes, longer duration of intervention, multi-center trials, and inclusion of niacinamide would be pertinent future investigations.
Numerous studies have attempted either raising NAD levels or directly providing NAD in PD. Niacin remains a natural source for NAD and acts on the niacin receptor GPR109A, unlike other forms of vitamin B3 [7]. Niacin supplements and agonists of the niacin receptor are shown to be neuroprotective and lead to enhanced motor function in animal models of PD (BHB, niacinamide, PINK1 fruit y study) [5,15,16]. In a serendipitous nding, a high-dose niacin supplement was observed to reduce bradykinesia and rigidity in a PD case report [17].
The niacin-treated group demonstrated a signi cant decrease in UPDRS III scores from six to twelve months in which they took the open-label niacin supplement. Both groups, when comparing baseline to one year, demonstrated a trending reduction in UPDRS III scores. Individual components of the UPDRS III showed improvements in gait, nger tapping, rising from a chair, posture, and rapid alternating movements after niacin treatment. A signi cant decrease in rigidity was observed in the placebo-treated group from six months to one year when they received niacin. Although the overall tremor score did not show any signi cance in the niacin-treated group, individual limb tremor scores decreased in the niacin- Almost all reported secondary measures demonstrated a trend towards improvement over the one-year period. However, serotonin levels and the FSS scores stood out. Serotonin levels were signi cantly down in the placebo-treated group but not in the niacin-treated group. The FSS scores were signi cantly better in the niacin-treated group but not the placebo group. Both of these ndings may explain the reporting of increased mood by PD subjects who received niacin for one year.

Study Strengths
It is a novel approach utilizing an over-the-counter vitamin supplement at a low dose in PD. The commonly used therapies for PD subjects do not currently include niacin. Placebo control was used for the rst six months, and codes were not broken until patients completed the 12-month study. The ushing effect of niacin was negligible and did not deter the PD patients from the study. The PD patients and caregivers were very enthusiastic after the 6-month open-label niacin supplementation. Dropout rates were low. A single rater captured the motor outcome scores for all of the subjects, which extended higher con dence in the reliability of the outcomes.

Study Limitations
The sample size is small. We did not titrate the dosages of niacin. The clinical trial recruited patients primarily through the Charlie Norwood VA Medical Center. Due to veterans and PD patients being predominantly men, we were only able to recruit eight women. Therefore, the potential gender bias was not adequately addressed. In addition, the sample population was primarily Caucasian (only three African American subjects).
Many outcome scores within the trial were self-reported surveys, including the FSS, VAFS, and GDS, although the groups were not found to be different at baseline. Furthermore, one year of niacin supplementation may be necessary to nd signi cant differences from placebo, so a longer placebocontrolled study should be performed in the future.

Conclusions
Among the PD patients, treatment with low-dose daily niacin supplementation compared to placebo

Declarations
Ethics approval and consent to participate: The study was approved by the IRB at CNVAMC and Augusta University. All subjects or their legally authorized caregivers signed informed consents.

Consent for Publication: Not applicable
Availability of data and materials: Upon reasonable request, de-identi ed individual participant data will be available beginning 9 months and ending 36 months following the publication of this article.
Proposals may be submitted up to 36 months following publication of this article. 17. Alisky JM. Niacin improved rigidity and bradykinesia in a Parkinson's disease patient but also caused unacceptable nightmares and skin rash-a case report. Nutr Neurosci. 2005;8:327-9. Figure 1 Flowchart showing participant ow in the Niacin for Parkinson's Disease trial. Forty-seven participants enrolled in the study were randomly placed into the placebo or niacin-treated group. Randomized doubleblind portion lasted the rst six months, then a subsequent open-label niacin phase was implemented from six to twelve months.