Table 2.

Completed clinical trials exploring the effect of vitamin D supplementation in neurological diseases. ALS amyotrophic lateral sclerosis; ARR annualized relapse rate; CIS Clinically isolated syndrome; EDSS Expanded Disability Status Scale; IFN Interferon; IL interleukin; IU International Units; MS multiple sclerosis; ON optic neuritis; QoL quality of life; RNFL retinal nerve fiber layer; RRMS Relapsing Remitting Multiple Sclerosis; SC subcutaneous. To convert 25(OH)D from ng/mL to nmol/L the value is multiplied by 2.5.

Formulation	Indication(s)	Phase	Main Results	References
Cholecalciferol	2-year study, 181 RRMS patients with (1) a low serum 25-hydroxy vitamin D concentration (<75 nmol/L), (2) treatment with interferon beta-1a 44 μg (SC 3 times per week) 4 months ± 2 months before randomization, and (3) at least one documented relapse during the previous 2 years, randomized to oral cholecalciferol 100,000 IU or placebo every other week for 96 weeks	II	No change in the ARR at 96 week; good efficacy on MRI parameters (less new hypointense T1-weighted lesions; a lower volume of hypointense T1-weighted lesions, and a lower progression of EDSS)	NCT01198132 Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE) [248].
Cholecalciferol	229 RRMS patients treated with SC IFN-β-1a 44 μg 3 times weekly and serum vitamin D levels <150 nmol/were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113).	II	No significant difference in the proportion of patients with no evidence of disease activity at week 48. Better MRI outcomes (combined unique active lesions and change from baseline in total volume of T2 lesions) in those patients receiving SC IFN-β-1a plus oral high-dose vitamin D3	NCT01285401 Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a [247].
Cholecalciferol	CIS patients and healthy control participants were randomised to: placebo, 5000 IU or 10,000 IU vitamin D3/day (Vigantol oil)	I/II	No immunological, MRI or clinical evidence of benefit over 24 weeks	NCT01728922 Effects of vitamin D3 in clinically isolated syndrome and healthy control participants: A double-blind randomised controlled trial [246].
Cholecalciferol	52 patients with confirmed unilateral ON aged 15–38 years and low serum vitamin D levels. Patients were randomly allocated to receive 6 months of treatment with adding either 50,000 IU/week vitamin D or placebo	II	In the 27 patients treated with vitamin D, no significant effect on the thickness of RNFL or macula was found.	NCT01465893 Effects of vitamin D on retinal nerve fiber layer in vitamin D deficient patients with optic neuritis: Preliminary findings of a randomized, placebo-controlled trial [245].
Ergocalciferol	23 adults with clinically active RRMS were randomized to 6 months’ double-blind placebo-controlled high-dose vitamin D2, 6000 IU capsules, dose adjusted empirically aiming for a serum vitamin D 130–175 nmol/L. All received daily low-dose (1000 IU) D2 to prevent deficiency	I/II	No significant therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation was found	ACTRN12606000359538 A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis [244].
Cholecalciferol	45 IFNβ-treated MS patients were recruited. 21 patients were assigned to 800 IU of vitamin D3 per day, while 24 patients received 4370 IU per day for one year.	IV	No significant change in flu-like symptoms. IL-17 levels were significantly increased in the low dose group, while patients receiving high dose vitamin D had a heterogeneous IL-17 response. No significant differences in relapse rate, EDSS, QoL, serum IL10 and IFNγ were found	NCT01005095 Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties [243].
Cholecalciferol	40 patients with RRMS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months	I	Cholecalciferol with 10,400 IU daily is associated with reduction of IL-17 production by CD4+ T cells and decreased proportion of effector memory CD4+ T cells with concomitant increase in central memory CD4+ T cells and naive CD4+ T cells	NCT01024777 Safety and immunologic effects of high- vs. low-dose cholecalciferol in multiple sclerosis [242].
Cholecalciferol	35 adult and fully ambulatory RRMS patients were included in the vitamin D3 Supplementation with 20,000 IU weekly group and 33 in the placebo group	III	Supplementation with 20,000 IU vitamin D(3) weekly did not result in beneficial effects on the measured MS-related outcomes	NCT00785473 Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial [241].
Vitamin D	Peroral 20,000 IU once weekly as an add on therapy to IFNβ-1b vs placebo in patients with MS	IV	Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS (fewer new T2 lesions, T1 enhancing lesions). There was a tendency to reduced disability accumulation and to improved tandem gait. No significant differences in the ARR	NCT01339676 A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis [240].
Cholecalciferol	50 patients with RRMS aged 25 to 57 years and normal serum 25-hydroxyvitamin D were randomly allocated to receive 12 months of treatment with either escalating 1,25(OH)2D doses up to 0.5 μg/day or placebo combined with disease-modifying therapy	II	Adding low-dose vitamin D to routine disease-modifying therapy had no significant effect on the EDSS score or relapse rate	N/A Effects of Adjunct Low-Dose Vitamin D on Relapsing-Remitting Multiple Sclerosis Progression: Preliminary Findings of a Randomized Placebo-Controlled Trial [239].
Alfacalcidol	Alfacalcidol (1 mcg/d, n = 80) or placebo (n = 78) was administered for six consecutive months in MS patients	N/A	Alfacalcidol decreased the fatigue score and improved QoLas compared with placebo. The Alfacalcidol-treated group had reduced number of relapses and higher proportion of relapse-free patients	(The trial was not registered as Alfacalcidol is considered a natural supplement and not a drug in Israel) Effect of Alfa-calcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study [238].
Cholecalciferol	30 ON patients (15 in each of 2 groups, aged 20–40 years) with serum 25 hydroxyvitamin D levels of less than 30 ng/mL were enrolled. The treatment group received 50,000 IU of vitamin D3 weekly for 12 months and the control group received a placebo weekly for 12 months	N/A	Risk reduction of 68.4% for the conversion to MS after 12 months. Patients in the treatment group had a significantly lower incidence rate of cortical, juxtacortical, corpus callosal, new T2, new gadolinium-enhancing lesions and black holes. The mean number of total plaques showed a marginally significant decrease in the group receiving vitamin D3 supplementation as compared with the placebo group.	IRCT201205319919N1 Preventive effect of vitamin D3 supplementation on conversion of optic neuritis to clinically definite multiple sclerosis: a double blind, randomized, placebo-controlled pilot clinical trial [237].
Cholecalciferol	172 patients with RRMS, age 18 to 50 years, and EDSS ≤ 4.0, after completing a one-month run-in of glatiramer acetate, were randomized 1:1 to oral vitamin D3 5000 IU versus 600 IU daily	III	No significant difference was shown in terms of the proportion of subjects that experienced a relapse nor in terms of annualised relapse rate	NCT01490502 The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis [251].
Cholecalciferol	The EVIDIMS trial compared the effects of every other day high- (20,400 IU) vs low-dose (400 IU) cholecalciferol supplementation on clinical and imaging markers of disease activity in 53 MS patients of which 41 completed the study.	II	The Authors recognized that the sample size of this trial was underpowered but no significant difference in terms of clinical and MRI metrics (including lesion development, enhancing lesions, and brain atrophy) between the two groups, after 18 months.	NCT01440062 High-dose vitamin D supplementation in multiple sclerosis—results from the randomized EVIDIMS (efficacy of vitamin D supplementation in multiple sclerosis) trial [250].
Cholecalciferol	4143 women aged 65 and older without probable dementia at baseline who participated in the WHI Calcium and Vitamin D Trial and the WHI Memory Study. 2034 women were randomized to receive 1000 mg of calcium carbonate combined with 400 IU of vitamin D3 (treatment) and 2109 to placebo.	III	no association between treatment assignment and incident cognitive impairment	Part of NCT00000611 Calcium and Vitamin D Supplementation and Cognitive Impairment in the Women’s Health Initiative [313].
Vitamin D supplements	43 white outpatients with a new diagnosis of AD, who had not taken anti-dementia drugs or vitamin D supplements were prescribed memantine alone (n = 18), vitamin D alone (n = 17), or memantine plus vitamin D (n = 8) for an average of 6 months. Vitamin D supplements were given orally, either daily or monthly. The dose ranged between 400 and 1000 IU per day, or 100,000 and 200,000 IU per month.	N/A	Patients with AD who were treated for 6 months with the combination of memantine plus vitamin D supplements had a statistically and clinically significant gain in global cognitive performance	N/A Effectiveness of the Combination of Memantine Plus Vitamin D on Cognition in Patients with Alzheimer Disease [314].
Cholecalciferol	5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5–4.2 years).	III	Negative results on stroke prevention	ACTRN12611000402943 Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study: A Randomized Clinical Trial [315].
Cholecalciferol	The experimental group received an add-on oral vitamin D 5000 IU once daily and standard treatment (pregabalin, gabapentin, or amitriptyline) over eight weeks. The control group received standard treatment alone.	II/III	The addition of oral vitamin D 5000 IU to standard treatment significantly improves pain, mood, and vitamin D levels more effectively than standard treatment alone in patients with diabetic neuropathy.	NCT04689958 The Benefits of Add-on Therapy of Vitamin D 5000IU to the Vitamin D Levels and Symptoms in Diabetic Neuropathy Patients: A Randomized Clinical Trial [304].
Cholecalciferol	A single intramuscular dose of 600,000 IU of vitamin D to 143 participants with predominantly type 2 diabetes	N/A	Treatment with a single intramuscular dose of 600,000 IU of vitamin D in patients with painful diabetic neuropathy is associated with a significant decrease in the symptoms of painful diabetic neuropathy	NCT02737423 Vitamin D for the treatment of painful diabetic neuropathy [207].
Cholecalciferol	112 type 2 diabetic patients with diabetic peripheral neuropathy and vitamin D deficiency were assigned to a treatment group (n = 57) and a placebo group (n = 55). Patients received either oral vitamin D3 capsules or starch capsules once weekly for 8 weeks	N/A	Short-term oral vitamin D3 supplementation improved vitamin D status and the symptoms of neuropathy in patients with type 2 diabetes.	N/A Prospective Evaluation of the Effect of Short-Term Oral Vitamin D Supplementation on Peripheral Neuropathy in Type 2 Diabetes Mellitus [306].
Cholecalciferol	60 type 2 diabetic patients with painful diabetic neuropathy were enrolled and received weekly 50,000 IU of vitamin D3 for 12 weeks orally	N/A	Oral supplementation of vitamin D 3 (50,000 IU) once weekly for 12 weeks was associated with improvement in the serum level of vitamin D and significant decrease in the symptoms and sign of diabetic neuropathy.	IRCT2017102325266N2 Dose vitamin D supplementations improve peripheral diabetic neuropathy? A before-after clinical trial [305].
Cholecalciferol	Patients with migraine. 24 weeks of vitamin D3 (24 patients, 100 μg/day) or placebo (24 patients)	III	Vitamin D3 was superior to placebo in reducing migraine days in migraine patients	NCT01695460 A randomized, double-blinded, placebo-controlled, parallel trial of vitamin D3 supplementation in adult patients with migraine [286].
Cholecalciferol	80 episodic migraineurs who randomly assigned into two equal groups to receive either daily dose of vitamin D3 2000 IU (50 μg) or placebo for 12 weeks	N/A	Improvement of headache characteristics and reduction of neuro-inflammation in episodic migraine	IRCT20151128025267N6 Vitamin D3 might improve headache characteristics and protect against inflammation in migraine: a randomized clinical trial [316].
Cholecalciferol	31 female and 26 male 5–15-year-old children with migraine headaches were randomly allocated to receive 2 mg/kg/day of topiramate or 2 mg/kg/day of topiramate plus one 500,000 IU vitamin D3 pearl weekly for two consecutive months	N/A	the combination of topiramate and vitamin D3 was more effective than topiramate alone in reducing the monthly headaches frequency and disability score	IRCT201701092639N20 Efficacy of topiramate alone and topiramate plus vitamin D3 in the prophylaxis of pediatric migraine: A randomized clinical trial [317].
Cholecalciferol	39 patients in intervention group and 38 patients in the control group were allocated with simple randomization method (Vitamin D 50,000 IU/week vs placebo) during 10 weeks	N/A	Mean headache frequency and headache diary result were lower among the intervention group compared to placebo group	IRCT2012122911763N4 Effect of Vitamin D supplementation on symptoms and C-reactive protein in migraine patients [284].
Cholecalciferol	57 adults with episodic migraine were randomized to simvastatin 20 mg tablets twice-daily plus vitamin D3 1000 international units capsules twice-daily or matching placebo tablets and capsules for 24 weeks	II	Efficacy of simvastatin plus vitamin D3 in decreasing the number of migraine days from the baseline period	NCT01225263 Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial [285].
Cholecalciferol	48 ALS patients, 34 with deficient (<20 ng/mL) and 14 with insufficient (20–29 ng/mL) serum levels of vitamin D, were randomized and treated by 3 different doses of cholecalciferol [50,000, 75,000 and 100,000 IU /month] and evaluated after 6-months	N/A	no significant effects on motor dysfunction	Vitamin D supplementation has no effects on progression of motor dysfunction in amyotrophic lateral sclerosis (ALS) [205].