Disease-modifying therapies for diabetic peripheral neuropathy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Alpha-lipoic acid, epalrestat, and mecobalamin are widely used as monotherapies for diabetic peripheral neuropathy. However, whether a triple-combination therapy with these three drugs is superior to monotherapy or dual therapy remains debatable. METHODS: Nine randomized controlled trials were identified through a search on electronic databases such as PubMed, Web of Science, and Cochrane Library. The trial participants (N = 1153) were divided into the experimental group who received the triple-combination therapy and the control group who received conventional or dual therapy with the aforementioned drugs. RESULTS: Therapeutic outcomes were better in the experimental group than in the control group (odds ratio: 3.74; 95 % confidence interval: 2.57-5.45; I2 = 0 %; p < 0.00001). No statistic difference was noted in adverse effects. Compared with the control group, the experimental group exhibited significant improvements in median motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV, and vibration perception thresholds (VPT) in the left and right lower limbs. In the control group, a subgroup analysis by treatment strategy revealed similar improvements in total efficacy, MNCV, and SNCV. CONCLUSIONS: For diabetic peripheral neuropathy, the triple-combination therapy may be more effective than monotherapy or dual therapy.

Alpha-lipoic acid for diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a frequent complication in people living with type 1 or type 2 diabetes. There is currently no effective treatment for DPN. Although alpha-lipoic acid (ALA, also known as thioctic acid) is widely used, there is no consensus about its benefits and harms. OBJECTIVES: To assess the effects of alpha-lipoic acid as a disease-modifying agent in people with diabetic peripheral neuropathy. SEARCH METHODS: On 11 September 2022, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two clinical trials registers. We also searched the reference lists of the included studies and relevant review articles for additional references not identified by the electronic searches. SELECTION CRITERIA: We included randomised clinical trials (RCTs) that compared ALA with placebo in adults (aged 18 years or older) and that applied the study interventions for at least six months. There were no language restrictions. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. The primary outcome was change in neuropathy symptoms expressed as changes in the Total Symptom Score (TSS) at six months after randomisation. Secondary outcomes were change in neuropathy symptoms at six to 12 months and at 12 to 24 months, change in impairment, change in any validated quality of life total score, complications of DPN, and adverse events. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: Our analysis incorporated three trials involving 816 participants. Two studies included people with type 1 or type 2 diabetes, while one study included only people with type 2 diabetes. The duration of treatment was between six months and 48 months. We judged all studies at high risk of overall bias due to attrition. ALA compared with placebo probably has little or no effect on neuropathy symptoms measured by TSS (lower score is better) after six months (mean difference (MD) -0.16 points, 95% confidence interval (CI) -0.83 to 0.51; 1 study, 330 participants; moderate-certainty evidence). The CI of this effect estimate did not contain the minimal clinically important difference (MCID) of 0.97 points. ALA compared with placebo may have little or no effect on impairment measured by the Neuropathy Impairment Score-Lower Limbs (NIS-LL; lower score is better) after six months (MD -1.02 points, 95% CI -2.93 to 0.89; 1 study, 245 participants; low-certainty evidence). However, we cannot rule out a significant benefit, because the lower limit of the CI surpassed the MCID of 2 points. There is probably little or no difference between ALA and placebo in terms of adverse events leading to cessation of treatment within six months (risk ratio (RR) 1.48, 95% CI 0.50 to 4.35; 3 studies, 1090 participants; moderate-certainty evidence). No studies reported quality of life or complications associated with DPN. AUTHORS' CONCLUSIONS: Our analysis suggests that ALA probably has little or no effect on neuropathy symptoms or adverse events at six months, and may have little or no effect on impairment at six months. All the studies were at high risk of attrition bias. Therefore, future RCTs should ensure complete follow-up and transparent reporting of any participants missing from the analyses.

Evaluation of Safety and Efficacy of Add-on Alpha-Lipoic Acid on Migraine Prophylaxis in an Adolescent Population: A Randomized Controlled Trial.

Nutraceuticals like alpha-lipoic acid (ALA) may have potential benefits as prophylactic agents for adolescent migraine, with fewer adverse events than existing medications. The present study was conducted to evaluate the safety and efficacy of add-on ALA for prophylaxis in adolescent migraine. A randomized, open-label, add-on clinical trial was conducted with 60 adolescent migraineurs, who were randomized to receive flunarizine or flunarizine with an add-on ALA. A clinical evaluation of the frequency and severity of migraine, responder rate, Pediatric Migraine Disability Assessment (PedMIDAS) scoring, serum thiol, and serum calcitonin gene-related peptide (CGRP) was performed both at baseline and following 12 weeks of treatment. The frequency of acute attacks of migraine decreased significantly (P = .001) in the test group compared with the control group. The responder rate was found to be significantly higher (80%) in the test group than in the control group (33.3%) (P = .001). The mean monthly migraine headache days in the test group showed a significant reduction (-7.7 days, 95%CI -9.1 to -6.3 days; P = .010). The severity of acute migraine attacks (mild, moderate, severe) also showed a significant reduction in the test group (P = .001). PedMIDAS scores showed significant improvement in the test group (P = .021), in comparison with the control group. Serum thiol levels were significantly increased in the test group (18 mmol/L, 95%CI 13.5 to 36.1 mmol/L; P = .001). Serum CGRP levels showed a significant reduction with adjunctive ALA therapy (-122.4 pg/mL, 95%CI -142.3 to -89.0 pg/mL; P = .006). Add-on ALA with flunarizine as a prophylactic agent for migraine in adolescents can improve clinical outcomes by improving clinical and biochemical parameters.

Effects of alpha-lipoic acid on sperm quality in patients with varicocele-related male infertility: study protocol for a randomized controlled clinical trial.

BACKGROUND: Varicocele is a high incidence and is considered to be the most common and correctable cause of male infertility. Oxidative stress (OS) plays a central role in the pathogenesis of varicocele-related male infertility. In addition to varicocelectomy, antioxidant supplementation seems to be an effective scheme for the treatment of varicocele-related male infertility, but it is still controversial. The purpose of this study is to determine the effects of alpha-lipoic acid (ALA) supplementation on sperm quality in patients with varicocele-related male infertility. METHODS: In this randomized controlled clinical trial, we will randomize 80 patients with varicocele-related male infertility from Guilin People's Hospital. The non-surgical observation group (n = 20) will receive ALA, the non-surgical control group (n = 20) will receive vitamin E, the surgical observation group (n = 20) will receive ALA after the operation, and the surgical control group (n = 20) will receive vitamin E after the operation. The course of treatment will be 3 months. The results will compare the changes in semen parameters, sex hormones, testicular volume, sperm DNA fragment index (DFI), seminal plasma malondialdehyde (MDA), and total antioxidant capacity (TAC) between the groups at baseline and after 3 months of antioxidant supplementation. DISCUSSION: Whether it is necessary to use antioxidants in varicocele-related male infertility, how potent antioxidants should be used, postoperative application or non-surgical independent application still needs to be explored. This study attempts to compare the effects of two antioxidants (ALA and vitamin E) on sperm quality in patients with varicocele-related male infertility (surgical or non-surgical) and attempted to answer the above questions. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) ChiCTR2100054958. Registered on 29 December 2021.

Alpha lipoic acid decreases neuronal damage on brain tissue of STZ-induced diabetic rats.

Neuropathy that develops due to diabetic complications causes cognitive im-pairment due to functional and structural damage. The aim of this study was to evaluate the biochemical, histological and physiological effects of Alpha Lipoic Acid (ALA) against brain tissue damage caused by diabetes. Fourty male Wistar albino rats were separated into four groups as control, diabetes mellitus (DM), ALA and DM+ALA. Single dose of 50 mg/kg intraperitonal streptozotocin (STZ) was used to induce DM. For six weeks, ALA (100 mg/kg/day) was administered to the ALA and DM+ALA groups. At the end of the six week rats were sacrificed by collecting blood samples and collected brain tissues (hippocampus, cortex, hippotalamus and stri-atum) were histologically evaluated in addition to the oxidant-antioxidant parameters. ALA administration showed significant improvement in cognitive functions evaluated by MWM in rats with diabetes mellitus (p<0.05). SOD, CAT, GSH-Px activities, which were decreased in the DM group compared to the control group, increased statistically significantly in rats in DM+ALA group (p<0.05). While MDA and PC levels increased in the DM group, they decreased statistically significantly in the DM+ALA group (p<0.05). According to the histological examinations made by light and electron microscopies, it was determined that the ultrastructural damage and degeneration findings observed in the sections of the DM group were significantly ameliorated in the sections of rats in the DM+ALA group. ALA may be effective in restoring cell damage and cognitive functions in brain tissue with its antioxidant and neuroprotective effects without showing antidiabetic effects.

The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines.

The current study was performed to evaluate the effects of alpha-lipoic acid (ALA) supplementation on lactate, nitric oxide (NO), vascular cell adhesion molecule-1 (VCAM-1) levels, and clinical symptoms in women with episodic migraines. Considering the inclusion and exclusion criteria, ninety-two women with episodic migraines participated in this randomized, double-blind, placebo-controlled, parallel-design trial. The participants were randomly assigned to receive either 300 mg/day ALA or placebo, twice per day for 12 weeks. The primary outcomes included headache severity, headache frequency per month, and duration of attacks and the secondary outcomes included lactate (a marker of mitochondrial function), NO, and VCAM-1 serum levels were measured at baseline and the end of the intervention. At the end of the study, there was a significant decrease in lactate serum levels (- 6.45 ± 0.82 mg/dl vs - 2.27 ± 1.17 mg/dl; P = 0.039) and VCAM-1 (- 2.02 ± 0.30 ng/ml vs - 1.21 ± 0.36 ng/ml; P = 0.025) in the ALA as compared to the placebo group. In addition, the severity (P < 0.001), frequency (P = 0.001), headache impact test (HIT-6) (P < 0.001), headache dairy results (HDR) (P = 0.003), and migraine headache index score (MHIS) (P < 0.001) had significantly decreased in the intervention as compared to the control group. No significant changes were observed for NO levels and duration of migraine pains. ALA supplementation can be considered a potential adjunct treatment in patients with migraine due to its improving mitochondrial and endothelial functions and clinical symptoms.

EFFECTIVENESS OF ALPHA-LIPOIC ACID AND IPIDACRINE HYDROCHLORIDE IN PREVENTION OF PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY ASSESSED BY ELECTRONEUROMYOGRAPHY OF SUPERFICIAL PERONEAL AND SURAL NERVES.

AIM: To investigate the neurofunctional parameters in breast cancer (BC) patients with paclitaxel-induced peripheral neuropathy (PIPN) and to clarify the feasibility of using alpha-lipoic acid (ALA) in combination with the acetylcholinesterase inhibitor ipidacrine hydrochloride (IPD) for its prevention. MATERIALS AND METHODS: 100 BC patients (T1-4N0-3M0-1) prescribed for polychemotherapy (PCT) by the AT (paclitaxel, doxorubicin) or ET (paclitaxel, epirubicin) regimens in the neoadjuvant, adjuvant or palliative modes, were enrolled. The patients were randomized into two groups (n = 50 per group): group I treated by PCT only; group II treated with PCT plus the studied PIPN prevention scheme (ALA in combination with IPD). An electroneuromyography (ENMG) of the sensory (superficial peroneal and sural) nerves was performed before PCT, and after the 3 and 6 PCT cycles. RESULTS: According to ENMG data, the electrophysiological disturbances in the sensory nerves were manifested in the form of axonal sensory peripheral neuropathy of a symmetrical nature, which was reflected in a decrease in the amplitude of the action potential (AP) of the studied nerves. The AP reduction in sensory nerves was dominant, in contrast to the nerve conduction velocity, which in most patients remained within the reference values, thus evidencing on axonal degeneration rather than demyelination as an underlying cause of PIPN. The ENMG testing of the sensory nerve in the groups of BC patients treated by PCT with paclitaxel with or without PIPN prevention treatment established that the use of ALA in combination with IPD significantly improved AP amplitude, duration and area of ​​the response to the stimulation of the superficial peroneal and sural nerves after 3 and 6 PCT cycles. CONCLUSION: The use of ALA in combination with IPD significantly reduced the severity of damage to the superficial peroneal and sural nerves caused by PCT with paclitaxel and could be recommended for PIPN prevention.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: A monocentric, randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Extensive evidence suggests that alpha-lipoic acid (ALA) is effective in diabetic neuropathy pain management. However, little is known on its safety and efficacy in reducing idiopathic pain in normoglycemic subjects. The aim of this study was to evaluate ALA food supplement safety and efficacy in the reduction of different forms of idiopathic pain. METHODS: Two-hundred and ten normoglycemic adults suffering from idiopathic pain (i.e. 57 subjects with primitive neuropathic pain, 141 subjects with arthralgia with unknown etiology, and 12 subjects with idiopathic myalgia) were randomized to receive placebo, 400 mg/day, or 800 mg/day of ALA. Participants underwent two visits (at baseline = t0, and after 2 months = t1) in which two validated questionaries for pain (numerical rating scale [NRS] and visual analogue scale [VAS]) were collected; fasting blood glucose assessment, adverse effects, and renal and hepatic toxicity were also monitored. RESULTS: At t1, none of subjects treated with ALA reported a decreased glycemia or adverse effects. The treated subjects showed a significant reduction in NRS (p < 0.001) while the placebo group did not show any NRS reduction (p = 0.86). Similar results were also obtained for VAS. Statistical analysis aimed at detecting possible differences in NRS and VAS scores among treatment groups based on the source of pain did not reveal any significant effect. CONCLUSIONS: Since the management of idiopathic pain is challenging for physicians, the use of ALA food supplements could be a feasible option, based on its safety and efficacy compared to commonly-used analgesic drugs.

Effects of Lipoic Acid on Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury often occurred in some pathologies and surgeries. I/R injury not only harmed to physiological functions of corresponding organ and tissue but also induced multiple tissue or organ dysfunctions (even these in distant locations). Although the reperfusion of blood attenuated I/R injury to a certain degree, the risk of secondary damages was difficult to be controlled and it even caused failures of these tissues and organs. Lipoic acid (LA), as an endogenous active substance and a functional agent in food, owns better safety and effects in our body (e.g., enhancing antioxidant activity, improving cognition and dementia, controlling weight, and preventing multiple sclerosis, diabetes complication, and cancer). The literature searching was conducted in PubMed, Embase, Cochrane Library, Web of Science, and SCOPUS from inception to 20 May 2021. It had showed that endogenous LA was exhausted in the process of I/R, which further aggravated I/R injury. Thus, supplements with LA timely (especially pretreatments) may be the prospective way to prevent I/R injury. Recently, studies had demonstrated that LA supplements significantly attenuated I/R injuries of many organs, though clinic investigations were short at present. Hence, it was urgent to summarize these progresses about the effects of LA on different I/R organs as well as the potential mechanisms, which would enlighten further investigations and prepare for clinic applications in the future.

Lipoic acid. Kinetics and pluripotent biological properties and derivatives.

Lipoic acid (LA) is globally known and its supplements are widely used. Despite its importance for the organism it is not considered a vitamin any more. The multiple metabolic forms and the differences in kinetics (absorption, distribution and excretion), as well as the actions of its enantiomers are analysed in the present article together with its biosynthetic path. The proteins involved in the transfer, biotransformation and activity of LA are mentioned. Furthermore, the safety and the toxicological profile of the compound are commented, together with its stability issues. Mechanisms of lipoic acid intervention in the human body are analysed considering the antioxidant and non-antioxidant characteristics of the compound. The chelating properties, the regenerative ability of other antioxidants, the co-enzyme activity and the signal transduction by the implication in various pathways will be discussed in order to be elucidated the pleiotropic effects of LA. Finally, lipoic acid integrating analogues are mentioned under the scope of the multiple pharmacological actions they acquire towards degenerative conditions.

Lipoic Acid Exacerbates Oxidative Stress and Lipid Accumulation in the Liver of Wistar Rats Fed a Hypercaloric Choline-Deficient Diet.

Non-alcoholic fatty liver disease (NAFLD) is currently estimated as the most prevalent chronic liver disease in all age groups. An increasing body of evidence obtained in experimental and clinical data indicates that oxidative stress is the most important pathogenic factor in the development of NAFLD. The study aimed to investigate the impact of α-lipoic acid (LA), widely used as an antioxidant, on the effects of a hypercaloric choline-deficient diet. Male Wistar rats were divided into three groups: control diet (C); hypercaloric choline-deficient diet (HCCD), and hypercaloric choline-deficient diet with α-lipoic acid (HCCD+LA). Supplementation of HCCD with LA for eight weeks led to a decrease in visceral adipose tissue/body weight ratio, the activity of liver glutathione peroxidase and paraoxonase-1, plasma, and liver total antioxidant activity, as well as an increase in liver/body weight ratio, liver total lipid and triglyceride content, and liver transaminase activities compared to the HCCD group without LA. In conclusion, our study shows that α-lipoic acid detains obesity development but exacerbates the severity of diet-induced oxidative stress and lipid accumulation in the liver of male Wistar rats fed a hypercaloric choline-deficient diet.

Sodium R-lipoate and enzymatically-modified isoquercitrin suppressed IgE-independent anaphylactic reactions and stress-induced gastric ulceration in mice.

Anaphylaxis is a life-threatening allergic reaction, for which the worldwide prevalence is rapidly increasing. The currently used synthetic antiallergic drugs have a high tendency to cause adverse effects, like gastric ulcers, in long-term use. Therefore, a great deal of attention has been given to develop new safer and more effective antiallergic agents from natural compounds that are chemically/enzymatically-modified. Here, we evaluated/compared the efficacy of two different doses (50 and 100 mg/kg body weight "b.w", given orally) of sodium R-lipoate (NaRLA) and enzymatically-modified isoquercitrin (EMIQ) in alleviating both local/systemic non-immunological anaphylactic reactions and stress-induced gastric ulceration in mice, in comparison with sulfasalazine (SSZ) as a reference drug. The results indicated that the pre-treatment of animals with NaRLA or EMIQ (especially at 100 mg/kg b.w) completely succeeded, as SSZ, in alleviating the hind paw edema induced by either histamine or compound 48/80 (Cpd 48/80). Furthermore, NaRLA and EMIQ prevented the mast cell degranulation and anaphylactic shock caused by Cpd 48/80 (in a dose-dependent manner) and reduced significantly (P < 0.001) the histamine release from the mouse peritoneal mast cells, like SSZ. Moreover, their use was associated with alleviating both gastric histopathological and biochemical alterations in the water-restraint stress (WRS) mice model towards the control values. They also decreased the percentage of degranulated mesenteric mast cells in the WRS mice model. In conclusion, our findings provide possibility that both NaRLA and EMIQ may serve as an effective therapeutic agents for mast cells-dependent anaphylactic reactions without risks of inducing gastric ulcers.

Analysis of the clinical characteristics of insulin autoimmune syndrome induced by alpha-lipoic acid.

WHAT IS KNOWN AND OBJECTIVE: Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. METHODS: We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. RESULTS AND DISCUSSION: The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 µIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36). WHAT IS NEW AND CONCLUSION: ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

Assessment of adverse reactions to α-lipoic acid containing dietary supplements through spontaneous reporting systems.

BACKGROUND & AIMS: Alpha-lipoic acid (ALA)-containing dietary supplements are widely used in clinical practice, although their safety assessment is under-investigated. We characterize the safety profile of ALA-containing products by analysing spontaneous reports of suspected adverse reactions (ARs). METHODS: Suspected ARs to ALA-containing products were extracted from the Italian Phytovigilance System (IPS), and scrutinized in terms of seriousness and causality (through WHO UMC system), with a specific focus on important (IMEs) and designated medical events (DMEs). To characterize the reporting profile from an international perspective, the WHO-VigiBase was also queried. RESULTS: From March 2002 to February 2020, out of 2147 total reports, 116 reports concerning 212 ARs to ALA-containing products were collected. Women were involved in 68.1% of cases. Skin (44.9%) and gastrointestinal disorders (10.8%) were the most frequently represented ARs. Causality assessment resulted as definite (15), probable (35), possible (24), unlikely (5), and unclassifiable (37). In 70% of cases, events occurred within 30 days of ALA use. Forty-five reports were serious (38.8%), being insulin autoimmune syndrome the most frequently reported (N = 10). IMEs were recorded in 20 cases, including four DMEs (3 angioedema and one anaphylactic shock). Similar distribution emerged from the 5641 reports in the WHO-VigiBase. CONCLUSIONS: The remarkable reporting of unpredictable skin, immune and hepatic ARs, coupled with seriousness, strong causality and early onset, calls for a) careful risk-benefit assessment of ALA-containing products by regulators; b) awareness and monitoring by clinicians and c) continuous vigilance of their safety profile through valuable spontaneous reporting systems such as IPS.

Randomized clinical trial of combined therapy with oral α-lipoic acid and NB-UVB for nonsegmental stable vitiligo.

Vitiligo is associated with oxidant stress and α-lipoic acid (ALA) is an antioxidative agent. To evaluate the efficacy and safety of oral ALA in combination with NB-UVB phototherapy on nonsegmental stable vitiligo. The prospective, multi-center, parallel controlled, double-blind randomized clinical trial was conducted from 2012 to 2014, in seven comprehensive tertiary hospitals in China. The patients were randomized into oral ALA group or placebo group at a dose of 300 mg daily for 6 months. All of them received NB-UVB phototherapy three times weekly. The repigmentation rate was evaluated by 4-point grading scale of improvement: >98%, 50-98%, 10-49%, <10%. A total of 133 patients were enrolled in the study, including 72 cases in treatment group and 61 cases in control group. In treatment group, 2.04% (1/49) patients achieved ≥50% improvement at 1-month after enrollment (M1), and the percentage of patients increased to 8.51% (4/47), 14.0% (6/43), and 37.8% (14/37) at M2, M3, and M6, respectively. In control group, the percentages were similar at all timepoints. No significant difference was seen between the two groups (P > .05). For elder patients, younger patients, male or female, no significant differences were found between treatment group and control group at all timepoints. ALA did not show additional benefit to NB-UVB therapy in the treatment of nonsegmental stable vitiligo. More studies should be done to identify other protocols of ALA or other types of antioxidants for stable vitiligo.