Oe M, Sakai S, Yoshida H, Okado N, Kaneda H, Masuda Y, Urushibata O. Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period. Clin Cosmet Investig Dermatol. 2017;10:267-273. doi:10.2147/CCID.S141845

Publication Date: Annual 2017

Peer Reviewed: Yes

Study Design: double-blinded, placebo-controlled study

Methodology: "Sixty Japanese male and female subjects aged 22-59 years who presented with crow's feet wrinkles were randomly assigned to the HA 2 k or HA 300 k at 120 mg/day or the placebo group. The subjects were administered HA at a rate of 120 mg/day or a placebo for 12 weeks. The skin wrinkles were evaluated by image analysis of skin wrinkle replicas, and their skin condition was evaluated using a questionnaire survey."

Sample Size: "Sixty Japanese male and female subjects aged 22-59 years."

Controls Used: placebo group

Dose Used: "120 mg/day of HA"

Statistical Significance Declared: "The HA 300 k group showed significantly diminished wrinkles compared with the placebo group (p < 0.05). The HA 300 k group and the HA 2 k group showed suppressed wrinkles compared with the placebo group (HA 300 k, p = 0.046; HA 2 k, p = 0.052)."

Adverse Events: "No significant weight changes or negative side effects reported."

Conflict of Interest: "Ms. Mariko Oe, Mr. Seigo Sakai, Mr. Hideto Yoshida, Ms. Haruna Kaneda, Ms. Nao Okado, Dr. Yasunobu Masuda are employees of Kewpie Corporation. MD Osamu Urushibata is a professor of Toho University. The authors report no other conflicts of interest in this work."

Martinez-Puig D, Möller I, Fernández C, Chetrit C. Efficacy of oral administration of yoghurt supplemented with a preparation containing hyaluronic acid (Mobilee™) in adults with mild joint discomfort: a randomized, double-blind, placebo-controlled intervention study. *Mediterranean Journal of Nutrition and Metabolism*. 2013;6:63-68. doi:10.3233/s12349-012-0108-9

Publication Date: Published online 14 October 2012

Peer Reviewed: Yes

Study Design: randomized, double-blind, placebo-controlled intervention study

Methodology: "Participants were divided into 2 groups (n = 20) and ate yoghurt that was either supplemented or not supplemented with the hyaluronic acid product daily for a period of 90 days. The increase in the maximum peak torque of the knee extensors compared to baseline values was measured using an isokinetic dynamometer. Other parameters included total work and mean power, Lequesne score, and SF-36 survey."

Sample Size: "40 healthy individuals with joint discomfort."

Controls Used: placebo group

Dose Used: "80 mg of a preparation containing hyaluronic acid (65%) from rooster comb (MobileeTM) per day for a period of 90 days."

Statistical Significance Declared: "The increase in the maximum peak torque of the knee extensors compared to baseline values was 7.6 ± 7.6 Nm for the supplemented yoghurt group and 2.5 ± 4.7 Nm for the control group at 180/s (P = 0.0582), and 6.5 ± 5.8 Nm for the supplemented yoghurt group and -1.0 ± 7.1 Nm for the control group at 240/s (P<0.05)."

Adverse Events: "No significant weight changes or negative side effects reported."

Conflict of Interest: "None declared."

Nelson FR, Zvirbulis RA, Zonca B, Li KW, Turner SM, Pasierb M, Wilton P, Martinez-Puig D, Wu W. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatol Int. 2015;35(1):43-52. doi:10.1007/s00296-014-3047-6

Publication Date: Aug. 2023

Peer Reviewed: Yes

Study Design: "randomized, double-blind, placebo-controlled clinical trial"

Methodology: "Participants (n = 100) with mild osteoarthritis of the knee or hip joint were randomly assigned to receive either FP-MD or placebo once daily for 12 weeks. Efficacy was measured using the Korean Visual Analog Scale (K-VAS) and Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC). Safety evaluations included monitoring of adverse events and clinical pathology tests."

Sample Size: "100 participants"

Controls Used: "placebo group"

Dose Used: "one capsule once daily for 12 weeks"

Statistical Significance Declared: "FP-MD group had a statistically significantly greater mean reduction from baseline in the K-VAS at week 12 compared with placebo group (p = 0.0105). K-WOMAC total score significantly improved in FP-MD group at week 12 compared with placebo (p = 0.0489)."

Adverse Events: "A statistically significantly greater number of patients reported adverse events in the placebo group compared with the FP-MD group (16% vs. 4%, p = 0.0455), most commonly gastrointestinal disorders in both of the groups."

Conflict of Interest: "NOVAREX Co., Ltd. funded the study. Valensa International provided the FlexPro MD® ingredients, and NOVAREX Co., Ltd. encapsulated the test products. All authors were involved in the study design, data collection, analysis, interpretation, and manuscript writing."

Cai T, Tiscione D, Favilla V, et al. Oral Administration and Intralesional Injection of Hyaluronic AcidVersusIntralesional Injection Alone in Peyronie's Disease: Results from a Phase III Study.World J Mens Health. 2021;39(3):526-532. doi:10.5534/wjmh.200048

Publication Date: Published online 2020 Aug 14

Peer Reviewed: Yes

Study Design: "prospective, randomized phase III study"

Methodology: "Eighty-one patients were randomized into two groups. Group A consisted of 41 patients receiving oral administration of HA in combination with weekly intralesional injection of HA for 6 weeks. Group B consisted of 40 patients who received weekly intralesional injections of HA for 6 weeks, only. The main outcome measures were the changes from baseline to the end of therapy after three months in penile curvature (°) and changes in the international index of erectile function (IIEF-5) score and patient's global impressions of improvement (PGI-I) score."

Sample Size: "Eighty-one patients"

Controls Used: "Group B consisted of 40 patients who received weekly intralesional injections of HA for 6 weeks, only."

Dose Used: "Each oral dose contained a combination of 150 mg high molecular weight HA and 125 mg of avocado and soya unsaponifiables extracts."

Statistical Significance Declared: "Group A had a significantly larger reduction in penile curvature as compared with group B (Group A: −7.8°, Group B: −4.1° [p<0.001]). Group A also showed a higher improvement in IIEF-5 and PGI-I scores in comparison with Group B (Group A: +4 IIEF-5, Group B: +2 IIEF-5 [p<0.001]; Group A: 3 PGI-I, Group B: 1 PGI-I, [p<0.001])."

Adverse Events: "No significant adverse effects were reported."

Conflict of Interest: "Dr. Tommaso Cai, Dr. Alessandro Zucchi, and Dr. Alessandro Palmieri received speaker grants by IBSA, Italy, during national and international meetings but he made no influence on this work in relation with the company or its products. Other authors have no potential conflicts of interest to disclose."

Gao YR, Wang RP, Zhang L, Fan Y, Luan J, Liu Z, Yuan C. Oral administration of hyaluronic acid to improve skin conditions via a randomized double-blind clinical test. Skin Res Technol. 2023;29(11):e13531. doi:10.1111/srt.13531

Publication Date: 6 November 2023

Peer Reviewed: Yes

Study Design: randomized, double-blind clinical trial

Methodology: "The test was conducted from September 27th 2022 to January 16th 2023, and the panelists include 61 young (18–35 years old) and 67 elderly (45–65 years old) groups, with their skin types covering oily, normal and dry. The oral administration level of HA was designed as 0 mg/day (placebo, 100% Erythritol), 100 mg/day (95% Erythritol, 5% 300 KDa HA), and 200 mg/day (90% Erythritol, 10% 300 KDa HA)."

Sample Size: 129 female participants

Controls Used: placebo group

Dose Used: "0 mg/day (placebo, 100% Erythritol), 100 mg/day (95% Erythritol, 5% 300 KDa HA), and 200 mg/day (90% Erythritol, 10% 300 KDa HA)."

Statistical Significance Declared: "The HA groups showed better level of the whole sulcus volume ratio, wrinkle area ratio, and wrinkle volume ratio than the placebo group (p < 0.05)."

Adverse Events: "No significant weight changes or negative side effects reported."

Conflict of Interest: "The authors declare that they have no competing interests."

Hsu T-F, Su Z-R, Hsieh Y-H, Wang M-F, Oe M, Matsuoka R, Masuda Y. Oral Hyaluronan Relieves Wrinkles and Improves Dry Skin: A 12-Week Double-Blinded, Placebo-Controlled Study.Nutrients. 2021; 13(7):2220. https://doi.org/10.3390/nu13072220

Publication Date: Published: 28 June 2021

Peer Reviewed: Yes

Study Design: "randomized, double-blind, and placebo-controlled design"

Methodology: "The subjects received 120 mg/capsule/day of HA or the placebo (dextrin), taken orally, for 12 consecutive weeks. Skin hydration was evaluated using a capacitance method, barrier function by measuring transepidermal water loss, skin elasticity with Cutometer® MPA580, skin structure with ultrasound analysis, and facial photography was used for wrinkle analysis."

Sample Size: "41 subjects were enrolled into the trial; one subject withdrew from the study for personal reasons."

Controls Used: placebo group

Dose Used: "120 mg/capsule/day of HA"

Statistical Significance Declared: "The assessment showed that the HA group had significantly higher stratum corneum water content in the facial measurement sites (p = 0.02) as compared with the placebo group at 12 weeks after ingestion. The HA group showed a significantly higher percentage change in stratum corneum water content compared with the placebo group at 8 weeks (p = 0.01) and 12 weeks (p = 0.0003) for the face, 12 weeks (p = 0.005) for the arms, and 12 weeks (p = 0.005) for the waist. The assessment showed that the HA group had significantly lower transdermal water transpiration in the face versus the placebo group after 12 weeks of treatment (p = 0.009)."

Adverse Events: "No adverse events attributable to the consumption of HA."

Conflict of Interest: "This research was funded by Kewpie Corporation."

Cicero AFG, Girolimetto N, Bentivenga C, Grandi E, Fogacci F, Borghi C. Short-Term Effect of a New Oral Sodium Hyaluronate Formulation on Knee Osteoarthritis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial.Diseases. 2020; 8(3):26. https://doi.org/10.3390/diseases8030026

Publication Date: Published: 8 July 2020

Peer Reviewed: Yes

Study Design: "randomized, double-blind, placebo-controlled, two parallel groups, clinical trial"

Methodology: "60 subjects affected by clinical and/or radiological diagnosis of symptomatic knee OA were consecutively enrolled. The Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), the Lequesne Functional Index (LFI) and the Visual Analogue Scale (VAS) for pain (VAS-p) were administered. The range of knee joint motion (ROM) was also instrumentally measured."

Sample Size: "Sixty subjects were consecutively enrolled."

Controls Used: "placebo group"

Dose Used: "200 mg/day"

Statistical Significance Declared: "VAS-p, pain and total WOMAC score, LFI and ROM significantly improved compared to the baseline values (p < 0.05). At 60 days, the VAS-p and the pain WOMAC score were significantly lower after FS-HA® treatment when compared with placebo as well (p < 0.05)."

Adverse Events: "No adverse events attributable to the consumption of HA."

Conflict of Interest: "The authors declare no conflict of interest."

Göllner I, Voss W, von Hehn U, Kammerer S. Ingestion of an Oral Hyaluronan Solution Improves Skin Hydration, Wrinkle Reduction, Elasticity, and Skin Roughness: Results of a Clinical Study. *Journal of Evidence-Based Complementary & Alternative Medicine*. 2017;22(4):816-823. doi:10.1177/2156587217743640.

Publication Date: First published online December 4, 2017

Peer Reviewed: Yes

Study Design: "open, uncontrolled monocentric study"

Methodology: "Twenty female subjects with healthy skin in the age group of 45 to 60 years took the product once daily for 40 days. Different skin parameters were objectively assessed before the first intake, after 20 and after 40 days."

Sample Size: "Twenty female subjects"

Controls Used: None (open study)

Dose Used: "20 mL Regulatpro Hyaluron once daily"

Statistical Significance Declared: "Repeated-measures ANOVA, P < .001"

Adverse Events: "No side effects were noted throughout the study."

Conflict of Interest: "The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The project was funded by Dr Niedermaier Pharma GmbH, Georg-Knorr-Straße, 85662 Hohenbrunn, Germany."

Hermans J, Bierma-Zeinstra SMA, Bos PK, Niesten DD, Verhaar JAN, Reijman M. The effectiveness of high molecular weight hyaluronic acid for knee osteoarthritis in patients in the working age: a randomised controlled trial. BMC Musculoskelet Disord. 2019;20(1):196. doi:10.1186/s12891-019-2546-8

Publication Date: May 7, 2019

Peer Reviewed: Yes

Study Design: randomized controlled trial

Methodology: "In this open labelled randomized controlled trial, subjects aged between 18 and 65 years with symptomatic knee OA (Kellgren and Lawrence I-III) were enrolled and randomized to UC + 3 weekly injections with HMW-HA (intervention) or UC only (control). The primary outcome was the between group difference in responders to therapy according to OMERACT-OARSI criteria after 52 weeks. These criteria include the domains pain, knee related function and patient's global assessment (PGA). Function was evaluated with the KOOS questionnaire. Pain was assessed with the Numeric Rating Scale. Secondary outcome comprised the between group difference on the individual responder domains, as analysed with a random effects model. Odds Ratios (OR) were calculated by logistic regression analysis. Sensitivity analyses were performed."

Sample Size: "156 subjects were included (intervention group 77, control group 79)."

Controls Used: "UC only (control)"

Dose Used: "3 weekly injections with HMW-HA"

Statistical Significance Declared: "Subjects in the intervention group were statistically significant more often responder to treatment arm they were randomized to compared to the control group. When pain during rest was included in the responder domains, 57.1% of the subjects in the intervention group were responder to therapy, against 34.2% in the control group (p = 0.006). With pain during activity included, 54.5% of the subjects was responders to therapy in the intervention group versus 34.2% of the controls (p = 0.015)."

Adverse Events: "In the intervention group, more subjects reported any knee treatment related adverse events (AE) at 6 weeks (45% versus 18%. This difference was mainly due to flares or flare like symptoms of the study knee in this period (36% versus 10%), p > 0.001, number needed to harm (NNH) 4.0)."

Conflict of Interest: "The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article." ​

Bertolami CN, Gay T, Clark GT, Rendell J, Shetty V, Liu C, Swann DA. Use of sodium hyaluronate in treating temporomandibular joint disorders: A randomized, double-blind, placebo-controlled clinical trial. J Oral Maxillofac Surg. 1993;51(3):232-242. doi:10.1016/S0278-2391(10)80163-6

Publication Date: Sept. 2023

Peer Reviewed: Yes

Study Design: "experimental study"

Methodology: "An experimental study was conducted on Oryctolagus cuniculus rabbits, including 42 TMJs, distributed between (1) TMJ-C, control group; (2) TMJ-OA, group with OA; (3) TMJ-OA-wt, group with untreated OA; (4) group treated with HA-HV-1i; (5) group treated with HA-HV-2i; (6) group treated with HA-LV-1i; and (7) group treated with HA-LV-2i."

Sample Size: "42 TMJs"

Controls Used: "TMJ-C, control group"

Dose Used: "single intra-articular infiltration (1i) and two infiltrations (2i) of medium molecular weight hyaluronic acid (MMW-HA) of high viscosity (HV) and low viscosity (LV)"

Statistical Significance Declared: "The HA-HV-2i group showed significant differences in the degree of OA, in both the MC and MF, with the TMJ-OA group (p = 0.006; p = 0.04, respectively) and with the TMJ-OA-wt group (p = 0.008 p = 0.008, respectively). The HA-LV-2i group showed significant differences in the MC and MF, only with the TMJ-OA-wt group (p = 0.0001; p = 0.0001, respectively)."

Adverse Events: "No adverse events attributable to the consumption of HA."

Conflict of Interest: "The authors declare no conflict of interest."

Michelotti A, Cestone E, De Ponti I, Pisati M, Sparta E, Tursi F. Oral intake of a new full-spectrum hyaluronan improves skin profilometry and ageing: a randomized, double-blind, placebo-controlled clinical trial. Eur J Dermatol. 2021;31(6):798-805. doi:10.1684/ejd.2021.4176

Publication Date: Published: 17 February 2022

Peer Reviewed: Yes

Study Design: double-blind, randomized, placebo-controlled clinical trial

Methodology: Sixty subjects showing mild-to-moderate skin aging signs were enrolled in a double-blind, randomized, placebo-controlled clinical trial to receive 200 mg/day of FS-HA (ExceptionHYAL® Star), or placebo, for 28 days. Dermatological parameters were evaluated at T0d and T28d. Product efficacy and tolerance were further evaluated using a self-assessment questionnaire. In addition, HA serum levels were weekly evaluated in a proportion of enrolled subjects.

Sample Size: Sixty subjects

Controls Used: placebo

Dose Used: 200 mg/day of FS-HA (ExceptionHYAL® Star)

Statistical Significance Declared: p < 0.05

Adverse Events: No side effects or adverse events were reported throughout the study, and no drop-outs.

Conflict of Interest: "AM, EC, ID, MP and FT have no conflicts of interest to disclose."

De Souza AB, Chaud MV, Santana MHA. Hyaluronic acid behavior in oral administration and perspectives for nanotechnology-based formulations: A review. Carbohydr Polym. 2019;222:115001. doi:10.1016/j.carbpol.2019.115001.

Publication Date: Available online 18 June 2019

Peer Reviewed: Yes

Study Design: review

Methodology: "literature search was performed in various databases such as PubMed, Science Direct and Scopus"

Sample Size: not applicable (review study)

Controls Used: not applicable (review study)

Dose Used: not applicable (review study)

Statistical Significance Declared: not applicable (review study)

Adverse Events: none stated

Conflict of Interest: "The authors declare no conflict of interest"

Galia TL, Micali A, Puzzolo D, Cancellieri F. Oral Low-Molecular Weight Hyaluronic Acid in the Treatment of Atrophic Vaginitis. Int J Clin Med. 2014;5(11):617-624. doi:10.4236/ijcm.2014.511084

Publication Date: May 2014

Peer Reviewed: Yes

Study Design: double blind, placebo-controlled study

Methodology: "Twelve women with atrophic vaginitis were recruited for this double blind, placebo-controlled clinical study. Patients were randomized to receive either low-molecular weight HA tablets (220 mg hyaluronic acid per tablet) per os (two tablets/day for 10 days, and subsequently one tablet/day for three months) or placebo (two tablets/day for 10 days, and subsequently one tablet/day for three months). Vaginal biopsies were taken at baseline and after three months of treatment, and vaginal epithelium was analysed using light microscopy. The evaluation of symptoms was self-assessed by the patients."

Sample Size: Twelve women

Controls Used: placebo

Dose Used: "220 mg hyaluronic acid per tablet, two tablets/day for 10 days, and subsequently one tablet/day for three months"

Statistical Significance Declared: "p ≤ 0.05 was considered as statistically significant"

Adverse Events: "No adverse effects were noted."

Conflict of Interest: "The authors declare no conflict of interest."

Chalkidou A, Oikonomou E, Lambrinos D, et al. The Comparative Study of the Administration of the Combination Preparation of Isoflavones and Hyaluronic Acid in Menopausal Women for the Treatment of the Symptoms of Menopause, Urogenital Atrophy and Oteoporosis in Relation to Existing Hormone Replacement Therapies.Mater Sociomed. 2023;35(3):206-214. doi:10.5455/msm.2023.35.206-214

Publication Date: September 2023

Peer Reviewed: Yes

Study Design: double-blind, placebo-controlled clinical study

Methodology: "In this five-year, double-blind, placebo-controlled clinical study, a total of 274 postmenopausal women were enrolled and classified into three groups. Participants in group A, were 96 women who did not receive Hormone Replacement Therapy (HRT), in the second group, 92 received daily treatment with tibolone (2.5 mg) as monotherapy, and in the third group, 86 received treatment with a pharmaceutical formulation of hyaluronic acid 120 mg and isoflavones."

Sample Size: 274 postmenopausal women

Controls Used: placebo

Dose Used: "120 mg hyaluronic acid"

Statistical Significance Declared: "Differences were considered as statistically significant at a p-value < 0.05"

Adverse Events: "No serious, moderate to severe adverse events were recorded."

Conflict of Interest: "There are no conflicts of interest."