Research
This bibliography documents an unprecedented 38-year research journey from basic science discovery to clinical validation. The progression from understanding free radical biology in the cochlea conducted from 1988 through 2000, to developing the synergistic ACEMg formulation in 2007, to clinical trials and additional basic science from 2012 to 2020, and finally to real-world evidence of effectiveness in 2024, represents one of the most comprehensive translational research programs in auditory neuroscience.
The 2024 real-world evidence study, peer reviewed and published in 2026, represents a paradigm-shifting milestone: the first peer-reviewed clinical evidence that established sensorineural hearing loss cannot only be prevented from worsening, but also objectively improved using daily oral supplementation.
Foundational research on free radicals and inner ear blood flow by Josef M. (Joe) Miller and colleagues at the Kresge Hearing Research Institute, University of Michigan
Landmark publication demonstrating ACEMg reduces noise-induced hearing loss by 75%
Nine U.S. patents issued for the ACEMg formula
European Commission-funded medical innovation translational research grant to the ProHearing consortium of three universities and the University of Michigan patent licensee Hearing Health Science, Inc.
Genetic hearing loss basic research
Age-related hearing loss basic research
Real-world clinical evidence study preprint published on the Open Science Framework
Two U.S. patents issued for the ACEMg formula
Peer-reviewed real-world clinical evidence study published in Global Advances in Integrative Medicine and Health
J.M. Miller and colleagues at the University of Michigan
Sillman JS, Larouere MJ, Nuttall AL, Lawrence M, Miller JM
Annals of Otology, Rhinology & Laryngology, 97(Suppl 135), 1-8 (1988)
Significance: Established foundation for understanding that changes in blood flow influence cochlear diseases, including noise-induced hearing loss.
Key Finding: Demonstrated measurable changes in cochlear circulation caused by various physiological factors.
View on PubMedQuirk WS, Wright JW, Dengerink JA, Miller JM
Hearing Research, 33(2), 129-136 (1988)
Significance: First demonstration of vasospasm's role in hearing pathology.
View on PubMedMiller JM, Ren T-Y, Nuttall AL
Otolaryngology - Head and Neck Surgery, 112(1), 101-113 (1995)
Significance: Comprehensive review of inner ear blood flow demonstrating autoregulatory capabilities significantly greater than brain autoregulation.
Key Finding: Established that decreased blood flow responsiveness occurs in hydropic ear conditions.
View on PubMedYamasoba T, Nuttall AL, Harris C, Raphael Y, Miller JM
Brain Research, 784(1-2), 82-90 (1998)
Significance: First demonstration that endogenous antioxidant systems (glutathione) modulate noise-induced pathology.
Key Finding: GSH plays a critical protective role against noise-induced hearing loss (NIHL).
View on PubMedYamasoba T, Harris C, Shoji F, Lee RJ, Nuttall AL, Miller JM
Brain Research, 804(1), 72-78 (1998)
Significance: Demonstrated that noise exposure upregulates endogenous antioxidant systems.
Key Finding: Cochlear cells attempt to protect themselves by increasing GSH synthesis.
View on PubMedOhinata Y, Miller JM, Altschuler RA, Schacht J
Brain Research, 878(1-2), 163-173 (2000)
Significance: Identified specific lipid peroxidation products formed during noise exposure.
Key Finding: Free radicals create vasoactive compounds that further damage the cochlea.
View on PubMedShoji F, Miller AL, Mitchell A, Yamasoba T, Altschuler RA, Miller JM
Hearing Research, 146(1-2), 134-142 (2000)
Significance: Demonstrated neurotrophins have antioxidant properties that reduce NIHL.
View on PubMedShoji F, Yamasoba T, Magal E, Dolan DF, Altschuler RA, Miller JM
Hearing Research, 142(1-2), 41-55 (2000)
Significance: Established dose-response relationships for protective factors.
View on PubMedOhinata Y, Miller JM, Schacht J
Brain Research, 966(2), 265-273 (2003)
Significance: Demonstrated that agents preventing free radical-induced lipid peroxidation also prevent NIHL.
Key Finding: Established the causal pathway from free radicals to lipid peroxidation to hair cell death.
View on PubMedMinami SB, Yamashita D, Schacht J, Miller JM
Journal of Neuroscience Research, 78(3), 383-392 (2004)
Significance: Identified Calcineurin activation in NIHL pathway.
View on PubMedTakemura K, Komeda M, Yagi M, Himeno C, Izumikawa M, Doi T, Kuriyama H, Miller JM, Yamashita T
Hearing Research, 196(1-2), 58-68 (2004)
Significance: Demonstrated steroid treatment could attenuate NIHL.
View on PubMedYamashita D, Jiang HY, Schacht J, Miller JM
Brain Research, 1019(1-2), 201-209 (2004)
Significance: Found clinically significant late formation of free radicals 7-10 days post-noise, a critical discovery.
Key Finding: Treatment window extends well beyond the immediate post-exposure period.
View on PubMedYamashita D, Miller JM, Jiang HY, Minami SB, Schacht J
Neuroreport, 15(18), 2719-2722 (2004)
Significance: Identified gene expression of abnormal proteins leading to cell death.
View on PubMedYamashita D, Jiang HY, Le Prell CG, Schacht J, Miller JM
Neuroscience, 134(2), 633-642 (2005)
Significance: Demonstrated treatment can be effective even 3 days after noise exposure.
Key Finding: Opens therapeutic window for treatment after exposure has occurred.
Le Prell CG, Hughes LF, Miller JM
Free Radical Biology & Medicine, 42(9), 1454-1463 (2007)
Significance: Demonstration that the ACEMg combination provides synergistic protection far exceeding individual components.
Key Finding: ACEMg reduced NIHL by 75%; increased noise tolerance of cochlear cells by an average of 31 dB; maintained normal auditory function when SPL increased by 10x. Far superior to ACE alone, Mg alone, or control.
View on PubMedLe Prell CG, Yamashita D, Minami SB, Yamasoba T, Miller JM
Hearing Research, 226(1-2), 22-43 (2007)
Significance: Comprehensive review of NIHL mechanisms, identifying multiple intervention points.
Key Finding: Established that multiple pathways to NIHL justify combination therapies like ACEMg.
View on PubMedMinami SB, Yamashita D, Schacht J, Miller JM
Brain Research, 1148, 83-89 (2007)
Significance: Demonstrated that additional agents can provide protection.
View on PubMedMaruyama J, Yamagata T, Ulfendahl M, Bredberg G, Altschuler R, Miller J
Neurobiology of Disease, 25(2), 309-318 (2007)
Significance: Extended antioxidant benefits beyond hair cells to auditory nerve survival.
View on PubMedFrom Lab to Human Application
Le Prell CG, Johnson AC, Lindblad AC, Skjonsberg A, Ulfendahl M, Guire K, Green GE, Campbell KCM, Miller JM
Noise & Health, 13(55), 432-443 (2011)
Significance: First human safety and bioavailability study in the military population.
Key Finding: Nutrients are safely absorbed, and plasma levels are maintained during noise exposure.
View on PubMedLe Prell CG, Hensley BN, Campbell KC, Hall JW 3rd, Guire K
International Journal of Audiology, 50(Suppl 1), S21-S31 (2011)
Significance: Identified hidden hearing loss in young adults, establishing the need for preventive interventions.
View on PubMedScheper V, Schmidtheisler M, Lasch F, von der Leyen H, Koch A, Schwieger J, Buchner A, Lesinski-Schiedat A, Lenarz T
Trials, 21(1), 643 (2020)
Significance: First major randomized controlled trial of ACEMg in humans, demonstrated reduced hearing loss in ACEMg-treated patients compared to placebo-treated ones, suggesting that a perioperative oral administration of ACEMg is safe and may provide protection of residual hearing in cochlear implant patients.
View on PubMedThatcher A, Le Prell C, Miller J, Green G
International Journal of Pediatric Otorhinolaryngology, 78(3), 563-565 (2014)
Significance: First human case report. Three-year ACEMg regimen stopped progression and improved hearing in a child with Cx26 mutation.
Key Finding: Extended ACEMg application to genetic hearing loss.
View on PubMedGreen KL, Swiderski DL, Prieskorn DM, DeRemer SJ, Beyer LA, Miller JM, Green GE, Raphael Y
Scientific Reports, 6, Article 22690 (2016)
Significance: ACEMg can influence genetic hearing loss progression.
Key Finding: Hearing thresholds measured by ABR were significantly better for Gjb2-CKO mice fed ACEMg than for the control diet group.
View on PubMedExpanding Applications Beyond Noise: Demonstrating the Mechanism of Action
Alvarado JC, Fuentes-Santamaria V, Gabaldon-Ull MC, Blanco JL, Juiz JM
Frontiers in Neuroscience, 12, Article 527 (2018)
Significance: First demonstration that oral ACEMg provides effective adjuvant therapy for age-related hearing loss.
Key Finding: Oral ACEMg improves auditory function by limiting sensory hair cell death in the auditory receptor following NIHL.
View on PubMedAlvarado JC, Fuentes-Santamaria V, Melgar Rojas P, Gabaldon-Ull MC, Cabanes-Sanchis JJ, Juiz JM
Antioxidants, 9(12), 1177 (2020)
Significance: Definitive explanation of the ACEMg mechanism of action.
Key Finding: Oral ACEMg improves auditory function by limiting sensory hair cell death in the auditory receptor following NIHL. Regulation of the expression of antioxidant enzymes and apoptosis-related proteins in cochlear structures is involved as an otoprotective mechanism.
View on PubMedThe Paradigm Shift Milestone: Breakthrough Real-World Evidence Study
Seifer BS, Minor LA, Detweiler RA
Global Advances in Integrative Medicine and Health, 15 (2026)
Significance: First real-world effectiveness data collected under conditions of routine clinical practice, demonstrating OAE improvement in adults with established SNHL using objective physiological measurement. 75.3% of ACEMg users showed stability or improvement in OAE scores within 6 months of daily supplementation. Challenges the dogma that hearing loss is permanent.
Key Finding: 37.6% showed no decline; 37.7% showed improvement in objective cochlear function. 73.2% of the untreated group showed a decline. N=190 (Treatment n=93, Control n=97).
View on PubMedThese statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. The research cited above represents independent scientific investigation published in peer-reviewed journals.
