¹University "Magna Graecia" of Catanzaro, Department of Health Sciences, Catanzaro, Italy, ²Regional Center for Serious Brain Injuries S. Anna Institute, S. Anna Institute and Research in Advanced Neurorehabilitation (RAN), Crotone, Italy, ³Kyushu University, Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Fukuoka, Japan, ⁴Tohoku Medical and Pharmaceutical University, Laboratory of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Sendai, Japan, ⁵IRCCS Mondino Foundation, Scientific Direction, Pavia, Italy, ⁶University of Calabria, Preclinical and Translational Pharmacology, Department of Pharmacy, Cosenza, Italy

Background: Dementia currently affects some 57.4 million people worldwide and approximately 99% of patients with Alzheimer’s Disease (AD) exhibit neuropsychiatric symptoms (NPS). Agitation is a particularly resistant clinical burden characterized by verbal and physical aggression that compromises safety. Authorized treatments are limited to the dopamine D2 receptor antagonist risperidone and the dopamine D2 receptor partial agonist brexpiprazole; however, their use is restricted to 6–12 weeks due to significant cardio-cerebrovascular risks and increased mortality. Pain is a primary underdiagnosed trigger for NPS in severe dementia. Preclinical evidence of the anti-nociceptive effects of Bergamot Essential Oil (BEO) deprived of furocumarins provided the rationale for NPS treatment with NanoBEO, a nanotechnological device designed to overcome traditional methodological biases in essential oil clinical research, such as lack of blinding and poor reproducibility. The development of a rigorous, step-by-step preclinical-to-clinical translational pathway is required to address these noteworthy unmet medical needs.

Aims & Objectives: The objective of this study is to establish a rigorous preclinical-to-clinical translational pathway for NanoBEO to address the unmet medical need for safe, long-term treatment of agitation and pain in dementia.

Method: The BRAINAID clinical trial (NCT04321889) is a randomized, placebo-controlled, quadruple-masked study conducted under SPIRIT and CONSORT guidelines. This pilot phase evaluated transdermal NanoBEO for a 4-week treatment period in over 65 patients with severe dementia (MMSE≤12). The primary endpoint was agitation reduction (CMAI), while secondary endpoints included pain reduction (I-MOBID2) and efficacy at follow-up. Pharmacokinetic analyses were also performed to assess plasma concentrations of components after administration. Finally, any adverse event was noted.

Results: NanoBEO reduced the frequency of agitation by 28% and attenuated its severity. Significant reduction in agitation frequency was observed by week 2 and maintained through week 4 without need for rescue psychotropic medications. Furthermore, a significant analgesic effect (45.46% reduction in pain intensity) was observed after only one week. The safety profile was excellent, with no significant adverse events reported (1). Pharmacokinetic analyses deepened the knowledge on plasma concentrations of components after transdermal administration of NanoBEO (2).

Discussion & Conclusions: Preliminary phase results indicate that NanoBEO (Patent No. 102019000013353, European Regional Phase EP4003294A1) represents a significant innovation in the neglected field of NPS in neurodegenerative diseases. This formulation offers several key clinical advantages: it delivers a precise, stable dose of a titrated phytocomplex while protecting it from chemical-physical degradation, thereby extending shelf-life. Crucially, the "odor entrapment" technology renders the formulation indistinguishable from the placebo, allowing for the generation of robust, high-quality double-blind clinical evidence that was previously not achievable with essential oils. By successfully bridging the gap between translational and clinical research, NanoBEO emerges as a potential first-in-class, need-oriented treatment for agitation and pain in severe dementia. It offers an effective, safe solution suitable for long-term administration, potentially reducing the reliance on antipsychotics associated with higher mortality.
References
1. Scuteri D, et al., 2024. Front Pharmacol;15:141785. doi: 10.3389/fphar.2024.1417851.
2. Morrone LA, et al., 2026. Phytother Res;40(2):488-492. doi: 10.1002/ptr.70147.