Cognitive dysfunction affects up to 70 percent of individuals living with multiple sclerosis, creating profound challenges for employment, daily activities, and social functioning. Consequently, identifying targeted interventions to preserve and restore brain performance remains an urgent unmet clinical priority. Researchers recently explored intranasal insulin multiple sclerosis therapy as a novel strategy to enhance central nervous system metabolism and cognitive processing.

The Neurobiological Rationale for Intranasal Insulin

Insulin plays an essential role throughout the human central nervous system. In addition to regulating systemic glucose homeostasis, insulin signaling modulates synaptic plasticity, enhances neuroprotection, and promotes neuronal survival. The hormone actively supports long-term potentiation in hippocampal circuits, which governs learning and memory consolidation. Furthermore, brain insulin receptors show dense distribution across regions that coordinate executive function and information processing speed.

In multiple sclerosis, chronic neuroinflammation and metabolic axonal stress disrupt normal neuronal energy pathways. Therefore, delivering exogenous insulin directly to brain tissue offers an attractive therapeutic hypothesis. Subcutaneous administration cannot achieve adequate cerebral concentrations without triggering profound systemic hypoglycemia. In contrast, the intranasal delivery pathway bypasses the blood-brain barrier via olfactory and trigeminal nerve bundles. This unique delivery mechanism transports therapeutic peptides rapidly into cerebrospinal fluid while preventing systemic absorption. Prior clinical investigations in healthy volunteers and patients with amnestic mild cognitive impairment demonstrated that intranasal delivery boosts memory performance. Consequently, neuroscientists designed clinical trials to test whether this noninvasive strategy could effectively rescue cognitive decline in multiple sclerosis.

Trial Design and Protocol Architecture

To formally evaluate this concept, investigators executed a phase Ib/II, randomized, double-blind, placebo-controlled trial. The study enrolled 105 adults diagnosed with multiple sclerosis who exhibited measurable cognitive impairment at baseline screening. Furthermore, investigators stratified participants according to their disease phenotype, specifically separating relapsing-remitting multiple sclerosis from progressive disease cohorts. This stratification ensured that baseline neurodegenerative trajectories remained balanced across treatment groups.

The trial protocol randomized participants in a balanced 1:1:1 allocation across three parallel study arms. Specifically, patients received either low-dose intranasal insulin at 10 international units twice daily, high-dose intranasal insulin at 20 international units twice daily, or a matched intranasal placebo spray for 24 continuous weeks. Patients administered the nasal spray twice every day using standardized delivery devices designed for olfactory mucosa deposition. Moreover, clinical investigators conducted comprehensive multidimensional assessments at scheduled intervals. Among the 105 enrolled participants, 69 completed at least one formal follow-up visit during the active treatment phase. The study cohort presented a mean age of 52.4 years, while women constituted approximately 62 percent of the study population. Additionally, approximately 60 percent of patients carried a diagnosis of relapsing-remitting multiple sclerosis.

Investigating Intranasal Insulin Multiple Sclerosis Trial Outcomes

The researchers designated change in the Symbol Digit Modalities Test as the primary clinical outcome measure of the trial. The Symbol Digit Modalities Test represents the gold standard assessment tool for information processing speed in multiple sclerosis, reliably detecting subtle changes in cognitive efficiency. In addition, the investigative team administered comprehensive secondary neuropsychological evaluations, including the Controlled Oral Word Association Test and the Paced Auditory Serial Addition Test.

However, analysis of the primary endpoint revealed no statistically significant differences between the intranasal insulin cohorts and the placebo group. Participants receiving intranasal insulin multiple sclerosis regimens did not demonstrate superior improvements in processing speed compared to those receiving placebo sprays over 24 weeks. Similarly, secondary cognitive measures assessing verbal fluency, spatial orientation, and working memory failed to separate active treatment from control. Both dosage cohorts yielded comparable trajectories to placebo across all formal timepoints. Furthermore, subgroup analyses examining relapsing versus progressive multiple sclerosis cohorts did not uncover hidden therapeutic benefits. Therefore, despite strong biological plausibility, the intervention failed to achieve measurable clinical superiority on standardized cognitive testing.

Safety, Tolerability, and Adverse Event Analysis

Despite the neutral cognitive efficacy outcomes, the trial provided valuable safety data regarding long-term intranasal peptide administration. Overall, intranasal insulin demonstrated an exceptional safety profile and high patient tolerability throughout the 24-week intervention window. Because intranasal delivery restricts systemic absorption, clinicians observed no episodes of systemic hypoglycemia or symptomatic metabolic destabilization across any treatment cohort.

Nevertheless, participants experienced several mild, self-limiting local and systemic adverse events. The most frequent complaints among patients receiving active treatment included transient headaches, rhinorrhea, and mild dizziness. These symptoms resolved spontaneously without requiring drug discontinuation or specialized medical therapy. In addition, study personnel recorded 13 serious adverse events during the clinical trial. Importantly, independent monitoring committees determined that none of these serious events had any relation to the investigational drug. Furthermore, investigators recorded zero patient deaths throughout the trial duration. Consequently, the study confirmed that long-term intranasal insulin administration remains safe and feasible for patients managing complex neuroimmunological disease.

Methodological Challenges and Trial Limitations

Several methodological barriers may explain why this rigorous clinical trial did not detect cognitive improvement. First, the effective sample size remained relatively modest for a three-arm randomized trial design. This limited statistical power constrained the study's ability to identify small therapeutic effect sizes. Second, significant data missingness occurred during the active treatment period, largely driven by disruptions associated with the COVID-19 pandemic. As a result, only 69 of the 105 enrolled participants completed scheduled follow-up visits.

Moreover, the 24-week treatment duration might have provided insufficient time to alter chronic, multifactorial neurodegenerative damage. Standard cognitive screening instruments like the Symbol Digit Modalities Test may also exhibit insensitivity to subtle microstructural brain repair over short observation windows. Additionally, variable baseline cognitive reserve among participants might have masked subtle clinical benefits. In particular, patients with high pre-existing reserve often compensate for structural damage, complicating neuropsychological measurement. Finally, technical variability regarding nasal delivery devices could have influenced actual drug deposition within the olfactory neuroepithelium. Therefore, future studies require refined patient selection and advanced delivery verification to accurately evaluate central insulin modulation.

Clinical Implications and Future Directions for CNS Delivery

Although intranasal insulin did not improve cognitive performance in this cohort, the study offers crucial insights for neurotherapeutics. First, the investigation proves that people with multiple sclerosis can reliably perform long-term self-administration of intranasal therapeutics at home. This finding establishes strong clinical feasibility for testing other neuroprotective molecules through noninvasive routes. Bypassing the blood-brain barrier remains a paramount goal in neurotherapeutics, especially for large biologics, growth factors, and anti-inflammatory peptides that fail to penetrate brain parenchyma via systemic circulation.

Furthermore, future investigations must explore personalized biomarkers to identify which patients might benefit from metabolic interventions. For example, testing patients with documented cerebral insulin resistance or targeted metabolic dysregulation might yield greater therapeutic responsiveness. In addition, neuroscientists should evaluate longer trial durations alongside sensitive neuroimaging biomarkers, such as advanced magnetic resonance spectroscopy and functional connectivity mapping. Ultimately, while intranasal insulin monotherapy cannot currently be recommended for cognitive symptoms in multiple sclerosis, the intranasal route represents a promising frontier for central nervous system drug delivery.

Frequently Asked Questions

Did intranasal insulin improve cognitive test scores in the multiple sclerosis clinical trial?

No, the phase Ib/II trial demonstrated that intranasal insulin was not superior to placebo for cognitive function. Specifically, treated participants showed no significant improvements on the primary outcome measure, the Symbol Digit Modalities Test, or on any secondary neuropsychological assessments across the 24-week study duration.

What side effects were reported with intranasal insulin in people with multiple sclerosis?

Intranasal insulin proved safe and well-tolerated throughout the clinical study. The most common adverse effects reported by participants included transient headaches, rhinorrhea, and mild dizziness. Crucially, researchers noted no episodes of hypoglycemia, and none of the reported serious adverse events were related to the study medication.

Why might intranasal insulin have failed to enhance cognition in this patient cohort?

Several methodological factors may explain the neutral outcome. The trial had a relatively small sample size, significant missing data related to COVID-19 disruptions, and a short 24-week duration. Additionally, baseline cognitive reserve differences, outcome measure insensitivity, or variable nasal device deposition might have masked potential benefits.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. Healthcare professionals should exercise their independent clinical judgment when interpreting or applying this information. Clinical decisions must always be tailored to the individual patient's condition, contraindications, and current clinical guidelines. The authors and publishers disclaim any liability for adverse outcomes resulting from the use or application of information presented herein. Refer to the latest local and national guidelines for clinical practice.

References

1. Newsome SD et al. Intranasal insulin for improving cognitive function in multiple sclerosis. Neurotherapeutics. 2025 Jul. doi: 10.1016/j.neurot.2025.e00581. PMID: 40253245.


2. Craft S, Raman R, Chow TW, et al. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2020;77(9):1099–1109. doi: 10.1001/jamaneurol.2020.2317.


3. Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326-1334. doi: 10.1016/j.psyneuen.2004.04.003.