Could Sniffing GLP-1 Drugs Instead of Injecting Them Deliver the Peptide Directly to the Brain? | Research

The takeaway

Intranasal delivery of GLP-1 receptor agonists could bypass the blood-brain barrier to directly target brain appetite centers, potentially improving efficacy and reducing the GI side effects that cause many patients to stop injectable GLP-1 therapy.

Up to 70% discontinue injectable GLP-1 therapy within 1 year
Peripheral GI side effects from subcutaneous injection drive most patients to stop treatment — nasal delivery directly to the brain could bypass this problem entirely

What the researchers found

The review establishes that nose-to-brain (N2B) delivery pathways — primarily along the olfactory and trigeminal nerves — can transport GLP-1 receptor agonists directly to brain regions involved in appetite regulation, circumventing the blood-brain barrier that limits subcutaneous delivery.

Key challenges for nasal peptide delivery include nasal physiological barriers (mucociliary clearance, enzymatic degradation, limited epithelial permeability) and the peptide's physicochemical properties (size, charge, stability). Promising strategies to overcome these include cell permeation enhancers, mucoadhesive formulations that extend contact time with nasal epithelium, and nanocarrier systems. The review emphasizes that while preclinical results are encouraging, clinical effectiveness has not yet been demonstrated for this route of GLP-1 delivery.

Why it matters

Despite the transformative success of GLP-1 drugs, patient adherence is poor — up to 70% discontinue within the first year, largely due to GI side effects caused by high peripheral drug levels from subcutaneous injection. Intranasal nose-to-brain delivery could fundamentally change this: by targeting the brain directly, lower total drug doses could achieve the same appetite-suppressing effects while sparing the gut from the nausea-inducing exposure. This could also open new applications for GLP-1 drugs in cognitive disorders and addiction where brain targeting is essential.

How the study worked

This is a comprehensive narrative review published in Expert Opinion on Drug Delivery, synthesizing preclinical research on intranasal GLP-1 delivery, nasal anatomy and physiology, nose-to-brain transport mechanisms, and formulation strategies for nasal peptide delivery.

What this study cannot tell us

The review is based primarily on preclinical data — no clinical trial has yet validated intranasal GLP-1 delivery for obesity treatment. The nose-to-brain pathway delivers very small quantities of drug, and it's unclear whether sufficient GLP-1 can reach appetite centers to produce clinically meaningful effects. Individual variation in nasal anatomy, mucus production, and nasal congestion could significantly affect delivery. The review acknowledges that successful preclinical data does not guarantee clinical effectiveness. Safety of chronic intranasal peptide administration (nasal irritation, olfactory effects) requires further study.

How to read the evidence

This is a narrative review of primarily preclinical research. While published in a respected drug delivery journal and comprehensive in scope, it describes an approach that has not yet been validated in human clinical trials for GLP-1 specifically.

When this study was published

Published in 2024, this review reflects the current state of intranasal peptide delivery research and the ongoing search for non-injectable GLP-1 formulations.

The bigger picture

The nose-to-brain delivery concept has gained traction across neuroscience — it's already being explored for insulin (in Alzheimer's), oxytocin, and various neuropeptides. Applying it to GLP-1 drugs is a natural extension given the growing recognition that GLP-1's brain effects (appetite suppression, neuroprotection) are central to its therapeutic value. If successful, nasal GLP-1 delivery could create a new class of non-invasive obesity treatments while also enabling exploration of GLP-1 drugs for neurological conditions like Alzheimer's disease, where direct brain access is essential.

Questions still open

Can intranasal GLP-1 delivery achieve sufficient brain concentrations to produce weight loss comparable to subcutaneous injection?
Would nasal GLP-1 delivery truly reduce GI side effects, or do those effects arise from central brain signaling rather than peripheral drug exposure?
Could intranasal GLP-1 be developed for neurological indications (Alzheimer's, addiction) where brain targeting is the primary goal?

Common questions

How can a nasal spray get drugs to the brain without going through the blood?

The inside of the nose has nerve endings from the olfactory (smell) and trigeminal nerves that connect directly to the brain. Small molecules and peptides sprayed into the nose can travel along these nerve pathways directly into brain tissue, bypassing the blood-brain barrier — the protective shield that normally blocks drugs from entering the brain from the bloodstream. This 'nose-to-brain' route could deliver GLP-1 drugs right where they need to act.

Would a GLP-1 nasal spray cause less nausea than injections?

That's the theory. Much of the nausea from injectable GLP-1 drugs comes from high drug levels in the gut and peripheral circulation after subcutaneous injection. If a nasal spray could deliver GLP-1 directly to brain appetite centers, the body might need much less total drug, potentially reducing the peripheral exposure that causes GI side effects. However, this hasn't been proven in humans yet — it's possible that the brain signaling itself contributes to nausea.

Read the original research

Intranasal delivery of glucagon-like peptide-1 to the brain for obesity treatment: opportunities and challenges.

Expert opinion on drug delivery, 21(7), 1081-1101

View on PubMed ↗Publisher’s paper ↗

Citation

Khan, Tanisha Tabassum Sayka; Sheikh, Zara; Maleknia, Simin; Oveissi, Farshad; Fathi, Ali; Abrams, Terence; Ong, Hui Xin; Traini, Daniela. (2024). Intranasal delivery of glucagon-like peptide-1 to the brain for obesity treatment: opportunities and challenges.. Expert opinion on drug delivery, 21(7), 1081-1101. https://doi.org/10.1080/17425247.2024.2387110