Nasal Spray Treatments for Parkinson's Disease: What Clinical Studies Show

Table of Contents

• Key Points
• Background: Why Nasal Delivery Matters for Parkinson's Disease
• How This Review Was Conducted
• Motor Symptom Management
• Intranasal Apomorphine
• Intranasal Human Neural Stem Cells
• Cognitive and Non-Motor Symptom Management
• Intranasal Insulin
• Intranasal NeuroEPO (Recombinant Erythropoietin)
• Intranasal Rivastigmine
• Neuroprotection and Oxidative Stress Reduction
• Intranasal Cholecystokinin
• Intranasal Glutathione
• Specific Non-Motor Symptom Management
• Intranasal Ipratropium Bromide
• Intranasal Desmopressin
• Overall Side Effects Across All Studies
• Discussion and Clinical Implications
• Limitations
• Recommendations and Future Directions
• Frequently Asked Questions
• Source Information

Key Points

• Intranasal delivery can bypass the blood-brain barrier, offering faster onset, lower systemic exposure, and suitability for daily use in Parkinson's disease.
• In one study, intranasal apomorphine reduced daily off-hours from 5.37 to 0.56, with mean onset of 8.25 minutes and response lasting 57.5 minutes.
• In a study of 15 mid-stage patients, a single 200 mg intranasal glutathione dose significantly raised brain glutathione levels from 16 to 60 minutes.
• The most common side effect across studies was mild, temporary nasal or throat irritation, which did not require stopping treatment.
• Most intranasal Parkinson's treatments remain in clinical trial stages; larger, longer, placebo-controlled studies are needed before widespread use.

Background: Why Nasal Delivery Matters for Parkinson's Disease

Parkinson's disease (PD) is a progressive neurological disorder. It is characterized primarily by motor symptoms including bradykinesia (slowed movement), rigidity, tremor, and postural instability. A group of non-motor symptoms also plays a critical role in the disease burden. These non-motor symptoms include autonomic dysfunction, which means problems with automatic body functions like blood pressure and digestion. These non-motor symptoms also include behavioral changes.

The progressive loss of dopaminergic neurons (nerve cells that produce dopamine) in the substantia nigra (a region deep in the brain) leads to dopamine depletion in the striatum. This depletion is widely recognized as the primary pathological sign of Parkinson's disease.

Current treatments such as oral levodopa and dopamine agonists have transformed clinical management. However, these treatments have limitations in their pharmacokinetic profiles (how the body processes the drug). These limitations include variable absorption and delayed onset of action, which are significant challenges that new formulations may improve.

Based on these challenges, alternative drug delivery methods have attracted considerable interest. The surface area of the olfactory epithelium is low, and the volume that can be administered is low. The olfactory epithelium is the lining inside the nose involved in smell. Intranasal administration is a promising route for Parkinson's disease therapies. This is because it can bypass the blood-brain barrier through the olfactory and trigeminal nerve pathways.

This route can provide rapid drug absorption, faster onset of action, and lower systemic exposure compared to traditional oral or injectable dosage forms. Lower systemic exposure means less of the drug circulates throughout the entire body. It is also appropriate for daily use. Besides well-known intranasal solutions, there are various formulations such as mucoadhesive agents (substances that stick to the nasal lining), nanoparticles, gels, and lipid-based systems.

These features are favorable in the context of Parkinson's disease. Faster onset of action during "off" episodes (periods when Parkinson's symptoms return despite medication) and reduction of systemic effects can improve patient outcomes.

How This Review Was Conducted

This review was conducted to evaluate current clinical evidence on intranasal drug delivery for Parkinson's disease treatment. The authors asked whether intranasal delivery can be a better way of administration than conventional therapies.

The review addresses key findings regarding the clinical efficacy, safety, and tolerability of intranasally administered agents. These agents range from dopaminergic drugs such as apomorphine to emerging agents including insulin, glutathione, erythropoietin, and cell-based therapies.

For this review, the authors searched PubMed, Web of Science, Scopus, and Google Scholar databases using relevant keywords. The search yielded 2,103 records, of which 23 were related to the topic.

The review categorizes the studies into four areas:

1. Motor symptom management
2. Cognitive and other non-motor symptom management
3. Neuroprotection and oxidative stress reduction
4. Specific non-motor symptom management

Motor Symptom Management

Motor symptoms of Parkinson's disease include rest tremors, rigidity, bradykinesia (slowed movement), and loss of postural reflexes. These symptoms disable Parkinson's patients from daily activity. Using a fast-acting or long-acting agent can improve Parkinson's disease patients' quality of life.

Intranasal Apomorphine

Apomorphine is a short-acting D1 and D2-like receptor agonist (a drug that activates dopamine receptors). Apomorphine has dopaminergic side effects such as nausea and hypotonia (reduced muscle tone), as well as administration site reactions. These side effects can cause discontinuation of treatment.

Several clinical studies have investigated the efficacy of intranasal apomorphine:

Study 1: Intranasal vs. subcutaneous apomorphine. In one study comparing intranasal and subcutaneous (under the skin) apomorphine, intranasal apomorphine showed a bioavailability (the proportion of the drug that enters the bloodstream) of 45% relative to subcutaneous administration. The time to "on" and the duration of "on" were comparable between intranasal and subcutaneous routes. No statistically significant differences were observed in pharmacokinetic parameters or clinical outcomes between the two administration methods.

Study 2: UPDRS motor score improvement. In another study, intranasal apomorphine improved Unified Parkinson's Disease Rating Scale (UPDRS) motor scores compared with baseline (P < 0.04). The mean latency to response was 11 minutes. The duration of effect was 50 minutes. Between 72% and 81% of doses were rated effective versus 3% to 22% for placebo. Off-hours per day were reduced with apomorphine and trimethobenzamide (P = 0.02). Tapping and Webster's scores improved in one treatment arm (P < 0.04). Diary-based measures of response magnitude and percentage of effective doses were significantly better than placebo (P = 0.01 to 0.03).

Study 3: Inhaled apomorphine phase two trial. A phase two clinical study of inhaled apomorphine showed significant improvement of UPDRS 3 scores compared with placebo (26.8 vs. 14.9; least squares mean difference 11.6, P = 0.016). A higher proportion of apomorphine-treated patients converted from "off" to "on" compared with placebo (81.3% versus 46.7%, P = 0.025). Time to "on" and duration of "on" were numerically shorter and longer with apomorphine, but these differences were not statistically significant (P = 0.461). No dose-related effects were observed. Inhaled apomorphine can be a good candidate for replacement with intermittent subcutaneous injections.

Study 4: Dose-dependent efficacy. Another study using inhaled apomorphine showed dose-dependent efficacy in the proportion of patients switching from "off" to "on" (0% at 0.2 mg, 50% at 0.5 mg, 33.3% at 0.8 mg) versus 16.7% for placebo. Duration of "on" ranged from 0 to 40 minutes for apomorphine versus 20 minutes for placebo. UPDRS 3 upper limb scores suggested improvement at 0.8 mg. However, none of the outcomes, including proportion switching to "on," time to "on," duration of "on," or proportion achieving "on" or "partial on," reached statistical significance. Inhaled apomorphine is safe and well tolerated, but efficacy at these doses was limited.

Study 5: Three-part phase 1 study. In a three-part phase 1 study on Parkinson's disease patients, apomorphine inhalation reduced MDS-UPDRS III scores at 10 minutes compared with placebo: 10.7 (2 mg), 12.8 (3 mg), and 10.3 (4 mg) versus 4.8 for placebo. The proportion of patients achieving full "on" within 45 minutes was 17% (2 mg), 50% (3 mg), and 83% (4 mg) versus 0% for placebo. This intervention seems to be fast and well tolerated. In this study, apomorphine was rapidly absorbed, with a median Tmax (time to reach maximum concentration) of 1 to 2 minutes. At 4 mg, MDS-UPDRS III scores showed mean reductions of 6.8 points at 10 minutes and 6.1 points at 30 minutes post-dose. In the crossover study, 50% of patients achieved "on" at 10 minutes after 4 mg apomorphine, compared with 0% for placebo.

Study 6: Off-hours reduction. In the final study, intranasal apomorphine significantly reduced mean daily off-hours from 5.37 at baseline to 0.56, compared with 0.72 for subcutaneous administration. Mean onset was 8.25 minutes, and mean duration of response was 57.5 minutes. UPDRS motor scores improved, especially for bradykinesia and rigidity, without increasing dyskinesia (involuntary movements). Off-hours reductions were near-significant versus baseline (P < 0.0679) and favored intranasal versus subcutaneous (P < 0.069).

Intranasal Human Neural Stem Cells

In this study, intranasal human neural stem cell ANGE-S003 was well tolerated with no serious adverse events or MRI abnormalities. Functional improvements appeared by month 3, peaked at month 6, and persisted through month 12.

The mean MDS-UPDRS total score reduction was 19.9 points at month 6 (P < 0.001), independent of dose. This indicates sustained symptomatic improvement in advanced Parkinson's disease.

A promising preclinical study investigated magnetically targeted intranasal administration (MTCD) of alginate-coated, nanoparticle-labeled human olfactory ectomesenchymal stem cells (OE-MSCs) in a 6-hydroxydopamine-induced Parkinson's disease rat model. MTCD enhanced stem cell delivery, improved motor performance, increased dopaminergic neuron survival, and upregulated dopamine transporter (DAT), Nurr1, and paired-like homeodomain transcription factor 3 (TH) expression. MRI tracking confirmed robust targeting (P < 0.0001), with preserved cell viability. These findings highlight MTCD as a promising, non-invasive therapeutic strategy for future studies in Parkinson's disease.

Cognitive and Non-Motor Symptom Management

Depression, apathy, anxiety, sleep disorders, and sensory abnormalities are among the most frequent cognitive and non-motor symptoms. This section evaluates insulin, NeuroEPO, cholecystokinin, and rivastigmine on these symptoms.

Intranasal Insulin

Insulin resistance in the brain may play a role in the pathophysiology of Parkinson's disease. Using antidiabetic agents has gained interest as a potential Parkinson's disease treatment.

In a study using intranasal insulin, verbal fluency improved by 5.6% compared with a 6.4% decrease in placebo (P = 0.02). Hoehn and Yahr scores improved significantly in the insulin group versus placebo. MDS-UPDRS Part III (motor) scores improved in the insulin group (P = 0.02 vs. baseline) but not in placebo. No significant changes were observed in Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), or gait measures. Treatment showed an acceptable safety profile.

Two Phase 2 trials are investigating intranasal insulin in Parkinson's disease patients (NCT04687878; NCT04251585). These trials are searching for its efficacy on motor and non-motor symptoms in Parkinson's disease patients.

Intranasal NeuroEPO (Recombinant Erythropoietin)

Recombinant erythropoietin (EPO) is an erythropoiesis-stimulating agent (a substance that stimulates red blood cell production) used in anemia. It is produced and manufactured in Cuba (iorEPOCIM, CIMAB S.A, Havana, Cuba) and has neuroprotective properties. NeuroEPO is a nasal formulation of recombinant EPO containing a low quantity of sialic acid without hematopoietic effects (meaning it does not stimulate red blood cell production). It has shown neuroprotective effects in animals.

In one study, both recombinant human erythropoietin (rhEPO) and intranasal NeuroEPO demonstrated cognitive improvements in Parkinson's disease patients. rhEPO improved Dementia Rating Scale (DRS) scores in all patients after treatment (z = 2.84, P = 0.004). Intranasal NeuroEPO enhanced phonological verbal fluency at week 1 (z = 2.2, P = 0.02) and semantic fluency at six months (z = 2.13, P = 0.03). DRS scores improved at week 1 (P = 0.01, z = 2.5) and six months (P = 0.005, z = 2.8). Frontal Assessment Battery (FAB) scores and Rey Complex Figure memory and copy subtests also showed significant improvements at one week and six months post-treatment. No major adverse events were reported, though between-group differences for NeuroEPO versus placebo were not significant, indicating possible placebo effects.

In another study, the intervention consisted of weekly intranasal administrations of NeuroEPO (1 mL at 1 mg/mL) for 5 weeks in Parkinson's disease patients. NeuroEPO was acceptable, with mild and transient adverse effects reported in 20% of patients treated versus 9.1% in placebo. There were no significant changes in blood pressure and biochemical parameters. Statistical analyses confirmed no differences in adverse event frequency or laboratory measures (P > 0.05). The study demonstrated short-term safety of NeuroEPO over five weeks.

In a further study, intranasal NeuroEPO was administered at 1 mg weekly for 5 weeks in Parkinson's disease patients without cognitive impairment. NeuroEPO significantly improved cognition (P = 0.006), with 66% of the improvement mediated by quantitative electroencephalogram (qEEG) changes (P < 0.0001). Mediation analysis confirmed both strong indirect and direct effects (P = 0.002). The treatment demonstrated good tolerability, with no major safety concerns emphasized. These findings indicate that intranasal NeuroEPO enhances cognition in Parkinson's disease, primarily verbal fluency, through EEG-mediated mechanisms.

Intranasal Rivastigmine

Rivastigmine is a slow-reversible, noncompetitive carbamate cholinesterase inhibitor (a drug that prevents the breakdown of acetylcholine, a chemical messenger in the brain). It is approved for mild to moderate Alzheimer's disease treatment.

This study evaluated rivastigmine nasal spray's bioavailability and safety. Participants received rivastigmine intravenously (IV, 1 mg) and nasal spray (3.126 mg). The nasal spray demonstrated significant absolute bioavailability (F = 0.62, SD 0.15, P < 0.001) with an absorbed dose of 2.0 (0.6) mg, Tmax 1.1 (0.5) hours, Cmax 6.9 (2.0) ng/mL, and metabolite ratio 0.78 (0.19).

Two mild, transient adverse events (nasal/throat irritation) were observed, resolving within 20 minutes. No serious events were reported. Bioavailability exceeded historical oral (0.36) and transdermal (0.30 to 0.56) values.

Neuroprotection and Oxidative Stress Reduction

Intranasal Cholecystokinin

Cholecystokinin (CCK) is a neuropeptide (a small protein that nerve cells use to communicate) that supports memory, modulates dopamine signaling, and provides neuroprotection in Alzheimer's and Parkinson's diseases. It works via mitochondrial, autophagic, and anti-inflammatory pathways.

In this study, the intervention was a single intranasal administration of cholecystokinin-8 (CCK-8, 25 µg) in a double-blind, placebo-controlled, crossover design. In Parkinson's disease patients, CCK-8 significantly delayed N2/P3 latencies during cognitive testing, indicating impaired attentive processing. In healthy controls, latencies shortened and P3 amplitude increased, reflecting facilitation. No motor improvements were observed. These results suggest CCK-8 has cognitive, non-dopaminergic effects that are potentially deleterious in Parkinson's disease, with no demonstrated motor efficacy.

Intranasal Glutathione

In Parkinson's disease, redox dysfunction (problems with chemical reactions involving electron transfer) and neuro-oxidative stress occur. Lowered glutathione (GSH) levels and GSH/GSSG imbalance are linked to mitochondrial dysfunction, neuroinflammation, and neurodegeneration. However, it remains unclear whether GSH dysregulation is caused by Parkinson's disease or is a consequence of it.

Studies on intranasal glutathione are as follows:

Study 1: Dose comparison. In this study, intranasal glutathione was administered 3 times per day for one month in 3 groups. The groups were intranasal saline as placebo, intranasal glutathione 300 mg/day as low-dose group, and intranasal glutathione 600 mg/day as high-dose group. Treatment was safe and acceptable to patients, with high adherence (greater than 80%). UPDRS scores showed non-significant trends toward improvement in both glutathione arms compared with placebo.

Study 2: Retrospective survey. A retrospective survey of intranasal reduced glutathione (inGSH) covered conditions including Parkinson's disease, multiple chemical sensitivity, and allergies/sinusitis. The survey found that among 66 users (mean age 56.8 years), 78.8% reported a positive experience. Also, 62.1% perceived health benefits, such as symptom improvement, increased well-being, and higher energy. Mild adverse effects occurred in 12.1% (nasal irritation, headaches, epistaxis/nosebleeds). No adverse events were reported in Parkinson's disease participants, and 42.9% of them noted benefits including energy and symptom relief. Results suggest that inGSH is generally safe, well-tolerated, easy to administer, and potentially beneficial, supporting further controlled studies.

Study 3: Brain glutathione levels. In another study, a single 200 mg dose of intranasal reduced glutathione (inGSH) significantly increased brain GSH levels in 15 mid-stage Parkinson's disease patients. Researchers measured this using Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) and proton magnetic resonance spectroscopy (H-MRS). Elevations were not observed at 8 minutes but were sustained from 16 to 60 minutes post-dose, peaking around 45 to 60 minutes. Mild nasal irritation occurred in two participants. One-way repeated measures ANOVA confirmed significant time-dependent increases (F(6,84) = 12.34, P < 0.001). These findings indicate that intranasal GSH can rapidly and safely augment central nervous system GSH.

Study 4: Phase IIb trial. In a Phase IIb study, 45 mid-stage Parkinson's disease patients received intranasal reduced glutathione (inGSH) at 300 or 600 mg per day doses or placebo for 3 months, followed by a 1-month washout. The 600 mg/day intranasally administered glutathione showed within-group improvements in total UPDRS (-4.6, P = 0.0025) and motor scores (-2.2, P = 0.0485), as well as significant reductions in non-motor symptoms (NMSS -10.17, P = 0.0217). No alterations were observed in blood or central nervous system oxidative biomarkers. One case of cardiomyopathy (heart muscle disease) occurred in the high-dose group and was possibly treatment-related. High-dose GSH demonstrated modest symptomatic benefits without clear biomarker changes, and superiority over placebo was not established.

Specific Non-Motor Symptom Management

Sialorrhea (excessive drooling) and nocturia (excessive urination at night) are being investigated in this section. The majority of Parkinson's disease patients suffer from non-motor salivary symptoms such as sialorrhea and xerostomia (dry mouth), which impair patient oral health and overall quality of life. Another common complication is nocturia. Nocturia in these patients can result from reduced bladder capacity or nocturnal polyuria (excessive urine production at night).

Intranasal Ipratropium Bromide

Sialorrhea is a non-motor symptom in advanced Parkinson's disease. This study hypothesized that ipratropium bromide, an anticholinergic agent (a drug that blocks certain nerve signals), can reduce drooling in Parkinson's disease patients. The conventional option is systemic anticholinergics, which frequently cause side effects.

Ipratropium bromide spray used sublingually (under the tongue) did not significantly reduce saliva weight compared with placebo (P > 0.05). Secondary measures showed mild subjective improvements, but no significant differences were observed between treatment arms. The spray was well tolerated.

Intranasal Desmopressin

Desmopressin (dDAVP) is a synthetic analog of arginine vasopressin (a hormone that controls water balance). It enhances antidiuretic potency (reduces urine production), has minimal pressor activity (minimal effect on blood pressure), and has a prolonged effect. Its primary use is as the treatment of choice for central diabetes insipidus (a condition causing excessive urination). It can be administered intranasally or parenterally.

In this study using intranasal desmopressin in Parkinson's disease patients, a significant reduction in nocturnal voids at the higher dose was observed. Mean nocturnal voids decreased from 2.67 ± 0.14 at baseline to 1.51 ± 0.14 at the 20 μg dose (P = 0.0431; P = 0.011). Safety was generally acceptable. Patients reported symptomatic benefits, and four continued long-term therapy, although one case of hyponatremia (low blood sodium) occurred, which resolved upon discontinuation.

Overall Side Effects Across All Studies

Across the studies, the most reported adverse event was mild and transient nasal or throat irritation. This side effect was generally well tolerated and did not necessitate treatment discontinuation. This makes intranasal formulations more acceptable for patients and improves compliance.

Other side effects reported across studies included:

• Nausea (with apomorphine)
• Somnolence (with apomorphine)
• Vestibulitis (nasal vestibule inflammation, with apomorphine)
• Disabling irritation in 3 patients (with apomorphine)
• Mild nausea/vomiting (with NeuroEPO, in 20% of treated patients)
• Polyuria (with placebo in NeuroEPO studies, in 9.1%)
• Nasal irritation (with glutathione, in 12.1% of survey respondents)
• Headaches (with glutathione)
• Epistaxis or nosebleeds (with glutathione)
• Hyponatremia (with desmopressin, one case)
• Cardiomyopathy (with high-dose glutathione, one case, possibly treatment-related)

Discussion and Clinical Implications

In this review, the authors assessed intranasal interventions used in Parkinson's disease patients. The findings suggest several important clinical implications.

Intranasal apomorphine achieved faster onset of action (Tmax 1 to 2 minutes vs. 30 minutes for subcutaneous) and significant efficacy. UPDRS motor score improvements ranged from P = 0.016 to 0.023. Decreased "off" episode rates were observed (64.6% vs. 11.1%, P < 0.0001) compared to placebo.

Intranasal insulin improved verbal fluency and motor scores (P = 0.02), suggesting potential cognitive and motor benefits.

Glutathione increased central nervous system levels (P < 0.001) with trends toward UPDRS improvement, though placebo responses limited significance.

The general benefits of nasal administration for Parkinson's disease treatment include:

• Localized effects
• Fewer side effects
• Faster onset of action
• Improved bioavailability
• Enhanced therapeutic effectiveness

Limitations

The studies included in this review had several important limitations:

• Small sample sizes: Studies ranged from 4 to 55 participants for apomorphine, 18 for stem cells, 14 for insulin, 25 to 26 for NeuroEPO, and 13 for cholecystokinin.
• Variable dosing: Apomorphine doses ranged from 0.2 to 5.75 mg across studies.
• Lack of significant differences: Some outcomes did not reach statistical significance (P > 0.05).
• No dose-related effects: Some studies found no dose-related effects.
• Short duration: Some studies lasted only 4 to 5 weeks.
• Placebo influence: Placebo effects may have influenced some outcomes.
• Dose-escalation without placebo control: The stem cell study used dose-escalation without a placebo control group.
• Inclusion of patients with other conditions: One insulin study included a patient with possible multiple system atrophy (MSA).
• Single-dose design: The cholecystokinin study used a single-dose design.

Recommendations and Future Directions

This review highlights the potential applications, efficacy, and side effects of various intranasal medications for Parkinson's disease. The authors propose using new interventions for future studies.

Based on the findings, the following recommendations emerge:

1. Larger controlled trials are needed. Most studies had small sample sizes, limiting the strength of conclusions.
2. Longer study durations are needed. Some studies lasted only 4 to 5 weeks, which is insufficient to assess long-term efficacy and safety.
3. Placebo-controlled designs should be prioritized. Placebo effects may have influenced some outcomes.
4. Intranasal apomorphine shows the most promise as a rescue therapy during "off" periods, with rapid onset and significant efficacy.
5. Intranasal insulin and NeuroEPO show potential for cognitive benefits and warrant further investigation.
6. Intranasal glutathione is safe and well-tolerated but requires larger trials to establish efficacy over placebo.
7. Intranasal desmopressin is safe and effective for nocturnal polyuria in Parkinson's disease.
8. Intranasal stem cell transplantation is safe and associated with functional improvement, but requires larger controlled studies.
9. Rivastigmine nasal spray offers better bioavailability and fewer side effects compared with conventional forms.
10. Intranasal cholecystokinin and ipratropium bromide did not show significant benefits in the studies reviewed.

The most common adverse effect across all studies was mild transient nasal or throat irritation. This side effect profile makes intranasal formulations more acceptable for patients and may improve treatment compliance.

For patients considering intranasal therapies for Parkinson's disease, the evidence suggests that this route of administration offers several advantages. These advantages include localized effects, fewer side effects, faster onset of action, improved bioavailability, and enhanced therapeutic effectiveness. However, patients should discuss these options with their healthcare providers, as most of these treatments are still in clinical trial stages and not yet widely available.

Frequently Asked Questions

What is intranasal delivery and why is it being studied for Parkinson's disease?

Intranasal delivery means giving medication as a nasal spray. It can bypass the blood-brain barrier through the olfactory and trigeminal nerve pathways, giving rapid absorption, faster onset of action, and lower systemic exposure than oral or injectable forms. It is also suitable for daily use. Researchers are studying it to improve 'off' episodes and reduce body-wide side effects.

How does intranasal apomorphine compare with subcutaneous apomorphine for 'off' periods?

In one study, intranasal apomorphine had 45% bioavailability relative to subcutaneous injection, with comparable time to 'on' and duration of 'on'. Another study found a mean onset of 8.25 minutes and mean response duration of 57.5 minutes, with daily off-hours reduced from 5.37 to 0.56. Side effects can include nausea, low muscle tone, and nasal irritation.

What did studies of intranasal insulin show for thinking and movement symptoms?

In one study, intranasal insulin improved verbal fluency by 5.6% compared with a 6.4% decrease on placebo, and MDS-UPDRS Part III motor scores improved versus baseline. Hoehn and Yahr scores also improved. No significant changes were seen in Montreal Cognitive Assessment, Beck Depression Inventory, or gait measures. Two Phase 2 trials are ongoing.

Is intranasal glutathione safe, and does it raise brain glutathione levels?

In a study of 15 mid-stage patients, a single 200 mg dose significantly increased brain glutathione levels from 16 to 60 minutes after dosing, peaking around 45 to 60 minutes. Mild nasal irritation occurred in two participants. A Phase IIb trial found modest symptom improvements at 600 mg daily, but superiority over placebo was not established, and one case of cardiomyopathy occurred.

What side effects are common across intranasal Parkinson's treatments?

The most reported side effect across all studies was mild, temporary nasal or throat irritation, which was generally well tolerated and did not require stopping treatment. Other reported effects included nausea and sleepiness with apomorphine, mild nausea or vomiting with NeuroEPO, nasal irritation and headaches with glutathione, one case of low blood sodium with desmopressin, and one case of heart muscle disease with high-dose glutathione.

Are these intranasal treatments available now, and what should patients do?

Most of these treatments are still in clinical trial stages and not yet widely available. The evidence suggests intranasal delivery offers localized effects, fewer side effects, faster onset, and improved bioavailability for several Parkinson's treatments. Patients should discuss these options with their healthcare providers, as larger controlled trials are still needed to confirm long-term efficacy and safety.

What are the main limitations of the studies on intranasal therapies for Parkinson's disease?

Studies had small sample sizes, ranging from 4 to 55 participants for apomorphine, 18 for stem cells, 14 for insulin, 25 to 26 for NeuroEPO, and 13 for cholecystokinin. Dosing varied, some outcomes did not reach statistical significance, and some studies lasted only 4 to 5 weeks. Placebo effects may have influenced results, and one stem cell study lacked a placebo control group.

When should a patient with Parkinson's disease seek a second opinion about intranasal treatments?

Most intranasal Parkinson's therapies remain in clinical trial stages and are not yet widely available, so a second opinion is reasonable before changing any treatment plan. Intranasal apomorphine shows the most promise as a rescue therapy during "off" periods, while insulin and NeuroEPO show potential cognitive benefits and glutathione requires larger trials to establish efficacy over placebo. Intranasal cholecystokinin and ipratropium bromide did not show significant benefits. Discuss these options with your healthcare providers. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original Article Title: Clinical Studies Using Intranasal Therapies for Parkinson's Disease: A Review.

Journal: Advanced pharmaceutical bulletin

DOI: 10.34172/apb.025.46111

License: CC BY (open access)

Authors: Vahidi R, Bukanian M, Kachooeian M.

Author Affiliations: Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran

Publication: Advanced Pharmaceutical Bulletin, 2026;16(1):18-27

DOI: 10.34172/apb.025.46111

Article History: Received August 4, 2025; Revised October 4, 2025; Accepted December 18, 2025; Published online December 27, 2025

Corresponding Author: Maryam Kachooeian, Email: m.kachoo.15@gmail.com

Note: This patient-friendly article is based on peer-reviewed research. The original article is an open-access publication distributed under the terms of the Creative Commons Attribution (CC BY) license.