Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug

Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in-
development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic
interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain
health, as well as for age-related health concerns that can affect brain health (e.g.,
cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports
include evaluation of safety data, from clinical trials if available, and from preclinical models.

Intranasal Glutathione
Evidence Summary
Acutely elevates brain glutathione levels, but a more comprehensive pharmacokinetic study is needed
to find a dosing schedule to boost levels in disease-relevant brain regions in a clinically meaningful
manner.

Neuroprotective Benefit: Intranasal glutathione was not more effective than placebo in
clinical trials, but the studies were underpowered. The optimal dosing schedule to boost brain
levels has not been established.

Aging and related health concerns: Intranasal glutathione has not been investigated for
peripheral age-related diseases.

Safety: Primary adverse events include sinus irritation and headaches based on clinical trials
up to 3 months, and outpatient use for a median of 2 years. A single case of tachycardia was
reported at a high dose that may have been a treatment-related event.

1
 Availability: Rx Dose: Not established Chemical formula: C10H17N3O6S
MW: 307.33 g/mol

Half-life: Not established BBB: Penetrant

Clinical trials: Phase 1/2a (n=30) Observational studies: Safety
and Phase 2b (n=45) in survey of patient reported
Parkinson’s disease. outcomes (n=66).
Source: PubChem

What is it?

Glutathione is a tripeptide of the amino acids glutamate, cysteine, and glycine. It is an endogenous
antioxidant produced in the cytoplasm of cells that exists in reduced (GSH) and oxidized (GSSG) forms
[1]. The reduced form reacts to neutralize reactive oxygen species (ROS), and the oxidized form is a
byproduct of this reaction. Therefore, the ratio of the reduced (GSH) to oxidized forms (GSSG) serves as
a readout of cellular oxidative stress levels. Glutathione has very poor oral bioavailability, but as a small
polar molecule, it is a good candidate for intranasal administration. Intranasally administered reduced
glutathione has been tested in clinical trials for Parkinson’s disease, but the interpretation of the results
is challenging because the full pharmacokinetic profile of this route of administration has not been
established.

Neuroprotective Benefit: Intranasal glutathione was not more effective than placebo in clinical trials,
but the studies were underpowered. The optimal dosing schedule to boost brain levels has not been
established.

Types of evidence:

• 2 clinical trials in Parkinson’s disease (Phase 1/2a n=30; Phase 2b n=45)

• 3 MRI imaging studies for brain glutathione (PD n=15; AD/MCI n=130, Healthy Elderly n=15)

2
Human research to suggest prevention of dementia, prevention of decline, or improved cognitive
function?

Parkinson’s disease: No clear benefit

Postmortem studies have shown that glutathione is depleted in brain regions associated with
Parkinson’s disease (PD)-pathology, such as the substantia nigra [2], and the results from underpowered
pilot studies using intravenously administered glutathione suggested that PD patients may benefit from
glutathione supplementation [3; 4].

Two small, double-blind, placebo controlled RCTs were conducted testing intranasal reduced glutathione
in PD patients (Hoehn & Yahr Stage 1–3), and these studies were also not powered to determine clinical
efficacy relative to placebo [5; 6]. In both studies, glutathione was administered via a 1 mL syringe
attached to a to Mucosal Atomization DeviceTM (Teleflex, following acquisition of Wolfe-Tory Medical).
Patients used the device to administer saline, or saline supplemented with 100 mg or 200 mg of reduced
glutathione 3 times per day (TID) for a period of 3 months. In order to minimize the circadian variation in
PD symptoms, a given patient was tested at the same time of day for each study visit.

In the Phase 1/2a trial (n=30), there was a trend toward decline on the Total Unified Parkinson’s Disease
Rating Scale (UPDRS), however, the glutathione treated patients, especially the 600 mg/day group had,
on average, worse disease severity than the placebo group, so there may have been greater ability to
detect a small change in the treated group [5]. Unexpectedly, the slope of cognitive decline on the
Montreal Cognitive Assessment (MoCA), became steeper between the end of treatment and the 1-
month follow-up visit in the glutathione treated groups. However, it is unknown whether the rates of
decline for the three groups were the same during the 3 months prior to randomization, or whether the
differences observed in this short time period are clinically meaningful.

In the Phase 2b trial (n=45), all three groups (placebo, 300 mg, 600 mg) showed a similar trajectory of
improvement on the Total UPDRS, and glutathione treatment was not significantly better than placebo
on component measures of mentation (Part 1), activities of daily living (Part 2), or motor scores (Part 3)
[6]. The authors attributed this finding to an unexpectedly high placebo effect, however, it appears
likely that dosing may not have been adequate to meaningfully boost brain glutathione levels in disease-
relevant areas. Based on 1H-MRS measures, 300 mg/day of glutathione had no effect on levels of
glutathione in the putamen, whereas 600 mg/day led to a small, non-significant increase.

The primary difficulty in interpreting these results is that while levels in the healthy brain are estimated
to be approximately 1 to 2 mM, the reported normal range of glutathione in the brain is extremely

3
variable, and differs based on age, sex, and brain region [7]. Additionally, the presence of disease-
related pathology may lead to higher levels of oxidative stress, and thus a higher demand for antioxidant
capacity. Therefore, it is difficult to determine what level of glutathione supplementation would be
needed for restoration of brain levels, and consequently impedes the ability to test the hypothesis that
restoration of brain glutathione levels benefits cognitive function.

Human research to suggest benefits to patients with dementia:

Alzheimer’s disease: Unknown

Intranasal glutathione has not yet been clinically tested in patients with Alzheimer’s disease (AD), but
there is evidence to indicate that there is an increased burden of oxidative stress, and decrease in
glutathione levels in brain regions with AD-associated pathology.

Postmortem studies have indicated decreased glutathione levels in the brains of AD patients [8], more
recently, the use of magnetic resonance spectroscopy (1H-MRS) with the MEGA-PRESS sequence has
allowed for the detection of brain glutathione levels in living patients, in a non-invasive manner. One
study examining glutathione levels in the hippocampus (n=66) or frontal cortex (n=64) of participants
with AD, mild cognitive impairment (MCI), or healthy older adults found that there were region specific
alternations in glutathione in AD and MCI [9]. Both MCI and AD patients had lower levels of GSH in the
hippocampus, but levels were only significantly changed in the frontal cortex in AD. Meanwhile, neither
group had a significant change in glutathione levels in a brain region unaffected by AD pathology, the
cerebellum, suggesting that the decrease in the levels of this endogenous antioxidant may contribute to
disease progression. Cognitive function, based on Mini-Mental State Examination (MMSE) and Clinical
Dementia Rating (CDR), was also inversely associated with glutathione levels in the frontal and temporal
cortices, in cognitively impaired individuals.

A separate 1H-MRS study in cognitively normal healthy older adults (n=15) found that decreased levels
of glutathione were associated with greater levels of amyloid, based on PiB PET imaging, in the
temporal lobe [8]. However, the timing of the relationship has not been established, so it is not known
whether regions with high oxidative stress and low glutathione are likely to promote amyloid pathology,
or if amyloid-induced oxidative stress leads to depletion of glutathione, or both.

Since it is not clear whether the loss of glutathione plays a causal role, or is a byproduct of other brain
changes associated with AD, it is not clear whether boosting brain levels of glutathione would
meaningfully slow disease progression. Furthermore, it is not known how well the intranasal

4
administration of glutathione could reliably boost glutathione levels specifically in the hippocampus and
frontal cortices, where it is depleted in AD patients.

Mechanisms of action for neuroprotection identified from laboratory and clinical research:

Glutathione is an endogenous antioxidant involved in the scavenging of ROS, and thus protects cells
from oxidative stress damage [1]. Levels of glutathione have been shown to decrease with age, in
conjunction with the increased susceptibility to oxidative stress damage [7]. Therefore, glutathione
supplementation has been hypothesized as a way to protect cells against this damage. Orally
administered glutathione has very poor bioavailability, while frequent intravenous administration is
burdensome.

Intranasal administration allows therapeutics to access the brain directly via the olfactory nerve and
epithelium, and indirectly by crossing the blood-brain barrier (BBB) following entry into the systemic
circulation [10]. Since the surface area of the nasal cavity region that contributes to the systemic
circulation is larger, more of the drug is typically diverted to this path, but the therapeutic agent will also
be more extensively diluted, and thus may not reach biologically meaningful doses in peripheral organ
systems. The effectiveness of transport to the brain is heavily influenced by the physiological
environment of the nasal cavity, such as the pH.

An 1H-MRS imaging study in PD patients (n=15) found that intranasal administration of reduced
glutathione led to an increase in brain levels of glutathione from 20 to 45 minutes after administration
[11]. However, there was considerable variation in the baseline levels and magnitude of increase, and
there were also some within-subject fluctuations.

Since 60 minutes was the last time point assessed in this study, and it was only assessed in one subject,
it is not known how long glutathione levels remain elevated in the brain. Additionally, this study used a
region of interest centered over the left dorsal putamen, and it has not been established whether the
glutathione distributes uniformly, or preferentially within certain brain regions. A more comprehensive
pharmacokinetic study is needed to determine a dosing schedule that leads to consistently elevated
glutathione levels in the brain regions of interest.

APOE4 interactions:

Brain tissue from ApoE4 carrier AD patients was found to have higher levels of oxidative stress and
lower levels of reduced glutathione relative to ApoE3 carriers [12], suggesting that ApoE4 carriers may
preferentially benefit from glutathione supplementation and/or that they would require higher doses

5
for efficacy. However, the efficacy of intranasal glutathione for AD patients with or without ApoE4 has
not been tested.

Aging and related health concerns: Intranasal glutathione has not been investigated for peripheral age-
related diseases.

Types of evidence:

• None

Reduced glutathione (GSH) levels decrease with age in conjunction with the rise in oxidative stress,
leading to the hypothesis that supplementation of reduced glutathione could prevent age-related
oxidative stress damage [13]. However, the pharmacokinetics and pharmacodynamics of intranasal
glutathione have not been fully characterized, so it is not known how much enters the peripheral
circulation relative to the amount that enters the brain. Furthermore, it is unclear if the concentration
of glutathione that reaches peripheral organ systems following intranasal administration is high
enough to exert biologically meaningful activity. The peripheral contribution is likely to vary from
person to person depending on nasal architecture and physiochemistry [10].

Safety: Primary adverse events include sinus irritation and headaches based on clinical trials up to 3
months, and outpatient use for a median of 2 years. A single case of tachycardia was reported at a high
dose that may have been a treatment-related event.

Types of evidence:

• 2 clinical trials in Parkinson’s disease (Phase 1/2a n=30 + 4; Phase 2b n=45)

• 1 observational safety survey from pharmacy database (n=66)

A safety survey was conducted to assess patient-reported outcomes for intranasal glutathione [14].
Three hundred people from twenty states were randomly selected from the Key Pharmacy database, of
which 70 completed the survey, and 66 had filled a prescription for intranasal glutathione. The
treatment indications included multiple chemical sensitivity (n=29), allergies/sinusitis (n=25),
Parkinson’s disease (n=7), Lyme disease (n=3), fatigue (n=2), or other (n=10). The intranasal glutathione
was used for a median of 24 months (25th percentile to 75th percentile: 10 to 56 months). 78.8% (n=52)

6
reported an overall positive experience, with 62.1% (n=41) attributing health benefits to intranasal
glutathione use. 12.1% (n=8) reported experiencing adverse events, which primarily related to the
route of administration, including sinus irritation, headaches, or bloody nose.

In the Phase 1/2a trial in PD patients (n=30), placebo and glutathione treated groups had similar levels
of sinus irritation, both of which were greater than in the watchful waiting group (n=4) that did not
receive any treatment [5]. None of the patients showed a significant difference in measured laboratory
events, including complete blood count (CBC), white blood cell (WBC) count with differential, liver
enzymes (ALT, AST), creatine, blood urea, nitrogen, uric acid, or urinalysis.

In the Phase 2b trial in PD patients (n=45), one patient receiving 600 mg glutathione/day withdrew from
the study due to newly diagnosed cardiomyopathy following the onset of treatment [6]. The patient’s
tachycardia resolved after treatment cessation, suggesting this was a treatment-related event. The
study investigators state that the cardiac side effect may be related to the finding in rodent studies that
high levels of antioxidants can lead to reductive stress that injures cardiomyocytes. This suggests that
taking high doses of glutathione in combination with other potent antioxidants may increase the risk for
adverse events.

Sources and dosing:

The clinical trials testing intranasal glutathione used powdered glutathione from MEDISCA that was
compounded by Key Pharmacy (Kent, Washington), and administered three times per day at doses of
100 or 200 mg/day in 1mL of saline in a syringe attached to a Mucosal Atomization DeviceTM (Teleflex).
Neither dose was associated with significant increases in brain glutathione levels or clinical efficacy over
the course of 3 months, and the optimal dosing schedule for neurodegenerative conditions has not been
established. The glutathione used in the safety survey was also compounded through Key Pharmacy, but
it is not known whether the same glutathione source or the nasal administration device supplied by the
pharmacy was the same for all prescriptions. The compounded glutathione used a stabilization formula
resulting in >97.4% stability after 30 days, and >94% stability after 60 days [14].

Research underway:

There are no reported planned or ongoing trials for intranasal glutathione.

7
Search terms:

Pubmed, Google: Intransal glutathione

• Alzheimer’s disease, Parkinson’s disease, neurodegeneration, aging, clinical trials, safety

Websites visited for Intranasal Glutathione:

• Clinicaltrials.gov (intranasal glutathione)

• DrugAge (glutathione)
• Examine.com (glutathione)
• Geroprotectors (glutathione)
• Drugs.com (glutathione)
• WebMD.com (glutathione)
• PubChem (glutathione)
• DrugBank.ca (glutathione)

References:

1. Pizzorno J (2014) Glutathione! Integr Med (Encinitas) 13, 8-12.https://www.ncbi.nlm.nih.gov/pubmed/26770075

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684116/

2. Sofic E, Lange KW, Jellinger K et al. (1992) Reduced and oxidized glutathione in the substantia nigra of patients with
Parkinson's disease. Neuroscience Letters 142, 128-
130.http://www.sciencedirect.com/science/article/pii/030439409290355B

3. Sechi G, Deledda MG, Bua G et al. (1996) Reduced intravenous glutathione in the treatment of early parkinson's disease.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 20, 1159-
1170.http://www.sciencedirect.com/science/article/pii/S0278584696001030

4. Hauser RA, Lyons KE, McClain T et al. (2009) Randomized, double-blind, pilot evaluation of intravenous glutathione in
Parkinson's disease. Movement Disorders 24, 979-983.https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.22401

5. Mischley LK, Leverenz JB, Lau RC et al. (2015) A randomized, double-blind phase I/IIa study of intranasal glutathione in
Parkinson's disease. Mov Disord 30, 1696-1701.https://www.ncbi.nlm.nih.gov/pubmed/26230671
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609266/

6. Mischley LK, Lau RC, Shankland EG et al. (2017) Phase IIb Study of Intranasal Glutathione in Parkinson's Disease. J
Parkinsons Dis 7, 289-299.https://www.ncbi.nlm.nih.gov/pubmed/28436395
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438472/

7. Rae CD, Williams SR (2017) Glutathione in the human brain: Review of its roles and measurement by magnetic
resonance spectroscopy. Analytical Biochemistry 529, 127-
143.http://www.sciencedirect.com/science/article/pii/S0003269716304341

8
8. Chiang GC, Mao X, Kang G et al. (2017) Relationships among Cortical Glutathione Levels, Brain Amyloidosis, and Memory
in Healthy Older Adults Investigated In Vivo with (1)H-MRS and Pittsburgh Compound-B PET. AJNR Am J Neuroradiol 38,
1130-1137.https://www.ncbi.nlm.nih.gov/pubmed/28341718
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471116/

9. Mandal PK, Saharan S, Tripathi M et al. (2015) Brain Glutathione Levels; A Novel Biomarker for Mild Cognitive
Impairment and Alzheimer's Disease. Biological Psychiatry 78, 702-710.https://doi.org/10.1016/j.biopsych.2015.04.005

10. Hong S-S, Oh KT, Choi H-G et al. (2019) Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and
Future Perspectives. Pharmaceutics 11, 540.https://www.mdpi.com/1999-4923/11/10/540

11. Mischley LK, Conley KE, Shankland EG et al. (2016) Central nervous system uptake of intranasal glutathione in
Parkinson's disease. NPJ Parkinsons Dis 2, 16002-16002.https://www.ncbi.nlm.nih.gov/pubmed/28725693
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516583/

12. Ramassamy C, Averill D, Beffert U et al. (2000) Oxidative Insults Are Associated with Apolipoprotein E Genotype in
Alzheimer's Disease Brain. Neurobiology of Disease 7, 23-
37.http://www.sciencedirect.com/science/article/pii/S0969996199902735

13. Singh RJ (2002) Glutathione: A marker and antioxidant for aging. The Journal of Laboratory and Clinical Medicine 140,
380-381.https://doi.org/10.1067/mlc.2002.129505

14. Mischley LK, Vespignani MF, Finnell JS (2013) Safety survey of intranasal glutathione. J Altern Complement Med 19,
459-463.https://www.ncbi.nlm.nih.gov/pubmed/23240940
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651682/

Disclaimer: Cognitive Vitality Reports® do not provide, and should not be used for, medical
advice, diagnosis, or treatment. You should consult with your healthcare providers when
making decisions regarding your health. Your use of these reports constitutes your agreement
to the Terms & Conditions.

If you have suggestions for drugs, drugs-in-development, supplements, nutraceuticals, or

food/drink with neuroprotective properties that warrant in-depth reviews by ADDF’s Aging and
Alzheimer’s Prevention Program, please contact [email protected]. To view our official
ratings, visit Cognitive Vitality’s Rating page.