Mild Cognitive ImpairmentPhase 1/2NCT03641404
Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline (Pilot)
A Phase 1/2 study testing L-ergothioneine in people with Mild Cognitive Impairment, run by National University Hospital, Singapore at 1 site in Singapore.
Trial summary
With the growing burden of dementia (including Alzheimer's disease), and the lack of efficacious therapies, there is an urgent need to identify new therapeutics. Ergothioneine (ET) is a naturally occurring thiol derivative of histidine, obtained solely through diet and is able to accumulate in the body and brain… Read more about this study
- Who is it for?
- Ages 60 to 90 yearsHealthy volunteers can take part
- Conditions the study is for
- Mild Cognitive Impairment
- What is being tested?
- L-ergothioneine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 19 participants
- Where
- 1 siteSingapore
- Study dates
- 1 Aug 2019to 31 Dec 2023
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 to 90 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Elderly individuals 60 - 90 years of age
- Chinese ethnicity (from other local cohort studies)
- Demonstrate amnestic mild cognitive impairment (assessed by panel of psychiatrists)
- Independent and able to travel to study site without assistance
- No other severe underlying conditions or terminal illnesses
- Capable of understanding the study and requirements and able to provide informed consent to participate
- Willing to commit to the year-long study, comply with study administration and periodic blood and urine sampling
Who cannot join
- Inability to understand the risks and requirements of the study for any reason
- Any intolerance to lactose, and/or allergies to mushrooms
- History of cardiovascular complications, diabetes, hypertension or hypercholesterolemia, or other pre-existing condition that may prevent them from completing the study
- Evidence of anaemia or other significant haematological conditions
- History or mental illness, depression or other underlying psychiatric illnesses
- History of drug or alcohol abuse
Show all 9Show fewer
- Involvement in another study requiring administration of an investigational compound in the past 30 days
- Subjects whose blood analysis reveal and extremes of liver or kidney function markers (from baseline screening)
- Deemed unfit for any reason as determined by the principal/co-investigator
Trial locations and contacts
1 site in 1 country.
Singapore1 site
National University Cancer Institute, Singapore
Singapore, Singapore, 119074
About this study
Official title: Pilot Study to Investigate the Efficacy of Ergothioneine to Delay Cognitive Decline in Mild Cognitively Impaired Subjects
With the growing burden of dementia (including Alzheimer's disease), and the lack of efficacious therapies, there is an urgent need to identify new therapeutics.
Ergothioneine (ET) is a naturally occurring thiol derivative of histidine, obtained solely through diet and is able to accumulate in the body and brain, through the action of a specific transporter, OCTN1. In addition to a wide variety of in vitro and in vivo (animal) studies demonstrating the antioxidant, anti-inflammatory properties of ET, several studies have demonstrated the neuroprotective potential of ET in various cell and animal models.
Based on the ability of ET to counteract the underlying pathology of AD dementia, it is hypothesize that ET supplementation may prevent cognitive decline, especially in individuals at risk of cognitive impairment. This will be assessed using a randomized, double blinded, placebo-controlled, intervention study to test the ability of ET to delay or reverse cognitive impairment in elderly individuals with mild cognitive impairment.
Read the detailed description
Ergothioneine (ET) is a naturally occurring thiol/thione obtained in humans solely through diet. It is able to accumulate in specific cells and tissues (including the brain), via a specific transporter, OCTN1, at high levels. Although the exact physiological function(s) of ET have yet to be elucidated, numerous reports have demonstrated that this compound can scavenge reactive oxygen species (such as hydroxyl radicals, hypochlorous acid, and peroxynitrite), modulate inflammation, and chelate divalent metal ions. These processes are all implicated in the pathology of dementia. Various studies in cell and animal models have also highlighted the potential neuroprotective capabilities of ET following insult by various neurotoxic agents such as cisplatin and amyloid beta peptide.
Studies demonstrated that ET dose-dependently protected PC12 cells against beta amyloid-induced apoptotic death, and later was shown to protect against neuronal injury caused by direct administration of amyloid beta into the mouse hippocampus, thereby increasing scores in active avoidance and water maze tests. ET also dose-dependently extend lifespan of a transgenic Caenorhabditis elegans model of AD by reducing amyloid oligomer formation. Other studies also demonstrated that ET is also able to attenuate oxidative stress and prevents cognitive deficits in a D-galactose-induced dementia mouse model; protect against N-methyl-D-aspartate-induced cytotoxicity in rat retinal neurons; and prevent cisplatin-induced neuronal damage in cell cultures and mice.
To date no studies have evaluated the therapeutic ability of ET, clinically, to delay or halt cognitive decline. Prior studies administering pure ET to humans provide insights into the pharmacokinetics and demonstrate the safety of this compound, laying the foundations for this clinical study. The present proposal will shed light onto a relatively lesser known natural compound and the therapeutic capabilities it possesses, which has the potential to significantly impact the economic and societal burdens of dementia.
- Conditions
- Mild Cognitive Impairment
- Being tested
- L-ergothioneine, Placebo
- Keywords
- ergothioneine, mild cognitive impairment, dementia, dietary antioxidant
- Medical subject headings
- Cognitive Dysfunction, Dementia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-ergothioneineDrug
Ergothioneine is naturally occurring thiol compound obtained solely from diet in humans. Ergothioneine is widely reported to be a natural antioxidant and anti-inflammatory compound. In addition we hypothesize that this compound will be beneficial in improving cognition.
PlaceboDrug
Placebo. Study control (99% microcrystalline cellulose, 1% magnesium stearate)
| Study group | Role | What they receive |
|---|---|---|
| Ergothioneine | Active comparator | Subjects will consume 25mg ergothioneine (capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks. Receives: Drug: L-ergothioneine |
| Placebo | Placebo comparator | Subjects will be given placebo (99% microcrystalline cellulose, 1% magnesium stearate; capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Demonstrating uptake of ergothioneine following dietary supplementation
This pilot study will evaluate the ability of oral ergothioneine supplementation to raise levels of ergothioneine in the body (blood measurements) over the one year period
Measured: 12 months
Demonstrate safety of oral ergothioneine supplementation
This study will evaluate the safety oral ergothioneine supplementation over a period of 12 months. Safety is monitored through monthly visits (assessment and feedback on adverse reactions) and quarterly blood assessment (blood counts, liver and renal function).
Measured: 12 months
Evaluating the impact of ergothioneine supplementation to modulate oxidative damage
The ability of oral ergothioneine supplementation to modulate oxidative stress in the subjects will be assessed through changes in plasma and urinary oxidative damage biomarkers collected at baseline and quarterly (every 3 months) over the 12-month study duration.
Measured: Over 12 months
Evaluate the impact of ergothioneine supplementation to modulate inflammation
The ability of oral ergothioneine supplementation to modulate inflammatory status in the subjects will be assessed through measurement of inflammatory cytokines in the plasma at baseline and quarterly (every 3 months) over the 12-month study duration.
Measured: Over 12 months
Secondary outcomes (11)
Assessment of plasma neurofilament light chain (NfL) protein levels
Elevated levels of NfL are suggested to be a biomarker of neurodegeneration and hence changes in this biomarker could reflect pathological changes. Increasing levels of NfL suggest progression or increasing severity of neurodegeneration and cognitive impairment whereas unchanged or decreasing levels of NfL may indicate a stabilisation or mitigation of neurodegeneration.
Measured: 12 months (assessed at baseline and every 3 months)
Evaluation of cognition using the Singapore Modified - Mini Mental State Examination Scores (Cognitive function assessment)
30 point questionnaire to assess for cognitive function and memory recall, with a minimum score of 0 and maximum of 30; where higher is better. A score of less than 7 may be indicative of cognitive impairment.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of dementia stage using the Clinical Dementia Rating Scale (CDR).
CDR evaluates multiple domains including memory, orientation, judgement and problem solving, home and hobbies, community and personal care using a 5-point scale (0, 0.5, 1, 2, 3, where higher score indicates increasing severity of dementia) from 0 (no dementia) to a maximum of 3 (severe dementia). A 0.5-1 score indicates possible to mild cognitive impairment.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological test battery: Rey Auditory Verbal Learning Test (Cognitive function assessment)
The Rey Auditory Verbal Learning Test (RAVLT) evaluates short-term auditory-verbal memory, rate of learning, learning strategies, retroactive, and proactive interference, presence of confabulation of confusion in memory processes, retention of information, and differences between learning and retrieval. Participants are given a list of 15 unrelated words repeated over five different trials and are asked to repeat the words. Another list of 15 unrelated words are given and the client must again repeat the original list of 15 words and then again after 30 minutes. A score out of 75 for immediate recall and 30 for secondary and delayed recall, whereby higher indicates better verbal learning and memory.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Digit Span test (Cognitive function assessments)
The digit span task is a measure of working memory, based on a person's ability to recall a sequence of numerical digits evaluating short-term and working memory. A maximum score of 16 for forward and 14 for backward where higher indicates score indicates better short-term and working memory and cognitive control.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Block Design Test (Cognitive function assessment)
The block design test examines the spatial visualisation ability and motor skills of an individual where the subject is asked to replicate a different design patterns using cubes. Scoring as based on timing and correct pattern with a maximum score of 68 with higher indicating better spatial visualisation.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Symbol Digit Modality Test scores (Cognitive function assessment)
The symbol digit modality is a cognitive assessment test for evaluating information processing speed and attention. Increased written and oral symbol score (1 point per correct answer, minimum of 0 and maximum of 100 limited by the test form) over 90 seconds indicates better processing speed.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Semantic Verbal Fluency Test (Cognitive function assessment)
The Semantic Verbal Task involves asking the subject to name as many animals (part 1) and fruits (part 2) as they can in 60 seconds, which each correct answer adding one point. Scores are tallied from parts 1 and 2, with higher scores (no limit, only based on time) indicating better language, semantic memory, and processing ability.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Colour Trials Test (Cognitive function assessments)
The colour trails test assesses sustained and dividend attention, and executive function involving parts 1 - connecting numbered circles in sequence and part 2 - requires alternating between circles of different colours (pink and yellow) while connecting them in numerical order. The time taken to complete parts 1 and 2 are recorded (as well as errors) with faster time indicating better attention and cognitive flexibility.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Anxiety Inventory (Neuropsycological assessment)
The geriatric anxiety inventory is a self-reported assessment to identify anxiety syndromes in elderly individuals, through a series of 20 questions (with minimum of 0 and maximum score of 20) with a higher score indicating the possibility of underlying anxiety and greater than 9 indicating the possibility of an underlying anxiety disorder. At the conclusion of the study a reduction or absence of change is expected in the geriatric anxiety score.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Depression Scale (Neuropsycological assessment)
The geriatric depression scale is a self-reported assessment to identify depressive symptoms in elderly individuals, through a series of 15 guided questions (with minimum of 0 and maximum score of 15) with a higher score indicating greater severity and greater than 5 indicating the possibility of an underlying depressive syndromes. At the conclusion of the study a reduction or absence of change is expected in the geriatric depression scale.
Measured: 12 months (assessed baseline, 6 months and 12 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2018
- Study start1 Aug 2019
- Primary completion31 Dec 2023
- Study completion31 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Mild Cognitive ImpairmentStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, double-blinded, placebo-controlled study
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- National University of Singapore, National University Health System, Singapore
- Responsible party
- Sponsor
- Investigators
- Rathi Mahendran, Principal investigator, National University of SingaporeBarry Halliwell, Principal investigator, National University of SingaporeChristopher Chen, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03641404
- Sponsor's protocol ID
- 2017/00982
- Other IDs
- 1823117J (Clinical Trial No.), 2017
- Status last verified
- May 2018
- First submitted
- 16 Jul 2018
- Last updated
- 11 Jun 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Halliwell B, Cheah IK, Tang RMY. Ergothioneine - a diet-derived antioxidant with therapeutic potential. FEBS Lett. 2018 Oct;592(20):3357-3366. doi: 10.1002/1873-3468.13123. Epub 2018 Jun 15.
PubMed 29851075Cheah IK, Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta. 2012 May;1822(5):784-93. doi: 10.1016/j.bbadis.2011.09.017. Epub 2011 Oct 4.
PubMed 22001064Halliwell B, Cheah IK, Drum CL. Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis. Biochem Biophys Res Commun. 2016 Feb 5;470(2):245-250. doi: 10.1016/j.bbrc.2015.12.124. Epub 2016 Jan 6.
PubMed 26772879Cheah IK, Feng L, Tang RMY, Lim KHC, Halliwell B. Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration? Biochem Biophys Res Commun. 2016 Sep 9;478(1):162-167. doi: 10.1016/j.bbrc.2016.07.074. Epub 2016 Jul 19.
PubMed 27444382Cheah IK, Tang RM, Yew TS, Lim KH, Halliwell B. Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. Antioxid Redox Signal. 2017 Feb 10;26(5):193-206. doi: 10.1089/ars.2016.6778. Epub 2016 Sep 7.
PubMed 27488221Tang RMY, Cheah IK, Yew TSK, Halliwell B. Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Sci Rep. 2018 Jan 25;8(1):1601. doi: 10.1038/s41598-018-20021-z.
PubMed 29371632Gruber J, Fong S, Chen CB, Yoong S, Pastorin G, Schaffer S, Cheah I, Halliwell B. Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv. 2013 Sep-Oct;31(5):563-92. doi: 10.1016/j.biotechadv.2012.09.005. Epub 2012 Sep 27.
PubMed 23022622Halliwell B, Cheah I. Are age-related neurodegenerative diseases caused by a lack of the diet-derived compound ergothioneine? Free Radic Biol Med. 2024 May 1;217:60-67. doi: 10.1016/j.freeradbiomed.2024.03.009. Epub 2024 Mar 14.
PubMed 38492784Halliwell B, Tang RMY, Cheah IK. Diet-Derived Antioxidants: The Special Case of Ergothioneine. Annu Rev Food Sci Technol. 2023 Mar 27;14:323-345. doi: 10.1146/annurev-food-060822-122236. Epub 2023 Jan 9.
PubMed 36623925Wu LY, Cheah IK, Chong JR, Chai YL, Tan JY, Hilal S, Vrooman H, Chen CP, Halliwell B, Lai MKP. Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia. Free Radic Biol Med. 2021 Dec;177:201-211. doi: 10.1016/j.freeradbiomed.2021.10.019. Epub 2021 Oct 19.
PubMed 34673145Cheah IK, Ng LT, Ng LF, Lam VY, Gruber J, Huang CYW, Goh FQ, Lim KHC, Halliwell B. Inhibition of amyloid-induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model. FEBS Lett. 2019 Aug;593(16):2139-2150. doi: 10.1002/1873-3468.13497. Epub 2019 Jun 30.
PubMed 31211853Wu LY, Kan CN, Cheah IK, Chong JR, Xu X, Vrooman H, Hilal S, Venketasubramanian N, Chen CP, Halliwell B, Lai MKP. Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics. Antioxidants (Basel). 2022 Aug 30;11(9):1717. doi: 10.3390/antiox11091717.
PubMed 36139790Cheah IK, Halliwell B. Ergothioneine, recent developments. Redox Biol. 2021 Jun;42:101868. doi: 10.1016/j.redox.2021.101868. Epub 2021 Jan 26.
PubMed 33558182Yau YF, Cheah IK, Mahendran R, Tang RM, Chua RY, Goh RE, Feng L, Li J, Kua EH, Chen C, Halliwell B. Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study. J Alzheimers Dis. 2024 Dec;102(3):841-854. doi: 10.1177/13872877241291253. Epub 2024 Nov 15.
PubMed 39544014
Study at a glance
From the registry record, last updated by the sponsor on 11 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study to Investigate the Efficacy of Ergothioneine to Delay Cognitive Decline in Mild Cognitively Impaired Subjects
- ClinicalTrials.gov ID
- NCT03641404
- Acronym / sponsor ID
- 2017/00982
- Conditions
- Mild Cognitive Impairment
- Keywords
- ergothioneine, mild cognitive impairment, dementia, dietary antioxidant
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Collaborators
- National University of Singapore, National University Health System, Singapore
- Study start
- 1 Aug 2019 (actual)
- Primary completion
- 31 Dec 2023 (actual)
- Study completion
- 31 Dec 2023 (actual)
- First posted
- 22 Aug 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
With the growing burden of dementia (including Alzheimer's disease), and the lack of efficacious therapies, there is an urgent need to identify new therapeutics.
Ergothioneine (ET) is a naturally occurring thiol derivative of histidine, obtained solely through diet and is able to accumulate in the body and brain, through the action of a specific transporter, OCTN1. In addition to a wide variety of in vitro and in vivo (animal) studies demonstrating the antioxidant, anti-inflammatory properties of ET, several studies have demonstrated the neuroprotective potential of ET in various cell and animal models.
Based on the ability of ET to counteract the underlying pathology of AD dementia, it is hypothesize that ET supplementation may prevent cognitive decline, especially in individuals at risk of cognitive impairment. This will be assessed using a randomized, double blinded, placebo-controlled, intervention study to test the ability of ET to delay or reverse cognitive impairment in elderly individuals with mild cognitive impairment.
Detailed description
Ergothioneine (ET) is a naturally occurring thiol/thione obtained in humans solely through diet. It is able to accumulate in specific cells and tissues (including the brain), via a specific transporter, OCTN1, at high levels. Although the exact physiological function(s) of ET have yet to be elucidated, numerous reports have demonstrated that this compound can scavenge reactive oxygen species (such as hydroxyl radicals, hypochlorous acid, and peroxynitrite), modulate inflammation, and chelate divalent metal ions. These processes are all implicated in the pathology of dementia. Various studies in cell and animal models have also highlighted the potential neuroprotective capabilities of ET following insult by various neurotoxic agents such as cisplatin and amyloid beta peptide.
Studies demonstrated that ET dose-dependently protected PC12 cells against beta amyloid-induced apoptotic death, and later was shown to protect against neuronal injury caused by direct administration of amyloid beta into the mouse hippocampus, thereby increasing scores in active avoidance and water maze tests. ET also dose-dependently extend lifespan of a transgenic Caenorhabditis elegans model of AD by reducing amyloid oligomer formation. Other studies also demonstrated that ET is also able to attenuate oxidative stress and prevents cognitive deficits in a D-galactose-induced dementia mouse model; protect against N-methyl-D-aspartate-induced cytotoxicity in rat retinal neurons; and prevent cisplatin-induced neuronal damage in cell cultures and mice.
To date no studies have evaluated the therapeutic ability of ET, clinically, to delay or halt cognitive decline. Prior studies administering pure ET to humans provide insights into the pharmacokinetics and demonstrate the safety of this compound, laying the foundations for this clinical study. The present proposal will shed light onto a relatively lesser known natural compound and the therapeutic capabilities it possesses, which has the potential to significantly impact the economic and societal burdens of dementia.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomized, double-blinded, placebo-controlled study
| Arm | Type | Receives |
|---|---|---|
| Ergothioneine | Active comparator | Drug: L-ergothioneineSubjects will consume 25mg ergothioneine (capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks. |
| Placebo | Placebo comparator | Drug: PlaceboSubjects will be given placebo (99% microcrystalline cellulose, 1% magnesium stearate; capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks. |
Who may qualify
- Ages
- 60 to 90 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Elderly individuals 60 - 90 years of age
- Chinese ethnicity (from other local cohort studies)
- Demonstrate amnestic mild cognitive impairment (assessed by panel of psychiatrists)
- Independent and able to travel to study site without assistance
- No other severe underlying conditions or terminal illnesses
Key exclusion criteria (9 listed)
- Inability to understand the risks and requirements of the study for any reason
- Any intolerance to lactose, and/or allergies to mushrooms
- History of cardiovascular complications, diabetes, hypertension or hypercholesterolemia, or other pre-existing condition that may prevent them from completing the study
- Evidence of anaemia or other significant haematological conditions
- History or mental illness, depression or other underlying psychiatric illnesses
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-ergothioneineErgothioneine is naturally occurring thiol compound obtained solely from diet in humans. Ergothioneine is widely reported to be a natural antioxidant and anti-inflammatory compound. In addition we hypothesize that this compound will be beneficial in improving cognition. | Drug | Ergothioneine |
| PlaceboPlacebo. Study control (99% microcrystalline cellulose, 1% magnesium stearate) | Drug | Placebo |
Primary outcome
Demonstrating uptake of ergothioneine following dietary supplementation
Time frame: 12 months
This pilot study will evaluate the ability of oral ergothioneine supplementation to raise levels of ergothioneine in the body (blood measurements) over the one year period
Demonstrate safety of oral ergothioneine supplementation
Time frame: 12 months
This study will evaluate the safety oral ergothioneine supplementation over a period of 12 months. Safety is monitored through monthly visits (assessment and feedback on adverse reactions) and quarterly blood assessment (blood counts, liver and renal function).
Evaluating the impact of ergothioneine supplementation to modulate oxidative damage
Time frame: Over 12 months
The ability of oral ergothioneine supplementation to modulate oxidative stress in the subjects will be assessed through changes in plasma and urinary oxidative damage biomarkers collected at baseline and quarterly (every 3 months) over the 12-month study duration.
Evaluate the impact of ergothioneine supplementation to modulate inflammation
Time frame: Over 12 months
The ability of oral ergothioneine supplementation to modulate inflammatory status in the subjects will be assessed through measurement of inflammatory cytokines in the plasma at baseline and quarterly (every 3 months) over the 12-month study duration.
11 secondary outcomes
Assessment of plasma neurofilament light chain (NfL) protein levels
Time frame: 12 months (assessed at baseline and every 3 months)
Evaluation of cognition using the Singapore Modified - Mini Mental State Examination Scores (Cognitive function assessment)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of dementia stage using the Clinical Dementia Rating Scale (CDR).
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological test battery: Rey Auditory Verbal Learning Test (Cognitive function assessment)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Digit Span test (Cognitive function assessments)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Block Design Test (Cognitive function assessment)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Symbol Digit Modality Test scores (Cognitive function assessment)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Semantic Verbal Fluency Test (Cognitive function assessment)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Colour Trials Test (Cognitive function assessments)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Anxiety Inventory (Neuropsycological assessment)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Depression Scale (Neuropsycological assessment)
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jun 2025.
- Background: PubMed 29851075Halliwell B, Cheah IK, Tang RMY. Ergothioneine - a diet-derived antioxidant with therapeutic potential. FEBS Lett. 2018 Oct;592(20):3357-3366. doi: 10.1002/1873-3468.13123. Epub 2018 Jun 15.
- Background: PubMed 22001064Cheah IK, Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta. 2012 May;1822(5):784-93. doi: 10.1016/j.bbadis.2011.09.017. Epub 2011 Oct 4.
- Background: PubMed 26772879Halliwell B, Cheah IK, Drum CL. Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis. Biochem Biophys Res Commun. 2016 Feb 5;470(2):245-250. doi: 10.1016/j.bbrc.2015.12.124. Epub 2016 Jan 6.
- Background: PubMed 27444382Cheah IK, Feng L, Tang RMY, Lim KHC, Halliwell B. Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration? Biochem Biophys Res Commun. 2016 Sep 9;478(1):162-167. doi: 10.1016/j.bbrc.2016.07.074. Epub 2016 Jul 19.
- Background: PubMed 27488221Cheah IK, Tang RM, Yew TS, Lim KH, Halliwell B. Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. Antioxid Redox Signal. 2017 Feb 10;26(5):193-206. doi: 10.1089/ars.2016.6778. Epub 2016 Sep 7.
- Background: PubMed 29371632Tang RMY, Cheah IK, Yew TSK, Halliwell B. Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Sci Rep. 2018 Jan 25;8(1):1601. doi: 10.1038/s41598-018-20021-z.
- Background: PubMed 23022622Gruber J, Fong S, Chen CB, Yoong S, Pastorin G, Schaffer S, Cheah I, Halliwell B. Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv. 2013 Sep-Oct;31(5):563-92. doi: 10.1016/j.biotechadv.2012.09.005. Epub 2012 Sep 27.
- Background: PubMed 38492784Halliwell B, Cheah I. Are age-related neurodegenerative diseases caused by a lack of the diet-derived compound ergothioneine? Free Radic Biol Med. 2024 May 1;217:60-67. doi: 10.1016/j.freeradbiomed.2024.03.009. Epub 2024 Mar 14.
- Background: PubMed 36623925Halliwell B, Tang RMY, Cheah IK. Diet-Derived Antioxidants: The Special Case of Ergothioneine. Annu Rev Food Sci Technol. 2023 Mar 27;14:323-345. doi: 10.1146/annurev-food-060822-122236. Epub 2023 Jan 9.
- Background: PubMed 34673145Wu LY, Cheah IK, Chong JR, Chai YL, Tan JY, Hilal S, Vrooman H, Chen CP, Halliwell B, Lai MKP. Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia. Free Radic Biol Med. 2021 Dec;177:201-211. doi: 10.1016/j.freeradbiomed.2021.10.019. Epub 2021 Oct 19.
- Background: PubMed 31211853Cheah IK, Ng LT, Ng LF, Lam VY, Gruber J, Huang CYW, Goh FQ, Lim KHC, Halliwell B. Inhibition of amyloid-induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model. FEBS Lett. 2019 Aug;593(16):2139-2150. doi: 10.1002/1873-3468.13497. Epub 2019 Jun 30.
- Background: PubMed 36139790Wu LY, Kan CN, Cheah IK, Chong JR, Xu X, Vrooman H, Hilal S, Venketasubramanian N, Chen CP, Halliwell B, Lai MKP. Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics. Antioxidants (Basel). 2022 Aug 30;11(9):1717. doi: 10.3390/antiox11091717.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rathi Mahendran principal investigator
National University of Singapore
Barry Halliwell principal investigator
National University of Singapore
Christopher Chen principal investigator
National University Hospital, Singapore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing L-ergothioneine in people with Mild Cognitive Impairment, run by National University Hospital, Singapore at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Demonstrating uptake of ergothioneine following dietary supplementation (time frame: 12 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03641404, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2025.