Mecamylamine Challenge for Cognitive Impairment

(AMoCC-SCD Trial)

Overseen By Kimberly Albert, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Vanderbilt University Medical Center

Disqualifiers: Stroke, Epilepsy, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 1 week

80 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will use an anticholinergic pharmacological probe to examine attention network function in SCD using EEG. The overall hypothesis is that in older adults with SCD, normal cognitive performance is maintained by compensatory attention network activity, supported by enhanced cholinergic function. The investigators anticipate that SCD will be associated with greater compensatory attention network activity and that disrupting this compensatory process through anticholinergic challenge will result in a greater negative effect on attentional performance (Attention Network Test, ANT) and attention network functioning (EEG) in older adults with greater subjective cognitive concern.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is Mecamylamine safe for human use?

Mecamylamine, originally used for high blood pressure, is now studied at lower doses for various brain-related conditions. It has been used in research for disorders like addiction and depression, and while it has side effects at high doses, it is generally considered safe at lower doses used in recent studies. ^{1 2 3 4 5}

How is the drug Mecamylamine unique for treating cognitive impairment?

Mecamylamine is unique because it acts as a nicotinic acetylcholine receptor antagonist, which means it blocks certain receptors in the brain involved in cognitive processes. Unlike other treatments, it can cross the blood-brain barrier at low doses, potentially reducing side effects while targeting central nervous system disorders. ^{1 6 7 8 9}

Research Team

Paul Newhouse, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for non-smokers aged 55 or older who feel their memory isn't as good as it used to be but can still score above 25 on a cognitive test (MoCA) and have mild concerns about their memory without serious impairment. People with medical issues that make the drug risky, or major brain conditions like stroke or epilepsy cannot join.

Inclusion Criteria

Montreal Cognitive Assessment (MoCA) score must be greater than 25 AND Global Deterioration Scale (GDS) rating must be less than 3

Must be non-smokers

I am 55 years old or older.

Exclusion Criteria

I cannot take certain medications due to health risks.

I have a history of a major brain disorder like stroke or epilepsy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants undergo two study visits with double-blinded administration of mecamylamine or placebo, including cognitive testing and EEG sessions

1 week

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Mecamylamine
• Placebo Comparator Challenge

Trial Overview The study is testing how an anticholinergic drug called Mecamylamine affects attention in people with slight memory concerns by comparing it to a placebo. Researchers will use EEGs to look at brain activity and tests of attention to see if the drug changes how well participants can focus.

Participant Groups

Group I: Anticholinergic Challenge Experimental Treatment 1 Intervention

All participants will receive oral mecamylamine for 1 day

Group II: Placebo Challenge Placebo Group 1 Intervention

All participants will receive oral placebo for 1 day

Mecamylamine is already approved in United States, Canada for the following indications:

Approved in United States as Inversine for:

• Hypertension
• Nicotine dependence

Approved in Canada as Inversine for:

• Hypertension

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Findings from Research

Mecamylamine, originally used as an antihypertensive agent, is now being explored for its effectiveness at much lower doses (2.5 - 10 mg) in blocking nicotine's effects and treating neuropsychiatric disorders due to its ability to cross the blood-brain barrier.

Recent Phase II clinical trials have shown that mecamylamine may have antidepressant effects and could serve as an augmentation therapy for patients with major depression who do not respond to standard SSRI treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders. Bacher, I., Wu, B., Shytle, DR., et al.[2013]

In a study involving 60 adults aged 50-79, memantine was found to improve attention and information processing speed in individuals with Age-Associated Memory Impairment (AAMI) over a 90-day treatment period.

The treatment was well-tolerated, with no significant differences in adverse events between those taking memantine and those on a placebo, indicating its safety for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI). Ferris, S., Schneider, L., Farmer, M., et al.[2013]

A six-month study involving 50 patients with mild to moderate Alzheimer's disease found that both original memantine and the generic version (memantal) showed similar efficacy in improving cognitive functions and neuropsychiatric symptoms.

There were no significant differences in safety or effectiveness between the two medications, indicating that the generic memantal is a viable alternative to the original memantine for treating dementia in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of the efficacy and safety of memantal and original memantine in the treatment of mild and moderate dementia in Alzheimer's disease]. Shiryaev, OY., Shapovalov, DL., Polozova, TM., et al.[2018]

Memantine, used for treating moderate to severe Alzheimer's disease, has been shown to have a favorable safety and tolerability profile, with adverse events similar in frequency to those experienced by patients on placebo, based on data from 2311 patients in six trials lasting at least 24 weeks.

The analysis indicates that both short- and long-term treatment with memantine is safe, with minimal adverse effects, and discontinuation rates due to side effects were comparable between memantine and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine for the treatment of Alzheimer's disease: tolerability and safety data from clinical trials. Farlow, MR., Graham, SM., Alva, G.[2021]

A review of cardiovascular adverse drug reactions (ADRs) associated with memantine identified 36 cases, including 18 reports of bradycardia, indicating a potential link between memantine and heart-related side effects.

Most cases of bradycardia resolved after discontinuing memantine, suggesting that while memantine may cause cardiac ADRs, the exact mechanism behind these effects is still not well understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does memantine induce bradycardia? A study in the French PharmacoVigilance Database. Gallini, A., Sommet, A., Montastruc, JL.[2013]

Memantine is a groundbreaking medication for moderate to severe Alzheimer's disease, acting as a moderate-affinity, uncompetitive NMDA receptor antagonist that helps to regulate glutamate activity in the brain.

Since its FDA approval in 2003, memantine has been shown to improve cognitive function, reduce behavioral issues, enhance daily living activities, and delay the need for institutional care in patients, especially when used alongside donepezil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Classics in Chemical Neuroscience: Memantine. Alam, S., Lingenfelter, KS., Bender, AM., et al.[2022]

In a double-blind, randomized, placebo-controlled trial involving subjects with multiple sclerosis and cognitive impairment, memantine did not show any significant improvement in cognitive performance compared to placebo, as measured by the PASAT and CVLT-II tests.

While memantine was generally safe with no serious adverse events reported, it was associated with increased fatigue and neurological side effects, and family members reported less cognitive improvement and more neuropsychiatric symptoms in those taking memantine compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Lovera, JF., Frohman, E., Brown, TR., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders. [2013]

2. England pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI). [2013]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[A comparison of the efficacy and safety of memantal and original memantine in the treatment of mild and moderate dementia in Alzheimer's disease]. [2018]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Memantine for the treatment of Alzheimer's disease: tolerability and safety data from clinical trials. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Does memantine induce bradycardia? A study in the French PharmacoVigilance Database. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Potential therapeutic uses of mecamylamine and its stereoisomers. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Classics in Chemical Neuroscience: Memantine. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Memantine: Updating a rare success story in pro-cognitive therapeutics. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. [2021]