Cholinergic Blocker for Cognitive Impairment

Overseen By Kimberly Albert, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Vanderbilt University Medical Center

Disqualifiers: Stroke, Epilepsy, others

Compensation: Varies

Number of Visits: 2

Duration: 1 day per visit, 2 visits total

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 SCD compared to those without SCD.

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.

What data supports the effectiveness of the drug Mecamylamine for cognitive impairment?

The research suggests that the cholinergic system, which Mecamylamine affects, plays a role in cognitive processes. However, studies show that blocking nicotinic receptors with Mecamylamine can lead to cognitive impairments, particularly in memory, which may not support its effectiveness for improving cognitive impairment. ^{1 2 3 4 5}

Is the cholinergic blocker Mecamylamine safe for humans?

Mecamylamine has been studied for various conditions and is known to cause cognitive impairments, especially at higher doses, and older adults may be more sensitive to these effects. It can also cause side effects related to its action on the nervous system, but at lower doses, it has been used safely in research settings. ^{3 4 6 7 8}

How does the drug differ from other treatments for cognitive impairment?

This drug is unique because it targets both muscarinic and nicotinic receptors, which are involved in memory and attention processes. By blocking these receptors, it may provide a more comprehensive approach to addressing cognitive impairments compared to treatments that target only one type of receptor. ^{2 3 4 6 9}

Research Team

Paul Newhouse, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for non-smoking adults aged 55 or older who have mild cognitive issues but are generally in good health. They should score above 25 on the MoCA test, indicating only slight memory concerns, and have a GDS rating below 3, showing minimal daily life impact.

Inclusion Criteria

You do not smoke cigarettes or tobacco products.

You have a good score on a test called Montreal Cognitive Assessment (MoCA), which measures your memory and thinking skills, and your Global Deterioration Scale (GDS) rating shows that you have mild or no cognitive impairment.

I am 55 years old or older.

Exclusion Criteria

I have a primary neurological disorder like stroke or epilepsy.

I cannot take certain medications due to health risks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo anticholinergic or placebo challenge with cognitive testing and EEG sessions

1 day per visit, 2 visits total

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 tests how an anticholinergic drug called Mecamylamine affects attention in aging individuals with slight cognitive decline. Participants will be compared to those taking a placebo while their brain activity and attention performance are monitored using EEG and specific tests.

Participant Groups

Group I: Anticholinergic Challenge Experimental Treatment 1 Intervention

All participants will receive oral mecamylamine or IV scopolamine for 1 day

Group II: Placebo Challenge Placebo Group 1 Intervention

All participants will receive oral placebo for 1 day

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Findings from Research

A 7-day treatment with a low dose of galantamine, an acetylcholinesterase inhibitor, improved late episodic learning and delayed recall in subjects with mild cognitive impairment (MCI), suggesting that enhancing cholinergic neurotransmission can benefit memory function.

Functional MRI results indicated that galantamine treatment increased activity in the hippocampal region during spatial navigation, highlighting the importance of the cholinergic system in memory processes for individuals with MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. Grön, G., Brandenburg, I., Wunderlich, AP., et al.[2013]

The combination of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight elderly volunteers showed a trend toward greater memory impairment compared to scopolamine alone, suggesting that this drug combination may more accurately mimic the memory deficits seen in Alzheimer's disease.

Physiological changes, such as increased pupil size and alterations in blood pressure and pulse, were observed with the combined drug treatment, indicating that this pharmacologic model could provide insights into the mechanisms of memory failure in Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses. Little, JT., Johnson, DN., Minichiello, M., et al.[2018]

In a study involving 15 healthy males, the muscarinic antagonist scopolamine significantly impaired memory performance, specifically in free recall and recognition tasks, highlighting its role in cognitive processes.

The nicotinic antagonist mecamylamine did not affect cognitive performance, suggesting that the muscarinic receptor system plays a more critical role in memory compared to the nicotinic system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive performance and cholinergic transmission: influence of muscarinic and nicotinic receptor blockade. Voss, B., Thienel, R., Reske, M., et al.[2021]

A study involving 27 healthy participants (12 young males and 15 elderly subjects) found that the nicotinic antagonist mecamylamine significantly impaired learning abilities, particularly at a 20-mg dose, indicating its potential to mimic cognitive deficits seen in Alzheimer's and Parkinson's diseases.

Elderly subjects were more sensitive to mecamylamine, with a 10-mg dose causing significant learning impairments not observed in younger participants, highlighting age-related differences in nicotinic receptor function and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. Newhouse, PA., Potter, A., Corwin, J., et al.[2015]

The M1 muscarinic acetylcholine receptor positive allosteric modulator (PAM) VU0453595 enhances arousal and cognition in young animals without disrupting sleep/wake architecture, showing promise for treating age-related cognitive decline.

Unlike traditional treatments like donepezil, which can cause adverse effects, VU0453595 was effective in improving REM sleep duration in aged mice without inducing cholinergic side effects in nonhuman primates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of arousal and sleep/wake architecture by M1 PAM VU0453595 across young and aged rodents and nonhuman primates. Gould, RW., Russell, JK., Nedelcovych, MT., et al.[2022]

Scopolamine, a muscarinic antagonist, significantly disrupted working memory performance in rats, especially in tasks with longer delays, indicating that muscarinic receptors play a crucial role in working memory.

Mecamylamine, a nicotinic antagonist, showed a more complex effect; while it disrupted performance at higher doses, it also enhanced working memory under certain delay conditions, suggesting that nicotinic receptors may have a protective role in memory tasks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential effects of scopolamine and mecamylamine on working and reference memory in the rat. Moran, PM.[2019]

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]

The study found that the nicotinic antagonist mecamylamine impaired memory performance in rats during a passive avoidance task, indicating the importance of the central nicotinic cholinergic system in learning and memory.

Mecamylamine inhibited the synthesis of acetylcholine in various brain regions, suggesting that presynaptic nicotinic receptors play a crucial role in regulating cholinergic activity and may be key to understanding memory processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation of the amnestic effects of nicotinic antagonists with inhibition of regional brain acetylcholine synthesis in rats. Elrod, K., Buccafusco, JJ.[2015]

In a study involving 12 healthy young volunteers, antagonism of muscarinic receptors with scopolamine led to significant cognitive deficits in working memory, declarative memory, visual attention, and psychomotor speed, while nicotinic receptor antagonism with mecamylamine showed no effects on cognition.

The simultaneous blockade of both muscarinic and nicotinic receptors resulted in even greater cognitive impairments than muscarinic blockade alone, particularly affecting working memory and attention, indicating that these receptors may interact synergistically and suggesting potential therapeutic strategies that target both systems for cognitive enhancement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. Ellis, JR., Ellis, KA., Bartholomeusz, CF., et al.[2019]

References

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

Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. [2013]

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

Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

Cognitive performance and cholinergic transmission: influence of muscarinic and nicotinic receptor blockade. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. [2015]

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

Modulation of arousal and sleep/wake architecture by M1 PAM VU0453595 across young and aged rodents and nonhuman primates. [2022]

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

Differential effects of scopolamine and mecamylamine on working and reference memory in the rat. [2019]

7. England pubmed.ncbi.nlm.nih.gov

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

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

Correlation of the amnestic effects of nicotinic antagonists with inhibition of regional brain acetylcholine synthesis in rats. [2015]

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

Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. [2019]