Donepezil + Cognitive Training for Alcoholism

Overseen By Gihyun Yoon, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Connecticut Healthcare System

Must not be taking: Opioids, Benzodiazepines

Disqualifiers: Psychotic disorder, Unstable cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 13 weeks

160 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining donepezil with cognitive training can reduce heavy drinking in individuals with alcohol use disorder. Participants will be randomly assigned to one of four groups: donepezil with cognitive training, donepezil with placebo training, placebo medication with cognitive training, or both placebo medication and training. The trial is suitable for those with alcohol use disorder who have experienced at least one heavy drinking day in the past month and are willing to attend follow-up visits over 13 weeks. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you do not currently take opioids or benzodiazepines, as these may affect new learning. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that donepezil is generally safe for use. Doctors often prescribe it for Alzheimer's disease, indicating trust in its long-term use. Common side effects include nausea, diarrhea, and trouble sleeping, but these are usually mild.

Cognitive Remediation Therapy (CRT) differs slightly. It acts like a workout for the brain, aiming to improve thinking skills. Studies have shown that people tolerate this therapy well, with no major side effects reported. It aids individuals with substance use issues by enhancing brain function, which can help reduce substance use.

In this trial, participants will receive either donepezil and CRT together or a placebo version of them. Since both donepezil and CRT are known to be safe, joining this trial should involve minimal risk based on existing research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for alcoholism because they combine medication with cognitive training in a novel way. Unlike standard treatments that often rely on counseling or medication alone, the experimental treatment uses donepezil, a drug typically used for Alzheimer's, to potentially enhance cognitive function. Additionally, combining donepezil with Cognitive Remediation Therapy (CRT) could offer a dual approach: improving cognitive deficits and addressing alcohol use, which is not a typical focus of current treatments. This innovative combination aims to provide more comprehensive support for individuals struggling with alcoholism.

What evidence suggests that this trial's treatments could be effective for alcohol use disorder?

Research has shown that donepezil, a drug often used for Alzheimer's, might help people with alcohol use disorder by improving brain function. Some studies suggest it can enhance thinking skills, potentially leading to better decision-making and less drinking. In this trial, one group of participants will receive both donepezil and cognitive remediation therapy (CRT), while another group will receive donepezil with placebo CRT. CRT has gained attention for its ability to improve thinking and help manage emotions, both crucial for overcoming addiction. Although research is ongoing, CRT is considered a helpful tool for recovery in people dealing with alcohol use. Together, donepezil and CRT could form a strong combination to help reduce heavy drinking. ^{1 2 6 7 8}

Who Is on the Research Team?

Gihyun Yoon, MD

Principal Investigator

Yale University, VA Connecticut Healthcare System

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with alcohol use disorder who can read English at a 6th grade level or higher. Participants must have had heavy drinking days recently and be willing to attend follow-ups and undergo Breathalyzer and urine tests. Exclusions include those with certain mental health conditions, current opioid/benzodiazepine treatment, significant cognitive impairments, sensory issues affecting training, legal/incarceration risks, unstable housing or medical conditions, low IQ estimates, pregnancy/nursing women, or donepezil allergies.

Inclusion Criteria

Last alcohol use and at least one heavy drinking day within the past 30 days

I can fluently speak and read English at a 6th grade level or higher.

Willingness to submit to Urine Toxicology screenings

Exclusion Criteria

Pre-morbid intelligence quotient (IQ) estimate below 70

Unstable cardiovascular disease or unstable medical condition-clinically determined by a physician

Residential plans that would interfere with participation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive donepezil and cognitive remediation therapy or placebo for 13 weeks

13 weeks

Weekly visits for Time Line Follow Back (TLFB) assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cognitive Remediation Therapy (CRT)
• Donepezil

Trial Overview

The study is testing if donepezil combined with cognitive remediation therapy (CRT) helps reduce heavy drinking in people with alcohol use disorder more effectively than placebo treatments. It's a double-blind trial where participants are randomly assigned to receive either the drug plus CRT, the drug plus placebo CRT, placebo medication plus CRT or both placebos.

How Is the Trial Designed?

Group I: Placebo medication + Placebo CRT Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) placebo medication and (2) placebo CRT. Subjects will take placebo oral medication in the evening for the first 4 weeks, then placebo oral medication in the evening until week 13.

Group II: Placebo medication + Cognitive remediation therapy (CRT) Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) placebo medication and (2) cognitive remediation therapy (CRT). Subjects will take placebo oral medication in the evening for the first 4 weeks, then placebo oral medication in the evening until week 13.

Group III: Donepezil + Placebo CRT Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) donepezil and (2) placebo CRT. Subjects will take 5 mg/day of oral donepezil in the evening for the first 4 weeks, then 10 mg/day of oral donepezil in the evening until week 13.

Group IV: Donepezil + Cognitive remediation therapy (CRT) Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) donepezil and (2) cognitive remediation therapy (CRT). Subjects will take 5 mg/day of oral donepezil in the evening for the first 4 weeks, then 10 mg/day of oral donepezil in the evening until week 13.

Cognitive Remediation Therapy (CRT) is already approved in United States, European Union for the following indications:

Approved in United States as Cognitive Remediation Therapy for:

• Alcohol Use Disorder
• Schizophrenia
• Attention Deficit Disorders
• Brain Injury
• Mood Disorders

Approved in European Union as Cognitive Remediation Therapy for:

• Schizophrenia
• Attention Deficit Disorders
• Brain Injury
• Mood Disorders

Who Is Running the Clinical Trial?

VA Connecticut Healthcare System

Lead Sponsor

Trials

86

Recruited

8,800+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Published Research Related to This Trial

In a 12-week study involving 468 patients with mild to moderately severe Alzheimer disease, donepezil hydrochloride significantly improved cognitive function and clinical outcomes compared to placebo, with notable improvements in ADAS-cog and CIBIC plus scores.

Donepezil was well-tolerated, with a similar incidence of side effects compared to placebo, and did not show the hepatotoxic effects seen with other cholinesterase inhibitors, making it a safe option for treating Alzheimer's symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Rogers, SL., Doody, RS., Mohs, RC., et al.[2022]

A 30-week double-blind study in the US showed that Donepezil (5 or 10 mg) significantly improved cognitive and clinical assessments compared to placebo, indicating its efficacy in treating cognitive decline.

The use of Donepezil in the UK emphasizes the importance of addressing non-cognitive behaviors, which can greatly enhance quality of life, alongside cognitive improvements, without significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with Donepezil (Aricept) in the UK. Wilkinson, D.[2019]

In a study involving 509 alcohol-dependent patients, those who received Cognitive Bias Modification (CBM) training showed significantly lower relapse rates one year after treatment compared to those who only received standard treatment.

The effectiveness of CBM was linked to changes in alcohol-approach bias, with older patients and those with a strong initial approach bias benefiting the most from the intervention, suggesting that CBM can effectively address maladaptive cognitive processes in alcoholism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approach bias modification in alcohol dependence: do clinical effects replicate and for whom does it work best? Eberl, C., Wiers, RW., Pawelczack, S., et al.[2022]

In a 24-week study involving 30 adults with Down syndrome and mild to moderate Alzheimer's disease, donepezil was found to be generally safe and well-tolerated, with no life-threatening side effects reported.

While the results showed some potential efficacy, with 50% of donepezil patients improving in dementia scores compared to 31% on placebo, the small sample size limited the statistical significance of these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study. Prasher, VP., Huxley, A., Haque, MS.[2019]

Cognitive remediation therapy was implemented successfully in a study of 16 abstinent alcohol-dependent patients over 6 months, showing significant improvements in cognitive performance as measured by the Mini-Mental State Examination (MMSE) and the Memory Alteration Test (M@T).

The therapy was well-received by participants, indicating high satisfaction and viability, suggesting that cognitive remediation can be an effective intervention for cognitive impairments in alcohol-dependent patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remediation therapy in patients with alcohol use disorders and neurocognitive disorders: A Pilot Study. Frías-Torres, C., Moreno-España, J., Ortega, L., et al.[2019]

Cognitive remediation (CR) therapy significantly improved cognitive functioning, particularly in attention and memory, in 41 alcohol-dependent inpatients who received 12 sessions of CR alongside conventional treatment.

Patients who underwent CR also experienced greater improvements in psychological well-being and reduced alcohol craving, suggesting that CR not only enhances cognitive abilities but also positively impacts overall treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive remediation therapy during treatment for alcohol dependence. Rupp, CI., Kemmler, G., Kurz, M., et al.[2022]

In an open-label trial involving 11 older male veterans with Alcohol Use Disorder and Mild Cognitive Impairment, the combination of donepezil and Cognitive Remediation Therapy led to significant improvements in neurocognitive functions, particularly in learning, memory, and executive function (p < .0001).

Participants also showed a high rate of clinical recovery, with 90.9% reporting improvement on the Clinical Global Impression scale, compared to 59.5% of historical controls, suggesting that this combined treatment approach may be beneficial for individuals with AUD-MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil and cognitive remediation therapy to augment treatment of alcohol use disorder related mild cognitive impairment (AUD-MCI): An open label pilot study with historical controls. Bell, MD., Pittman, B., Petrakis, I., et al.[2022]

Cognitive remediation therapy (CRT) significantly improved working memory and executive function in outpatient veterans with substance use disorders, compared to standard work therapy alone, based on a pilot study with 48 participants over 6 months.

Both treatment groups showed excellent substance use outcomes, with high rates of abstinence, indicating that while CRT enhanced cognitive functions, it did not significantly change overall substance use recovery rates compared to work therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized controlled trial of cognitive remediation and work therapy in the early phase of substance use disorder recovery for older veterans: Neurocognitive and substance use outcomes. Bell, MD., Laws, HB., Petrakis, IB.[2018]

Citations

1.

mental.jmir.org

mental.jmir.org/2025/1/e67167

Double-Blinded, Randomized Controlled Efficacy Trial Among ...

So far, evidence suggesting that cognitive training can improve alcohol-related outcomes has been scarce [ ...

2.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0740547221000362

Implementing cognitive remediation in substance use ...

CR is likely to improve outcomes for people with drug and alcohol problems in residential rehabilitation programs. This study suggests that there is strong ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3610413/

A Role for Cognitive Rehabilitation in Increasing the ...

A new generation of research aims to facilitate treatment process and improve AUD treatment outcomes by directly promoting cognitive recovery.

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10073279/

Cognitive training and remediation interventions for ...

Expert recommendations on cognitive training and remediation for SUD highlight the relevance of targeting implicit biases, reward, emotion regulation, and ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02929979

Cognitive Remediation for Alcohol Use Disorder and ...

This study will lay the groundwork to investigate the potential for cognitive training to remediate neurocognitive disruptions in other dually diagnosed SUD ...

6.

frontiersin.org

frontiersin.org/journals/public-health/articles/10.3389/fpubh.2024.1388935/full

Cognitive training interventions for substance use disorders

Cognitive training (CT) has emerged as a potential therapeutic approach for substance use disorders (SUD), aiming to restore cognitive impairments and ...

7.

sciencedirect.com

sciencedirect.com/science/article/pii/S1936657422000280

Improving treatment for people with cognitive impairment ...

Other cognitive remediation studies have demonstrated reduced substance use and re-hospitalisation rates, and achievement of functional behavioural goals.

8.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01410110

Cognitive Remediation and Work Therapy in the Initial ...

The study compares a rehabilitation program that combines work therapy with computer-based cognitive training of attention, memory and executive functions to ...