Tolcapone for Alcoholism and ADHD

Overseen By Kristen Raymond, BA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: Psychoactive medications

Disqualifiers: Substance use disorder, Psychotic, Mood, 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: 8

62 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called tolcapone to determine its effects on individuals with both alcohol use disorder (AUD) and attention-deficit/hyperactivity disorder (ADHD). Researchers aim to assess whether tolcapone influences reactions to alcohol, decision-making, and brain activity related to alcohol. Participants will receive either tolcapone or a placebo (a pill with no active medication) at different times during the study. This trial may suit individuals who have both AUD and ADHD, are not currently seeking treatment, and live near the study site. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant findings.

Do I have to stop taking my current medications to join the trial?

Yes, you must not be taking any medication for AUD, ADHD, or any psychoactive medication to participate in this trial.

Will I have to stop taking my current medications?

Yes, you must not be taking any medication for Alcohol Use Disorder (AUD) or Attention-Deficit/Hyperactivity Disorder (ADHD) to participate in this trial.

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

A study with healthy volunteers found that tolcapone did not cause any serious side effects or unusual lab results, suggesting it is generally safe when used as directed. Tolcapone is already approved for treating Parkinson's disease, indicating prior safety evaluation. Some participants in studies experienced mild side effects, such as headaches or nausea, but these were not serious. Research has shown that tolcapone is well-tolerated overall. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for alcoholism and ADHD?

Unlike the standard treatments for alcoholism, such as naltrexone, acamprosate, and disulfiram, and ADHD treatments like stimulants (e.g., methylphenidate) and non-stimulants (e.g., atomoxetine), tolcapone is intriguing because it targets the brain's dopamine regulation. Tolcapone inhibits the enzyme COMT (catechol-O-methyltransferase), which helps maintain dopamine levels in the brain. This approach could offer a new way to manage symptoms of both alcoholism and ADHD by potentially improving impulse control and reducing cravings. Researchers are excited because this dual-action on dopamine could be a game-changer for individuals struggling with both conditions simultaneously.

What evidence suggests that tolcapone might be an effective treatment for alcoholism and ADHD?

Research suggests that tolcapone, one of the treatments in this trial, might help with alcohol use disorder by increasing dopamine, a brain chemical related to reward and self-control. One study found that people taking tolcapone performed better on self-control tasks and drank less alcohol. In animal studies, tolcapone reduced alcohol consumption in alcohol-dependent rats. For ADHD, tolcapone also increases dopamine, but studies show mixed results. Some research indicates it doesn't improve attention and might worsen performance when someone is sleep-deprived. Overall, tolcapone's effects on alcohol use appear promising, but its impact on ADHD remains uncertain. Participants in this trial will receive tolcapone in one treatment period and a placebo in the other. ^{5 6 7 8 9}

Who Is on the Research Team?

Joseph P Schacht, PhD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults aged 21-65 who meet the criteria for both Alcohol Use Disorder (AUD) and Attention-Deficit/Hyperactivity Disorder (ADHD), but are not currently seeking treatment or taking medication for these conditions. Participants must live within 50 miles of the study site, be able to understand consent forms, and not have any severe medical issues or metal in their body.

Inclusion Criteria

Currently not engaged in, and does not want treatment for, AUD or ADHD

You currently meet the criteria for Alcohol Use Disorder and Attention-Deficit/Hyperactivity Disorder according to specific diagnostic assessments.

I am between 21 and 65 years old.

Exclusion Criteria

Current charges pending for a violent crime (not including DUI-related offenses)

I am not pregnant, nursing, and I use reliable contraception.

I have been diagnosed with a mental health disorder like schizophrenia, depression, or an eating disorder.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Assessment

Initial assessment visit to evaluate baseline characteristics and eligibility

1 week

1 visit (in-person)

Treatment Period 1

Participants receive either placebo or tolcapone for 8 days, including MRI scans and alcohol administration

2 weeks

3 visits (in-person)

Washout

A washout period between medication periods to clear the effects of the first treatment

1 week

Treatment Period 2

Participants receive the alternate treatment (tolcapone or placebo) for 8 days, including MRI scans and alcohol administration

2 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Tolcapone

Trial Overview The study tests if tolcapone, a drug that affects brain chemistry, changes how people with AUD/ADHD respond to alcohol, make decisions, react to alcohol cues in the brain, control impulses and focus attention compared to a placebo. It also looks at whether it affects their drinking habits.

How Is the Trial Designed?

Group I: Tolcapone then Placebo Experimental Treatment 2 Interventions

Participants in this arm will receive tolcapone during the first medication period (1 capsule containing 200 mg tolcapone on study days 1 and 2; 3 capsules containing a total of 600 mg tolcapone on study days 3-8), and placebo during the second medication period (1 capsule on study days 1 and 2; 3 capsules on study days 3-8).

Group II: Placebo then Tolcapone Experimental Treatment 2 Interventions

Participants in this arm will receive placebo during the first medication period (1 capsule on study days 1 and 2; 3 capsules on study days 3-8), and tolcapone during the second medication period (1 capsule containing 200 mg tolcapone on study days 1 and 2; 3 capsules containing a total of 600 mg tolcapone on study days 3-8).

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Published Research Related to This Trial

Nalmefene shows limited efficacy in reducing alcohol consumption among adults with alcohol dependence, with a significant reduction in the number of heavy drinking days compared to placebo, but no substantial differences in mortality or quality of life outcomes.

The analysis revealed a higher rate of withdrawals due to safety concerns in the nalmefene group compared to placebo, indicating potential safety issues that need to be considered when evaluating its use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks and Benefits of Nalmefene in the Treatment of Adult Alcohol Dependence: A Systematic Literature Review and Meta-Analysis of Published and Unpublished Double-Blind Randomized Controlled Trials. Palpacuer, C., Laviolle, B., Boussageon, R., et al.[2018]

In two large studies involving 379 patients with Parkinson's disease, tolcapone at doses of 300 and 600 mg/day significantly improved 'on' time and reduced 'off' time, indicating better motor function while on levodopa treatment.

While tolcapone was effective in enhancing motor control, the most common side effect was increased dyskinesia, although hallucinations were rare, suggesting a need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highlights of the North American and European experiences. Goetz, CG.[2019]

Tolcapone, a COMT inhibitor, showed a good oral bioavailability of approximately 60% and was rapidly absorbed, reaching peak plasma concentrations within about 2 hours after administration, indicating its potential effectiveness in treating conditions like Parkinson's disease.

Both oral and intravenous doses of tolcapone were well tolerated by the 16 healthy male volunteers in the study, and the drug demonstrated a strong relationship between plasma concentration and COMT inhibition, suggesting it could be a valuable adjunct therapy to levodopa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics after oral and intravenous administration of tolcapone, a novel adjunct to Parkinson's disease therapy. Jorga, KM., Fotteler, B., Heizmann, P., et al.[2019]

Tolcapone, a novel COMT inhibitor, was well tolerated in healthy volunteers across a wide range of doses (5 to 800 mg) without significant adverse effects or changes in vital signs.

The drug effectively inhibited COMT activity in erythrocytes by over 80% at doses of 200 mg and higher, demonstrating dose-proportional pharmacokinetics and a rapid onset of action, suggesting its potential for further study in treating Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans. Dingemanse, J., Jorga, KM., Schmitt, M., et al.[2018]

Nalmefene, used as needed for alcohol dependence, was generally well-tolerated among patients, with 74.7% experiencing treatment-emergent adverse events (TEAEs) compared to 62.7% in the placebo group, indicating a manageable safety profile.

Despite a higher dropout rate due to TEAEs in the nalmefene group (13.0% vs. 5.9% for placebo), no significant safety concerns were identified, including no increased risk of suicide-related behavior, suggesting nalmefene can be a viable option for reducing alcohol consumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme. van den Brink, W., Strang, J., Gual, A., et al.[2015]

Tolcapone, a COMT inhibitor, significantly reduced ethanol self-administration in alcohol-dependent rats, suggesting its potential as a targeted treatment for Alcohol Use Disorder (AUD).

The study found that tolcapone did not affect drinking behavior in non-dependent rats or those consuming saccharin, indicating its effects are specific to alcohol dependence, and its efficacy varied based on the estrous cycle in female rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Catechol-O-Methyltransferase inhibition and alcohol use disorder: Evaluating the efficacy of tolcapone in ethanol-dependent rats. Doyle, MR., Dirik, S., Martinez, AR., et al.[2023]

In a 12-week study involving 378 adults with alcohol dependence, those taking nalmefene as needed significantly reduced their heavy drinking days by an average of 13.1 days per month, demonstrating its efficacy in lowering alcohol consumption.

The treatment was well tolerated, with common side effects including nausea (18.3%) and dizziness (17.7%), indicating that nalmefene can be a safe option for managing alcohol dependence in primary care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene, Given as Needed, in the Routine Treatment of Patients with Alcohol Dependence: An Interventional, Open-Label Study in Primary Care. Castera, P., Stewart, E., Großkopf, J., et al.[2019]

Acamprosate and naltrexone are the only two medications approved for treating alcohol use disorders (AUDs) that have strong evidence from numerous clinical trials, making them effective options for patients.

Several off-label medications, such as topiramate and gabapentin, show promise for treating AUDs, but more research is needed to confirm their efficacy and safety in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of alcoholism - an update on approved and off-label medications. Soyka, M., Müller, CA.[2018]

In a study involving 36 older adults (over 50 years) with alcohol dependence, naltrexone was found to be well tolerated, showing no significant differences in adverse effects compared to a placebo group.

While naltrexone did not produce clinically significant adverse effects, its efficacy in treating alcohol dependence in this age group remains to be established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of naltrexone in treating older, alcohol-dependent patients. Oslin, D., Liberto, JG., O'Brien, J., et al.[2016]

Tolcapone is an effective adjunct treatment for Parkinson's disease, significantly reducing 'off' time and improving symptoms in patients who do not respond to other therapies, with a recommended dosage of 100 mg three times daily.

However, tolcapone carries risks of serious side effects, including potential liver damage, necessitating regular liver function tests and careful monitoring of patients during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolcapone: a novel approach to Parkinson's disease. Micek, ST., Ernst, ME.[2019]

Bromocriptine is the standard treatment for motor fluctuations in Parkinson's patients on levodopa, while the efficacy of entacapone compared to bromocriptine remains unclear, as no significant benefits were found for tolcapone over entacapone.

Tolcapone, although reintroduced to the market, has a negative risk-benefit balance due to serious potential side effects, including liver damage, and does not show significant efficacy compared to other treatments like bromocriptine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolcapone: new drug. In Parkinson's disease: unacceptable risk of severe hepatitis. [2013]

Tolcapone significantly increased the plasma levels of levodopa in healthy volunteers, effectively doubling the area under the plasma concentration-time curve and extending the half-life of levodopa, particularly at a 200 mg dose.

The study found that tolcapone was well-tolerated with only minor adverse effects across all tested doses, suggesting it is a safe add-on therapy for enhancing levodopa efficacy in Parkinson's disease treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of tolcapone on plasma levodopa concentrations after coadministration with levodopa/carbidopa to healthy volunteers. Sêdek, G., Jorga, K., Schmitt, M., et al.[2019]

Eszopiclone, approved in the U.S. in 2004, is an effective treatment for insomnia and has been studied for its use in patients with conditions like obstructive sleep apnea, highlighting its versatility in managing sleep disorders.

The review discusses safety concerns, including its effects on taste (dysgeusia) and potential impacts on memory and cognitive functions, which are important considerations for its use in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eszopiclone: an update on its use in insomnia. Owen, RT.[2017]

Citations

1. withpower.com withpower.com/trial/phase-3-attention-deficit-disorder-with-hyperactivity-7-2021-3c4fb

Tolcapone for Alcoholism and ADHD This trial tests tolcapone to see if it helps people with both alcohol use issues and attention problems. The study focuses on people with both AUD and ADHD ...

2. europepmc.org europepmc.org/article/med/35523943

a randomized, placebo-controlled trial of tolcapone. ... Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue- ...

3. cambridge.org cambridge.org/core/journals/cns-spectrums/article/systematic-review-of-the-cognitive-effects-of-the-comt-inhibitor-tolcapone-in-adult-humans/38C305AD5DA0600E6F78183904E804FB

A systematic review of the cognitive effects of the COMT ... They found that tolcapone did not improve sustained attention but rather further impaired sleep loss-induced performance, particularly in Val/ ...

4. sciencedirect.com sciencedirect.com/topics/neuroscience/tolcapone

Tolcapone - an overview | ScienceDirect Topics Tolcapone is a medication that inhibits catechol-O-methyltransferase, enhancing the action of dopamine. Initially used to prolong the half-life of levodopa, ...

5. go.drugbank.com go.drugbank.com/indications/DBCOND0074601/clinical_trials/DB00323?phase=2&status=recruiting

ADHD Recruiting Phase 2 Trials for Tolcapone (DB00323) ADHD Recruiting Phase 2 Trials for Tolcapone (DB00323). Back to ADHD. Also known as: Attention Deficit Hyper Activity / Attention-deficit Hyperactivity / ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02740582

Effects of Tolcapone on Decision Making and Alcohol ... If female, 10 or more alcoholic drinks must be consumed weekly. If male, 14 or more alcoholic drinks must be consumed weekly. Meets DSM-V criteria for Alcohol ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9073504/

a randomized, placebo-controlled trial of tolcapone - PMC These data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially ...

8. go.drugbank.com go.drugbank.com/drugs/DB00323

Tolcapone: Uses, Interactions, Mechanism of Action Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor used as adjunct therapy in the symptomatic management of idiopathic Parkinson's disease.

9. medchemexpress.com medchemexpress.com/tolcapone.html?srsltid=AfmBOopYP2fhxsCQM9B3-22vW73h9CBw5ViMSJEqqul3R9f3NWvF-Dak

Tolcapone (Ro 40-7592) | COMT Inhibitor Alcohol Use Disorder|Attention Deficit Hyperactivity Disorder. 2021-08-16 ... SAFETY DATA SHEET (SDS). English - EN (459 KB) Français - FR (459 KB) ...