Belsomra + Methylphenidate for Smoking Cessation

Overseen By NIDA IRP Screening Team

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: National Institute on Drug Abuse (NIDA)

Must not be taking: CNS depressants, CYP3A inhibitors

Disqualifiers: Psychotic disorders, Neurological disorders, Obesity, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1-2 months

140 Participants Needed

Trial Summary

What is the purpose of this trial?

Study Description: Despite the availability of pharmacotherapy for some substance use disorders, relapse vulnerability is still a significant issue. This suggests medications with alternative mechanisms of action should be explored to address this unmet need. Substantial preclinical research indicates that orexin antagonism blunts the internally and externally triggered motivation to attain abused substances. This research project will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to those with a substance use disorder. Suvorexant s ability to blunt neurobiological correlates of substance misuse will be assessed. This will be assessed following acute and repeated drug administration. Baseline individual differences will be considered to determine whether neurobiological variance influences suvorexant s impact in those with nicotine dependence. In an independent arm, the interaction between suvorexant and a dopamine agonist (methylphenidate) on cognitive function will be assessed in non-smoking individuals. Objectives: The objective is to determine the acute and chronic impact of the orexin antagonist, suvorexant, on neurobiological and behavioral factors linked with substance use disorders. Whether such effects are mediated by baseline characteristics will be tested. Given suvorexant is an FDA approved treatment for insomnia, sleep will be evaluated as well in the nicotine dependent arm. Endpoints: In nicotine-dependent individuals, suvorexant s impact on brain function will be assessed several ways by evaluating: 1) resting function, 2) reactivity to drug cues, 3) reactivity to non-drug related cognitive tasks. Sleep and nicotine use will be measured throughout the study period. In those without nicotine-dependence, the impact of suvorexant and the interaction of acute methylphenidate and suvorexant on brain function will be assessed. This arm will provide insight into how suvorexant impacts reward/cognition as well as impacts the pharmacological influence of methylphenidate on those same measures. Study Population:\<TAB\> Nicotine dependence arm:140 subjects; Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Control arm: 80 subjects; Volunteers who are between the ages of 18-60 and are non-smokers/vapers This study will be conducted at the NIDA-IRP, Biomedical Research Center, in Baltimore, MD. Description of Study Intervention: Nicotine dependence arm: Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days. Control arm: 1. Tolerability visit with one MRI scan post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max) Study Duration: 5 years Participant Duration: 1-2 months

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are using medications that depress the central nervous system or are CYP3A inhibitors/inducers, you may be excluded from the study. It's best to discuss your current medications with the study team.

How does the drug Belsomra combined with Methylphenidate differ from other smoking cessation drugs?

Belsomra (Suvorexant) is unique in smoking cessation as it is primarily used for insomnia, and its combination with Methylphenidate, a stimulant, is novel compared to traditional smoking cessation drugs like nicotine replacement therapy, bupropion, and varenicline, which focus on reducing nicotine withdrawal and cravings. ^{1 2 3 4 5}

Research Team

Amy Janes, Ph.D.

Principal Investigator

National Institute on Drug Abuse (NIDA)

Eligibility Criteria

This trial is for daily smokers/vapers aged 18-60 who have been using nicotine consistently for at least a year. They must not use other drugs or alcohol, be pregnant, or have certain health conditions like severe heart disorders, respiratory issues, major depression (unless stable on medication), obesity with BMI over 35, or neurological disorders.

Inclusion Criteria

I can become pregnant and will take pregnancy tests on all study days.

I am willing to follow the study's lifestyle requirements and have given my written consent.

I am between 18 and 60 years old.

Exclusion Criteria

Participants cannot self-report complex sleep behaviors

I have never had a major head injury that affected my thinking, caused seizures, or led to other brain problems.

Participants cannot meet DSM-5 criteria for lifetime and/or current psychotic disorders such as bipolar disorder, schizophrenia, schizoaffective disorder or medical conditions that impact reward function

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive suvorexant and/or methylphenidate to assess neurobiological and behavioral impacts

1-2 months

Multiple visits for drug administration and fMRI scans

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Belsomra
• Placebo

Trial Overview The study tests the drug suvorexant's impact on brain function and behavior in people with nicotine addiction. It also examines how suvorexant interacts with methylphenidate in non-smokers. Participants will take a single dose of suvorexant and then daily doses for about a week; control subjects will receive various combinations of the drugs and placebo.

Participant Groups

Group I: Nicotine Dependence Arm Experimental Treatment 2 Interventions

140 Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days.

Group II: Control Arm Active Control 3 Interventions

80 Volunteers who are between the ages of 18-60 and are non-smokers/vapers. 1. Baseline visit with 1 fMRI scans pre- and post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max)

Belsomra is already approved in United States, European Union for the following indications:

Approved in United States as Belsomra for:

• Insomnia characterized by difficulties with sleep onset and/or sleep maintenance

Approved in European Union as Belsomra for:

• Insomnia characterized by difficulties with sleep onset and/or sleep maintenance

Who Is Running the Clinical Trial?

National Institute on Drug Abuse (NIDA)

Lead Sponsor

Trials

2,658

Recruited

3,409,000+

Findings from Research

Varenicline is the most effective first-line pharmacotherapy for smoking cessation, showing a significant effect compared to placebo with an odds ratio of 2.27, followed by bupropion (1.69) and nicotine replacement therapy (1.60).

Despite some safety concerns, regulatory agencies deem bupropion and varenicline to have a favorable benefit/risk profile, but healthcare providers should monitor patients for potential neuropsychiatric symptoms, especially in those with psychiatric comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for smoking cessation: pharmacological principles and clinical practice. Aubin, HJ., Luquiens, A., Berlin, I.[2022]

Nicotine replacement therapies, including a new nicotine vapor inhaler and sublingual nicotine tablets, have shown effectiveness in treating nicotine dependence, with the vapor inhaler delivering nicotine to the oral mucosa and the sublingual tablet demonstrating efficacy in a placebo-controlled trial.

Combining pharmacotherapies, such as nicotine replacement with bupropion or mecamylamine, may enhance treatment outcomes by occupying more nicotine receptors, which could help reduce smoking rewards and support cessation efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New medications for nicotine dependence treatment. Hurt, RD.[2019]

In a 9-week study involving 25 adults with depressive disorders, the addition of bupropion sustained release (SR) to their SSRI treatment resulted in a modest smoking cessation success rate, with 32% of participants abstinent at the end of the study.

Bupropion SR was found to be safe, as there were no new depressive episodes reported, minimal weight gain (approximately 0.5 lb), and some participants even experienced improvements in sexual dysfunction associated with SSRIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupropion sustained release as a smoking cessation treatment in remitted depressed patients maintained on treatment with selective serotonin reuptake inhibitor antidepressants. Chengappa, KN., Kambhampati, RK., Perkins, K., et al.[2022]

Despite the availability of various smoking cessation pharmacotherapies, including nicotine replacement therapy and newer agents, less than 25% of smokers remain abstinent one year after treatment, highlighting the need for more effective options.

Combination therapies, particularly using nicotine replacement therapy alongside varenicline, have shown the highest rates of smoking cessation, while novel therapies like cytisine and N-acetylcysteine are emerging as promising alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking. Gómez-Coronado, N., Walker, AJ., Berk, M., et al.[2018]

Bupropion sustained release (SR) significantly aids smoking cessation, with higher doses (100, 150, and 300 mg/day) increasing the likelihood of quitting by 1.42, 1.69, and 2.84 times, respectively, compared to placebo, based on a study of 519 chronic smokers.

The study found that side effects like insomnia and dry mouth were linked to bupropion metabolite concentrations, suggesting that managing these side effects through dose adjustments could impact smoking cessation success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. Johnston, JA., Fiedler-Kelly, J., Glover, ED., et al.[2023]

References

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

Pharmacotherapy for smoking cessation: pharmacological principles and clinical practice. [2022]

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

New medications for nicotine dependence treatment. [2019]

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

Bupropion sustained release as a smoking cessation treatment in remitted depressed patients maintained on treatment with selective serotonin reuptake inhibitor antidepressants. [2022]

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

Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking. [2018]

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

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. [2023]