Impact of Daridorexant on Sleep, Daytime Alertness, and Smoking

Impact of Daridorexant on Sleep, Daytime Alertness, and Smoking During Abstinence

Tobacco use is the leading cause of preventable death in the U.S., with 480,000 deaths per year and 7.7 million deaths globally. A major clinical symptom associated with abstinence from both licit and illicit drugs is insomnia, which is a clinically verified, major risk factor for relapse. Roughly half of the 40 million smokers in the U.S. attempt to quit annually, with very low rates of success. One major hurdle is poor sleep quality during abstinence. Compounding the problem is that some pharmaceuticals to help reduce smoking can increase insomnia. Poor sleep is recognized as a major impediment to maintaining abstinence from several drugs of abuse, including nicotine. Blockers of orexin have recently been proposed as a promising therapy for smoking cessation. Insomnia has been reported in up to 40% of smokers, and 80% report regular sleep disturbances, which can be amplified during abstinence. A new orexin blocker, daridorexant, was FDA approved within the past two years for the treatment of insomnia, and while it has been tested in healthy individuals with insomnia, it has not been tested in smokers, who suffer from insomnia, particularly during the withdrawal phase when trying to quit. Daridorexant has an improved profile of beneficial effects for those with insomnia, the most notable advantage being its shorter duration of action that promotes daytime alertness, which is problematic for both active smokers and smokers during withdrawal. Poor sleep leads to daytime sleepiness, which often leads to smoking to maintain alertness.

Study Overview

• Status: Not yet recruiting
• Conditions: Smoking; Insomnia; Sleep; Addiction; Substance Use Disorders; Nicotine; Tobacco
• Intervention / Treatment: Drug: Daridorexant 50 mg; Other: Placebo

Detailed Description

The investigators will use a randomized, double-blind placebo-controlled design to determine how daridorexant given over 3 weeks of smoking abstinence will alter sleep, daytime alertness, and smoking behavior and craving for cigarettes. Sleep will be monitored using a sleep-tracking device, a sleep diary, and daytime alertness will be monitored using a performance metric (psychomotor vigilance task) three times per week for the 3 week study. Participants will also complete several other questionnaires related to smoking behaviors, craving, withdrawal, daytime sleepiness, and mood.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Barbara A. Sorg, PhD; Phone Number: 503-413-1934; Email: bsorg@downeurobiology.org

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97232
      • Legacy Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION

1. Adult participants who are cigarette smokers, 18-55 years of age.
2. Smokers: greater than 10 cigarettes/day.
3. Smoking for 1 year or longer.
4. Willingness to try to reduce or stay abstinent from cigarettes, smoking cessation aides (including nicotine gum or patches), smokeless tobacco, or electronic cigarettes for 3 weeks during the study.
5. Willingness to monitor sleep at home with an external device and maintain a simple sleep and smoking diary for 3 weeks.
6. Willingness to take a 5-min, mobile-based test 3X/day for 3 days/week during the 3 weeks.
7. Ability to travel to three Study Visits.
8. Are willing to abstain from consuming grapefruit products during the study.
9. Have an iPhone, best with iOS 17 or newer.

EXCLUSION:

1. Are currently taking any pharmaceutical drugs for smoking cessation, including: Nicotine patch or nicotine gum, buproprion (Wellbutrin, Zyban), varenicline (Chantix, Champix), other behavioral interventions such as cognitive behavioral therapy for smoking.
2. Are currently using cannabis or alcohol for sleep. Are currently taking any pharmaceutical drugs for insomnia, such as eszopiclone (Lunesta), zaleplon (Sonata) or zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist) benzodiazepines, or opioids.
3. Are currently taking stimulants commonly used for ADHD, such as methylphenidate (Ritalin Concerta, Daytrana) or amphetamines (Adderall, Dexedrine, Vyvanse).
4. Are currently taking anti-seizure drugs, including lamotrigine, pregabalin (Lyrica), or gabapentin (Neurontin, Horizant, or Gralise).
5. Have non-nicotine substance dependence (diagnosed with substance use disorder, including alcohol or cannabis use disorder (current cannabis use is acceptable, and past illicit drug use is acceptable if greater than 2 months prior to testing and does not meet current criteria for substance use disorders (SUDs) according to DSM-5).
6. Have a major neurological disorder such as Parkinson's disease, epilepsy, Alzheimer's disease, multiple sclerosis, or any other serious neurological disorder.
7. Have a history of serious psychiatric disorders including bipolar disorder, schizophrenia, or suicidality.
8. Had a stroke or head injury which caused loss of consciousness for longer than three minutes in the past 1 year.
9. Are pregnant or breastfeeding.
10. Have been diagnosed with sleep apnea or other diagnosed sleep disorders such as narcolepsy.
11. Have been diagnosed with thyroid problems.
12. Have been diagnosed with COPD.
13. Have been doing variable shift work in the past 1 month or traveled more than 1 time zone in past month.
14. Are currently taking the following medications, supplements, or food: Daridorexant can interact with strong inhibitors of CYP3A4, which should be discussed with The Study Doctor's office (some of these include clarithromycin, diltiazem, erythromycin, itraconzale, ketoconazole, ritonavir, and verapamil).
15. Have a BMI of 33 or higher.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment	Drug: Daridorexant 50 mg; Active daridorexant vs placebo comparator in smokers with insomnia
Placebo Comparator: No treatment	Other: Placebo; Placebo in Smokers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Quality	Sleep device to assess: latency to sleep, number of awakenings during the night, and sleep stages.	2 days + 3 weeks study: 2 days to assess sleep prior to taking daridorexant followed by 3 weeks of daily daridorexant administration.
Daytime alertness	Assess daytime alertness using a 5 min psychomotor vigilance task. Higher score indicates lower alertness.	Assessed 3 times per day (morning, midday, evening), 3 times per week for 3 weeks.
Insomnia Severity Index	Assesses extent of insomnia. Range is 0-28. Higher score indicates high level of insomnia.	Assess at prescreening and on last day of the study (3 weeks and 2 days)
Sleep Quality-sleep diary	Daily sleep diary to assess self-reported sleep	Assessed 2 days prior to taking daridorexant and daily for 3 weeks during daily daridorexant administration.
Pittsburgh Sleep Quality Index	Assesses sleep quality (duration, disturbance, latency) over last 1 month. Range is 0-21; higher score indicates worse sleep quality.	2 days before beginning study medication.
PROMIS Sleep-Short Form 8a	Assesses sleep quality over last 7 days. Range is 8-40, higher score indicates worse sleep/low alertness.	2 days before beginning study medication and last day of weeks 1, 2, 3.
Karolinska Sleepiness Scale	Assesses daytime alertness - single question. Range is 1-10. Higher score indicates lower alertness.	Given 3X/day on days 3, 5, 7 of weeks 1, 2, 3.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fagerstrom	Assesses extent of nicotine dependence. Range is 0-10. Higher score indicates higher dependence.	Measure at pre-screening and at the end of each week for 3 weeks.
Smoking History and Habits	Must smoke 10 or more cigarettes per day.	Measure at pre-screening.
Minnesota Scale Withdrawal from Nicotine	Assesses nicotine withdrawal symptoms over last 24 hr. Range is 0-60, higher score indicating higher withdrawal signs/symptoms.	2 days before beginning study medication, end of day on days 3, 5, 7 of weeks 1, 2, and 3.
QSU Brief Smoking Desire	Assesses desire to smoke. Range 7-49. Higher score indicates higher craving to smoke.	End of day on days 3, 5, 7 of weeks 1, 2, and 3.
Number of cigarettes/vape products smoked	Daily Sleep Diary includes number of cigarettes/vape products smoked.	Reported daily for entire study (2 days + 3 weeks).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morningness/Eveningness questionnaire	Scores range from 16-83, with higher score indicating morning type and lower score evening type.	2 days before beginning study medication
GAD-67 Anxiety	Assesses anxiety levels over last 2 weeks. Range is 0-21, higher score indicating higher anxiety.	2 days before beginning study medication and last day of the study (3 weeks, 2 days).
Patient Health Questionnaire 9 (PHQ 9 Depression)	Assesses depression levels. Range is 1-27, higher score indicating higher depression.	2 days before beginning study medication and last day of the study (3 weeks, 2 days).
Readiness to Quit	Readiness to quit tobacco. Scale is 1-10, with higher score indicating more important to quit.	2 days before beginning study medication and on last day of study (3 weeks, 2 days).

Collaborators and Investigators

• Sponsor: Legacy Health System
• Collaborators: Washington State University

Publications and helpful links

General Publications

• Mauries S, Rolland B, Mallevays M, Catoire S, Zehani F, Sauvage K, Davido G, Lejoyeux M, Geoffroy PA. Conditions of sleep restoration after smoking cessation: A systematic review. Sleep Med Rev. 2025 Apr;80:102041. doi: 10.1016/j.smrv.2024.102041. Epub 2024 Dec 9.
• Ruuls SR, Sedgwick JD. Cytokine-directed therapies in multiple sclerosis and experimental autoimmune encephalomyelitis. Immunol Cell Biol. 1998 Feb;76(1):65-73. doi: 10.1046/j.1440-1711.1998.00715.x.
• Fragale JE, James MH, Avila JA, Spaeth AM, Aurora RN, Langleben D, Aston-Jones G. The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System. Front Neurol Neurosci. 2021;45:117-127. doi: 10.1159/000514965. Epub 2021 May 28.
• Hamidovic A. Dual Orexin Receptor Antagonists (DORAs) as an Adjunct Treatment for Smoking Cessation. CNS Drugs. 2022 May;36(5):411-417. doi: 10.1007/s40263-022-00918-0. Epub 2022 Apr 22.
• Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CLA, Pain S, Kinter DS, Roth T; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022 Feb;21(2):125-139. doi: 10.1016/S1474-4422(21)00436-1. Erratum In: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00029-1. Lancet Neurol. 2022 Jun;21(6):e6. doi: 10.1016/S1474-4422(22)00144-2.

Study record dates

Study Major Dates

• Study Start (Estimated): February 10, 2026
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: December 30, 2025
• First Submitted That Met QC Criteria: January 7, 2026
• First Posted (Actual): January 9, 2026

Study Record Updates

• Last Update Posted (Actual): January 9, 2026
• Last Update Submitted That Met QC Criteria: January 7, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Smoking; Sleep; Insomnia; Tobacco; Addiction; Nicotine; Substance use disorders; Daridorexant
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Chemically-Induced Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Compulsive Behavior; Impulsive Behavior; Behavior; Substance-Related Disorders; Sleep Initiation and Maintenance Disorders; Behavior, Addictive; Smoking; daridorexant
• Other Study ID Numbers: 2233; 750140603 (Other Grant/Funding Number: Good Samaritan Foundation of Legacy Health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No