This is an open-label trial that tests the effectiveness of Dronabinol in treating obstructive sleep apnea (OSA). All participants will take oral Dronabinol for two weeks. Sleep studies will be conducted before and after treatment to measure OSA severity.

Obstructive sleep apnea (OSA), is a serious respiratory disorder that involves repetitive cessation of breathing during sleep. It is estimated that 15-20 million people in the United States suffer from OSAS, which has been linked to increased risk for hypertension, heart failure, depression, and diabetes. The current standard of care for OSA, positive airway pressure (PAP), involves a mechanical device with low patient tolerance and adherence. Upper airway surgical approaches are also an option but are invasive and often unsuccessful. Effective drug treatments for OSA remain to be identified.

This study will enroll up to 120 Veterans so that 45 Veterans may complete the two-week open-label Dronabinol treatment trials. The results of the study will be used to develop a prediction model for OSA severity reduction after 2-week Dronabinol treatment vs. pretreatment AHI. Participants clinical (age, sex, body mass index, comorbidity) and pretreatment polysomnographic characteristics (sleep architecture, respiratory disturbance, and endotypes; loop-gain, arousal threshold, upper airway collapsibility and compensation) will be used to develop a prediction model for improvement of OSA with Dronabinol treatment. This prediction model will be used for a randomized clinical trial after the completion of this trial.

Inclusion Criteria:

1. Adults 18 to 65 years of age.
2. AHI 15-50 per hour on pre-treatment polysomnography.

Exclusion Criteria:

1. Positive Airway Pressure (PAP) treatment of OSA: use > 4 hours per day for 30% of days within 3 months of enrollment. PAP use will be determined from device download data.

2. Hypoglossal nerve stimulator (HNS) or oral appliance device treatment with use > 4 hours per day for 30% of days within 3 months of enrollment. HNS use will be determined by device download and oral appliance use by self-report.

3. History of upper airway surgery for OSA (except adenotonsillectomy).

4. Central or mixed apneas >25% of respiratory events on diagnostic polysomnography.

5. Arterial oxygen saturation < 75% for > 5% sleep time on pretreatment polysomnography.

6. Body mass index > 45 kg/m2.

7. If post-bariatric surgery, weight must be stable ±5% (per electronic medical records) for at least 6 months before the first dose of the study drug.

8. Active enrollment in a weight loss program.

9. Shiftwork within 3 months of enrollment.

10. High-risk occupation: commercial driver and pilot.

11. Motor vehicle accident or near-miss incident within 1 year of enrollment.

12. Current drug or habitual alcohol use or positive urine drug screen.

13. Comorbid medical and psychiatric disorders:

    1. Primary sleep disorders: e.g., narcolepsy, restless legs syndrome.
    2. Uncontrolled mood disorder or a diagnosis of schizophrenia.
    3. Initiation of new antidepressant or antipsychotic medication within 3 months.
    4. Identified as high-risk for suicide in electronic health records.
    5. Uncontrolled medical disorders (coronary heart disease, arrhythmia, congestive heart failure, chronic obstructive pulmonary disease, chronic hypoxemic or hypercapnic respiratory failure, stroke within 6 months of enrollment, chronic liver or kidney disease, autoimmune disorders).

14. Use of sedative-hypnotic medications within 30 days of enrollment.

15. Complete blood count or liver function test values more than 1.5 times the upper limit of normal.

16. Pregnancy.

17. Allergy to cannabinoids or sesame oil.

18. Average weekly alcohol consumption of more than 10 servings.

19. Participation in other investigational protocols within 30 days of enrollment.