Obstructive sleep apnea (OSA) is a severe type of snoring causing people to choke in their sleep. It affects millions of Americans, causing many health problems. For example, patients with OSA often feel very sleepy and are at risk of falling asleep while driving. OSA also causes elevated blood pressure, memory problems and can severely affect quality of life. Patients with OSA are often treated with a face-mask that helps them breath at night but can be difficult to tolerate. In fact, about half the patients eventually stop using this mask. Because there are few other treatments (and no drug therapy), many OSA patients are still untreated.

Acetazolamide (a mild diuretic drug) has been used for over 50 years to treat many different conditions and is well tolerated. Recent data suggest, that acetazolamide may help OSA patients to not choke in their sleep and lower their blood pressure. Further, its low cost (66¢/day) and once-daily dosing may be attractive for OSA patients unable or unwilling to wear a mask each night. But previous studies had many limitations such as studying acetazolamide for only a few days and not capturing important outcomes. The goal of this study is to test if acetazolamide can improve sleep apnea, neurocognitive function and quality of life in adults with OSA, and to assess how it does that. Thus, the investigators will treat 60 OSA patients with acetazolamide or placebo for 4 weeks each. The order in which participants receive the drug or placebo will be randomized. At the end of each 4 week period the investigators will assess OSA severity, neurocognitive function and quality of life. Thus, this study will help assess acetazolamide's potential value for OSA treatment, and may also help to identify patients who are most likely to respond to acetazolamide.

Ultimately, this work promises a drug therapy option for millions of OSA patients who are unable to tolerate current treatments

The goal of this randomized, controlled, double-blind clinical trial is to compare the medication acetazolamide 500mg/day against placebo in adults who have at least moderate severe obstructive sleep apnea. The main questions this trial aims to answer are:

Is acetazolamide for 4 weeks more effective than placebo for treating obstructive sleep apnea? Is acetazolamide for 4 weeks more effective than placebo for improving neurocognitive function and quality of life? What are potential predictors and mechanisms of improvements with acetazolamide in sleep apnea, neurocognitive function and quality of life?

Participants will undergo the following activities:

• Eligibility screening (online or via phone; ~10min)
• Subjects who screen positive: in-person eligibility assessment (~1h) including a history, exam, blood testing, plus an overnight home sleep test
• Participants who are eligible: will come to the research lab (~15min) and be provided with a 4-week supply of the first study drug (i.e. acetazolamide or placebo) to be taken each night at home. Neither the researchers, nor the participants will know whether participants received acetazolamide or placebo. During this 4-week period, participants will wear a watch-sized activity tracker to measure their sleep amount and researchers will check in on participants weekly; at the end of the 4-week period participants are asked to come in for an overnight visit (~12h) which includes the following activities: general exam, questionnaires (e.g. quality of life), blood test, neurocognitive function tests, and an overnight sleep study to assess the severity of sleep apnea

Researchers will compare the effects of acetazolamide on sleep apnea severity, neurocognitive function and quality of life with the effects of placebo to see if acetazolamide may be an effective treatment for select patients with sleep apnea.

Inclusion Criteria:

• Age ≥18 years
• Body mass index ≤ 35 kg/m2
• Untreated moderate/severe OSA (AHI ≥15/h)

Exclusion Criteria:

• Substantial sleep hypoxemia (SpO2<80% for >10% of the monitoring time during the home sleep test, or for >25% of the total sleep time during any of the in-laboratory studies)
• Abnormally low blood counts/electrolytes or renal function at baseline
• Use of OSA therapy during the past 1 month, or plans to urgently resume/(re)start clinical OSA therapy within 3 months
• Significant, uncontrolled cardiac, pulmonary, endocrine, renal, hepatic, neurocognitive, psychiatric, or urologic (e.g., kidney stones) disorder
• Other major sleep disorder (e.g., narcolepsy)
• Urgent need to initiate effective OSA therapy (i.e., Epworth sleepiness score >18, commercial driver, prior sleep-related car accident, or based on MD judgment)
• Severe allergy to sulfa-drugs or taking another carbonic-anhydrase inhibitor (e.g., topiramate)
• Pregnancy/breastfeeding (current/planned)
• Prisoners
• Illicit substance abuse or >2 standard drinks of alcohol/day
• Medications that may affect OSA or ventilatory control (e.g., opiates, sedatives)
• Thiazide/loop diuretic (risk of hypokalemia)
• Inability to give consent or follow procedures
• Safety concern based on MD judgment