The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial

Study Objectives: The potential sedative effect of dronabinol and the high expression of cannabinoid receptors on the hypoglossal motor nuclei makes this agent a good candidate for obstructive sleep apnea (OSA) pharmacotherapy to be tested with atomoxetine, a noradrenergic reuptake inhibitor that reduced OSA severity in combination with oxybutynin. Here we tested the effect of atomoxetine 80 mg plus dronabinol (Ato-Dro) at 2 different doses (5 and 10 mg) vs. baseline and atomoxetine alone in a 2-center, open-label, dose-escalating trial. The primary outcome was the effect of Ato-Dro vs. baseline on OSA severity (apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation). Safety of the combination and self-reported outcomes were also assessed. Methods: Fifteen patients with OSA received progressively increasing Ato-Dro doses (dose escalation was performed every week, starting from Ato-Dro 40-2.5 mg, then 80-5 mg and finally 80-10 mg). A clinical, in-lab polysomnography was performed at baseline, on Ato-Dro 80-5 and Ato-Dro 80-10 mg. Results: Ato-Dro 80-10 mg did not significantly reduce apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation, and hypoxic burden and yielded limited clinical benefit vs. baseline and atomoxetine alone. However, Ato-Dro 80-5 mg did improve OSA severity (Dapnea-hypopnea index = 8.3[0.3, 16.3] events/h; mean [confidence interval]; Dhypoxic burden = 37.7[12.5, 62.7] %min/h) and multiple self-reported outcomes vs. baseline and/or atomoxetine alone. Ato-Dro administration was characterized by several potentially harmful side effects and treatment discontinuation in 1/3 of cases. Conclusions: Ato-Dro 80-5 mg might be useful to reduce OSA severity and lead to self-reported improvement in those who could tolerate the combination. However, given the numerous side effects and the exploratory nature of this open-label study, our results warrant further validation in larger trials. Clinical Trial Registration: Registry: ClinicalTrials.gov; Title: Study for Efficacy and Dose Escalation of AD313 + Atomoxetine (SEED) (SEED); URL: https:// clinicaltrials.gov/ct2/show/NCT05101122; Identifier: NCT05101122.