Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea

Carley, David W.; Prasad, Bharati; Reid, Kathryn J.; Malkani, Roneil G.; Attarian, Hryar; Abbott, Sabra M.; Vern, Boris A.; Xie, Hui; Yuan, Chengbo; Zee, Phyllis C.

doi:10.1093/sleep/zsx184

Cited by 106 publications

(64 citation statements)

References 32 publications

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“…Although undiluted DMSO alone did not alter apnea expression in these studies [4,8], DMSO may have altered the effects of dronabinol, since it is known to block fast axonal transport in the vagus nerve. Still, it is important to note that dronabinol dissolved in sesame oil rather than DMSO 9 did reduce apnea frequency in two clinical trials in patients with obstructive sleep apnea syndrome [25,26].…”

Section: Discussionmentioning

confidence: 99%

DMSO potentiates the suppressive effect of dronabinol, a cannabinoid, on sleep apnea and REM sleep

Calik

Carley

2019

Preprint

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312) 413-0581 Office mcalik@uic.edu ORCID iD: 0000-0001-6295-7420 2 Abstract Purpose: Dimethyl sulfoxide (DMSO) is an amphipathic molecule with innate biological activity that also is used to dissolve both polar and nonpolar compounds in preclinical and clinical studies. Recent investigations of dronabinol, a cannabinoid, dissolved in DMSO demonstrated decreased sleep apnea frequency and time spent in REM sleep in rats. Here, we tested the effects of dronabinol dissolved in 25% DMSO (diluted in phosphate-buffered saline) to rule out potentiating effects of DMSO.Methods: Sprague-Dawley rats were anesthetized and implanted with bilateral stainless steel screws into the skull for electroencephalogram recording and bilateral wire electrodes into the nuchal muscles for electromyogram recording. Each animal was recorded by polysomnography. The study was a fully nested, repeated measures crossover design, such that each rat was recorded following each of 8 intraperitoneal injections separated by three days: vehicle (25% DMSO/PBS); vehicle and CB 1 antagonist (AM 251); vehicle and CB 2 antagonist (AM 630); vehicle and CB 1 /CB 2 antagonist; dronabinol (CB 1 /CB 2 agonist); dronabinol and CB 1 antagonist; dronabinol and CB 2 antagonist; and dronabinol and CB 1 /CB 2 antagonist. Sleep was manually scored into NREM and REM stages, and apneas were quantified.Results: Dronabinol dissolved in 25% DMSO did not suppress apnea or modify sleep efficiency compared to vehicle controls, in contrast to previously published results. However, dronabinol did suppress REM sleep, which is in line with previously published results. Conclusions: Dronabinol in 25% DMSO partially potentiated dronabinol's effects, suggesting a concomitant biological effect of DMSO on breathing during sleep. 3 1 0100% DMSO, with their known effects on the vagus nerve as previously discussed, might decrease REM sleep to a greater extent.In conclusion, we show that dronabinol, a non-specific cannabinoid receptor agonist shown to suppress sleep-related apneas and REM sleep, does not suppress sleep-related apneas 25% DMSO vehicle. This adds to the growing literature that DMSO is not simply a compound used to dissolve polar and nonpolar compounds, but is a compound with its own innate biological activity.

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Section: Discussionmentioning

confidence: 99%

DMSO potentiates the suppressive effect of dronabinol, a cannabinoid, on sleep apnea and REM sleep

Calik

Carley

2019

Preprint

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“…5 This led to human studies that assessed the effectiveness of dronabinol in pill form of different strengths from 2.5 to 10 mg to treat patients with OSA. [6][7][8] Prasad et al reported a significant improvement in apneahypopnea index (AHI) of 32% at 3 weeks compared to baseline (−14.1 ± 17.5; P = .007). Side effects related to treatment were reported in most patients, and somnolence was reported in 29% to 50% of patients.…”

Section: Canna Bi S and Sleepmentioning

confidence: 99%

“…Eight percent of patients reported sleepiness and drowsiness. 8 Importantly, the long-term use of these products on other sleep quality measures, their tolerability, and safety are still unknown. Dronabinol is not FDA approved for treatment of OSA.…”

Section: Canna Bi S and Sleepmentioning

confidence: 99%

Medical Cannabis and the Treatment of Obstructive Sleep Apnea: An American Academy of Sleep Medicine Position Statement

Ramar

Rosen

Kirsch

et al. 2018

Journal of Clinical Sleep Medicine

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The diagnosis and effective treatment of obstructive sleep apnea (OSA) in adults is an urgent health priority. Positive airway pressure (PAP) therapy remains the most effective treatment for OSA, although other treatment options continue to be explored. Limited evidence citing small pilot or proof of concept studies suggest that the synthetic medical cannabis extract dronabinol may improve respiratory stability and provide benefit to treat OSA. However, side effects such as somnolence related to treatment were reported in most patients, and the long-term effects on other sleep quality measures, tolerability, and safety are still unknown. Dronabinol is not approved by the United States Food and Drug Administration (FDA) for treatment of OSA, and medical cannabis and synthetic extracts other than dronabinol have not been studied in patients with OSA. The composition of cannabinoids within medical cannabis varies significantly and is not regulated. Synthetic medical cannabis may have differential effects, with variable efficacy and side effects in the treatment of OSA. Therefore, it is the position of the American Academy of Sleep Medicine (AASM) that medical cannabis and/or its synthetic extracts should not be used for the treatment of OSA due to unreliable delivery methods and insufficient evidence of effectiveness, tolerability, and safety. OSA should be excluded from the list of chronic medical conditions for state medical cannabis programs, and patients with OSA should discuss their treatment options with a licensed medical provider at an accredited sleep facility. Further research is needed to understand the functionality of medical cannabis extracts before recommending them as a treatment for OSA.

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“…The results of the recent pharmacotherapy of apnea by cannabimimetic enhancement (PACE) trial that studied the effects of dronabinol (a cannabinoid) on the effects of obstructive sleep apnea look promising. 1 In light of this study and the upcoming legalization of marijuana in Canada, could the authors of the recent CMAJ review 2 on the diagnosis and treatment of obstructive sleep apnea in adults please comment on the use of marijuana and its pharmacologic derivatives in the treatment of obstructive sleep apnea?…”

Section: Medical Marijuana In Treating Obstructive Sleep Apneamentioning

confidence: 99%

Medical marijuana in treating obstructive sleep apnea

Pupko¹

2018

CMAJ

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Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea

Cited by 106 publications

References 32 publications

DMSO potentiates the suppressive effect of dronabinol, a cannabinoid, on sleep apnea and REM sleep

DMSO potentiates the suppressive effect of dronabinol, a cannabinoid, on sleep apnea and REM sleep

Medical Cannabis and the Treatment of Obstructive Sleep Apnea: An American Academy of Sleep Medicine Position Statement

Medical marijuana in treating obstructive sleep apnea

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