Proof of Concept Trial of Dronabinol in Obstructive Sleep Apnea

Abstract

Study Objective: Animal data suggest that Δ9-TetraHydroCannabinol (Δ9THC) stabilizes autonomic output during sleep, reduces spontaneous sleep-disordered breathing, and blocks serotonin-induced exacerbation of sleep apnea. On this basis, we examined the safety, tolerability, and efficacy of dronabinol (Δ9THC), an exogenous Cannabinoid type 1 and type 2 (CB1 and CB2) receptor agonist in patients with Obstructive Sleep Apnea (OSA). Design and Setting: Proof of concept; single-center dose-escalation study of dronabinol. Participants: Seventeen adults with a baseline Apnea Hypopnea Index (AHI) ≥15/h. Baseline polysomnography (PSG) was performed after a 7-day washout of Continuous Positive Airway Pressure treatment. Intervention: Dronabinol was administered after baseline PSG, starting at 2.5 mg once daily. The dose was increased weekly, as tolerated, to 5 mg and finally to 10 mg once daily. Measurements and Results: Repeat PSG assessments were performed on nights 7, 14, and 21 of dronabinol treatment. Change in AHI (ΔAHI, mean ± SD) was significant from baseline to night 21 (−14.1 ± 17.5; p = 0.007). No degradation of sleep architecture or serious adverse events was noted. Conclusion: Dronabinol treatment is safe and well-tolerated in OSA patients at doses of 2.5–10 mg daily and significantly reduces AHI in the short-term. These findings should be confirmed in a larger study in order to identify sub-populations with OSA that may benefit from cannabimimetic pharmacologic therapy.

Impact of Dronabinol on Quantitative Electroencephalogram (qEEG) Measures of Sleep in Obstructive Sleep Apnea Syndrome

“…Conversely, we found that subjects reported decreased daytime sleepiness while taking oral dronabinol. 3 Although not conclusive, these data are consistent with the possibility that the shift toward lower sleep EEG frequencies, and in particular the observed increase of relative theta power, reflects a direct CNS effect of dronabinol, and therefore a potential biomarker of its sedating properties.…”

“…We previously demonstrated that oral dronabinol decreased apnea hypopnea index (AHI) in subjects with OSA. 3 Interestingly, although overall sleep stage percentages did not change with treatment, daytime sleepiness decreased signifi cantly. Here, we hypothesized that simple sleep stage distributions may be insensitive to important aspects of sleep architecture contributing to improved alertness with dronabinol treatment.…”

“…Details of the underlying proof of concept trial have been published previously, 3 and are summarized here.…”

“…In this case, dronabinol treatment consistently decreased AHI, 3 and the lower the AHI at the end of treatment, the more sleepiness improved with treatment. As we have previously reported, 23,24 the most probable site of dronabinol action for reducing sleep related breathing disorder is cannabinoid receptors in the peripheral nodose ganglia of the vagus nerves.…”

“…In contrast, gaboxadol enhances both delta and theta activity, 19 similar to the dronabinol effects we observed. To examine whether the observed shift toward lower frequency EEG power may at least partially account for the decreased sleepiness reported by our subjects with OSA, 3 we performed a correlation analysis between qEEG measures, AHI, and change in sleepiness from baseline to end of treatment, assessed using the 7-point Stanford Sleepiness Scale. Figure 5 illustrates that after 21 days of dronabinol treatment, relative theta power during sleep was positively associated with change in sleepiness from baseline to end of treatment (r = 0.61; p = 0.02).…”