Dronabinol Is a Strong Contender for the First Sleep Apnea Pill

Dronabinol, synthetic THC, shows promise for the treatment of sleep apnea, and new advances from pharmaceutical companies suggest how it can be optimized.

By Lisa Spear

A pill for the treatment of obstructive sleep apnea (OSA) could soon become a reality. One of the most promising candidates is the molecule dronabinol, a synthetic form of the cannabinoid tetrahydrocannabinol (THC) that is cheap to produce and easy to ingest in a gel capsule and might be the solution many sleep apnea patients who can’t tolerate CPAP are searching for.

A handful of companies are working to develop pharmacological treatments for the sleep disorder and have made some recenties that could propel these potential discover medications forward.

New research from Melbourne, Australia-based Incannex suggests that the cannabinoid’s effects are boosted when taken with another ingredient: acetazolamide. A recent phase II proof-of-concept clinical trial in Australia at Melbourne’s Alfred Hospital and University of Western Australia Center for Sleep Science found that dronabinol’s therapeutic effects are significantly increased when taken with acetazolamide,1 A drug that is currently prescribed for the treatment of glaucoma, altitude sickness, edema, and epilepsy.

“It is exciting that this is a step closer to having an effective pharmacological option for the treatment of OSA,” says principal investigator Jen Walsh, PhD, director of the Center for Sleep Science at the University of Western Australia.

“A pharmaceutical treatment for OSA is highly desirable to some patients, so it would be great if two existing medications could work synergistically to provide a better outcome than when using only one. By combining the medications it might mean that a lower dose of each is required, which means fewer potential side effects. It is also possible that each medication treats a different pathophysiological cause of OSA so combining them might have a more powerful effect.”

The study found that just 2.5 mg of dronabinol and 125 mg of acetazolamide decreases the number of times that breathing is disrupted throughout the night better in people with sleep apnea than if each ingredient was administered independently. Though acetazolamide can cause excessive urination, that side effect has not appeared at this dose, and the low dose of synthetic THC is not enough to lead to intoxication.

The drug combination cut the apnea hypopnea index (AHI) of patients with moderate to severe sleep apnea by an average of just over 50%,1 a leap from the 33% drop seen when dronabinol is taken alone.2 The results support the researchers’ hypothesis that the ingredients work synergistically to reduce apneas.

At least 14 clinical trials have looked at acetazolamide as a potential treatment for sleep-disordered breathing with encouraging results.3 The new trial results make the case for using acetazolamide in combination with dronabinol.

In the recent study, conducted by Incannex, a cannabinoid and psychedelic compound medicine development company, 25% of participants saw their AHI decrease by more than 80%. These are exciting results, says Incannex chief scientific officer Mark Bleackley, PhD.

“Our drug combination was having a substantial and, importantly, a statistically significant effect on AHI,” says Bleackley.

Incannex recently met with the US Food and Drug Administration (FDA) to discuss the drug candidate IHL-42X, the name for its fixed-dose combination of dronabinol and acetazolamide, and is now using the feedback from the FDA meeting to refine and finalize the drug candidate formulation.

Overall, Bleackley says, “The FDA was really positive in the feedback that they provided us with.”

The trial looked at three different doses of IHL-42X for obstructive sleep apnea patients, each with a fixed ratio of dronabinol to acetazolamide. The patients underwent four treatment periods, seven nights each. During in-lab polysomnography on the seventh night, researchers gathered metrics, including AHI, oxygen desaturation index, and actigraphy data that they could then compare to the patients’ baseline sleep. Patient-reported sleep outcomes were also documented.

Unexpectedly, the lowest dose of IHL-42X had the highest reduction in AHI: A 50.7% drop compared to the baseline, while the highest dose only showed a 35.2% reduction. The medium dose dropped AHI scores by 48.1%.

The reason for the difference in efficacy with the lower dose remains a mystery, the researchers say, but it may have something to do with the way the ingredients synergize. Further investigation is needed to understand the cause.

“The main thing that was surprising to us was how effective the low-dose was, particularly in comparison to the high-dose and the medium-dose,” says Bleackley. “No matter which way you look at it, we are getting better efficacy than either drug as a monotherapy.”

Also, a large proportion of patients reported “good” or “very good” sleep when taking IHL-42X compared to placebo. Actigraphy data showed that patients were also sleeping better through the night. Overall, no serious adverse events occurred during the study, the drug candidate was well-tolerated, and the results were promising, the researchers say.

“We are having a therapeutic benefit for patients with sleep apnea across physiological measures, so it was really encouraging. That is really what gives us the motivation to keep pushing this forward,” Bleackley says.

“It’s really exciting for the company, but also for having a positive effect for tens if not hundreds of millions of people who are affected by sleep apnea….I think the safety profile is really what is going to differentiate us from some of the other drugs that are in development. Cannabis has been used for thousands of years as a traditional medicine and a therapeutic. Acetazolamide has been approved for decades. They both have very good safety profiles.”

Like acetazolamide, dronabinol is nothing new, approved by the FDA in the ’80s for the treatment of anorexia in AIDS and chemo-induced nausea. It’s been used for subsequent decades, but it first caught the attention of sleep scientists in recent years, starting with research from the University of Illinois at Chicago and Northwestern University that demonstrated how the molecule showed promise in treating patients with moderate to severe obstructive sleep apnea .1

Since then, the University of Illinois at Chicago has licensed intellectual property related to the experimental drug treatment to RespireRx Pharmaceuticals Inc, which is also focused on developing a potential dronabinol-based sleep apnea drug candidate, only its focus is optimizing the body’s absorption of dronabinol . The Glen Rock, NJ-based company has developed lipid nanoparticles that make the drug soluble, says Arnold Lippa, PhD, RespireRx’s chief scientific officer.

“It survives the acid environment of the stomach, meaning it makes it through unmetabolized and it makes it into the intestines where it can be absorbed into the lymphatic system and avoid liver metabolism on the first pass,” says Lippa, a molecular neurobiologist.

RespireRx now plans to move into animal and human pharmacokinetic studies to look at multiple new pro dronabinol formulation to choose the best one for a phase 3 clinical efficacy study in 2023.

Despite this emerging research, the most recent position statement from the American Academy of Sleep Medicine on the use of dronabinol for the treatment of sleep apnea states that because synthetic medical cannabis may have differential effects, with variable efficacy and side effects in the treatment of OSA , it should not be used for the treatment of OSA due to “unreliable delivery methods and insufficient evidence of effectiveness, tolerability, and safety.” Further research, the position statement says, is needed to understand the functionality of medical cannabis extracts before recommending them as a treatment for OSA.4

Still, if dronabinol-based treatments are brought to market, they may be a game-changer for patients who struggle to use CPAP and pave the way for the acceptance of pharmacological sleep apnea treatments.

The reported side effects are no different than placebo and the doses are relatively low compared to what people are consuming recreationally, says Lippa, PhD. “I know that there are differences in opinion, but I think the preponderance of information is that it is a relatively safe drug.”

Lisa Spear is associate editor of Sleep Review.

References

1. Iconnex investor presentation. IHL-42X for treatment of obstructive sleep apnoea: Phase II proof of concept clinical trial results. 2022 June 03.

2. Carley DW, Prasad B, Reid KJ, et al. Pharmacotherapy of apnea by cannabimetic enhancement, the PACE clinical trial: effects of dronabinol in obstructive sleep apnea. Sleep. 2018 Jan 1;41(1):zsx184.

3. Schmickl CN, Landry SA, Orr JE, et al. Acetazolamide for OSA and central sleep apnea: A comprehensive systematic review and meta-analysis. Chest. 2020 Dec;158(6):2632-45.

4. Ramar K, Rosen IM, Kirsch DB, et al. Medical cannabis and the treatment of obstructive sleep apnea: An American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2018 Apr 15;14(4):679-81.

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