Three months, three clinical trials, and three failures to beat placebo, and yet still cannabidiol (CBD) champions believe they can make low dose meds work for insomnia.
That’s going to surprise people who have grown up to believe that marijuana causes lethargy. But the CBD being tested is cannabidiol, a phytocannabinoid derived from Cannabis species, which is devoid of psychoactive activity, with analgesic, anti-inflammatory, antineoplastic and chemopreventive activities.
At least four Australian companies are pursuing a low dose CBD insomnia cure after the Therapeutic Goods Administration (TGA) changed the goalposts on the cannabinoid in 2020.
Today, big cash prizes await the first registered over-the-counter (OTC) CBD drug.
But there’s little compelling evidence for low dose CBD and particularly for insomnia, because CBD isn’t sedating, says Lambert Initiative for Cannabinoid Therapeutics researcher, Anastasia Suraev, who co-wrote a review paper for the regulator.
“Does CBD actually help someone sleep? So far we don’t have any evidence that this is the case, even at a higher dose. Even at 800mg, we do not have any published data to show this is the case,” Suraev told Cosmos Weekly.
“Which is surprising given how widely CBD is marketed for sleep in the US and Canada.”
ASX-listed companies Cann Group, Ecofibre, Avecho and Bod Science are scrambling to be the first to medicate the 60 per cent of adult Australians who told a Sleep Health Foundation survey in 2021 they experience minor insomnia.
The TGA’s controversial decision to allow pharmacies to sell CBD in sub-150mg doses paved the way for medical cannabis companies to bypass sceptical GP gatekeepers, and the complicated Special Access Scheme B regime, which allows them to prescribe unapproved drugs.
And that cash prize? The $97 million spent on pharmacy sleep aids in 2021, and the possibility of a massive payday: the only CBD-only drug registered anywhere around the world, Epidiolex for childhood epilepsy, was bought two years ago for $US7.2 billion.
The hurdle to access this new market is — proof.
Medical cannabis companies must prove their product actually does something, and it has to be for a condition mild enough not to need medical supervision, but not so mild it doesn’t need a drug.
Insomnia is one of the few conditions that fit the brief and is a plight that’s already one of the “most common reasons for the current use of medicinal cannabis”, wrote sleep researcher Jen Walsh in a review of the evidence last year.
She found studies supporting cannabis combinations helping sleep, but nothing definitive for CBD alone.
The three failures
Depending on who you talk to, the first three results either hint at the limitations of CBD, or are proof of bad clinical trial design.
Paul Gavin, CEO of biotech Avecho, says sleep studies are risky because of the high placebo effects that come with the inherently subjective data.
The risk rises when insomnia is mild – an eight to 14 score on the Insomnia Severity Index (ISI) – as the line between what makes a good sleep and a bad sleep, makes it even more hazy.
“The placebo effect will destroy half of these studies. If you’re coming in at eight [on the ISI] and the placebo effect is seven, then you have no dynamic range to see any improvement,” he told Cosmos Weekly.
“The horrible thing about this clinical trial situation that we’re all in is it’s a race to registration, because we all acknowledge that the first one or two to get registered have direct access to 26 million people… so there are a lot of people making calculated shortcuts.”
A gold-plated clinical trial is randomised, double-blind and with enough patients to provide a solid statistic at the end. This means patients will be randomly assigned the drug and placebo and neither they nor the doctors will know who gets what.
The three trials where CBD failed to beat the placebo were by Swinburne University, which studied just 30 people with moderate-severe insomnia for a three week trial, Cann Group and Ecofibre.
Cann Group enrolled 212 people for four weeks, and used the PROMIS sleep disturbance measure instead of ISI. Ecofibre planned to enrol 438 people for 10 weeks and minimum eligibility was an ISI of 10.
The next hopefuls
The two remaining trials are by Bod Science and Avecho. Both will gild their datasets with objective data from sleep monitoring devices.
Bod Science’s trial is underway now with sleep specialist the Woolcock Institute of Medical Research. It will test some 200 people with an ISI score of at least eight over eight weeks.
Suraev says the outcome of this trial will offer a “definitive” answer to the CBD-insomnia question.
Avecho’s will start later this year with a 500 person, eight week trial that also uses sleep monitors and requires a starting ISI of at least 15.
Gavin believes the expensive Avecho trial will provide the exhaustive evidence needed to prove whether CBD does anything for sleep – or not.
“In a year’s time I will look very smart and like nostradamus, or very stupid.”
From THC to CBD
Medical cannabis has only been around in Australia since 2016, when the federal government changed the law to enable the birth of a pharmaceutical industry.
But the industry didn’t take off as expected. It still hasn’t hit the $100 million market size that, in 2016, financial services broker Cannacord Genuity expected it to be by 2020. Layers of bureaucratic red tape and a smaller market than expected has hampered sales – SAS B approvals have hovered around 120,000 for the last two years, compared to government estimates of 600,000 people using it in total.
Along the way many of the charlatans, con artists and spivs have been pushed out and while pharmacy-only CBD is the latest medical cannabis gold rush, the proof hurdle is too high for all bar the moneyed and most serious to attempt entry.
If not sleep, then what?
There are clues that cannabis helps with sleep – stoner movie tropes about sleepy space cowboys with the munchies are memes for a reason – and all researchers agree there are enough green shoots of information to keep investigating.
Evidence is emerging about CBD’s efficacy for certain types of pain, anxiety and inflammation.
Its anti-anxiety properties could help people sleep, if stress is the root of a person’s insomnia, says Suraev.
“Based on what we found in our review we thought that would be a good angle but as we showed, usually 300mg to 400mg is where we’re starting to see those effects on stress and anxiety,” she says.
She also says the TGA quietly let it be known that if trials can show efficacy at a slightly higher dose, it might be convinced to bump up the limit for an OTC CBD medicine.
Woolcock sleep researcher Dr Camilla Hoyos is working on the Bod trial and says it’s unclear how cannabis affects sleep.
The Walsh review followed breadcrumbs about a lack of dreaming which might indicate less REM sleep, but again, didn’t find strong evidence either way.
“It also might be that quality sleep is associated with marijuana use,” Hoyos told Cosmos Weekly.
“We simply don’t know whether the quality is affected. For example, alcohol helps you sleep but it’s not good quality. There’s still a lot we don’t know. There was a lot of early work with certain cannabinoids but they were so long ago often they were looking at people who smoked a lot of cannabis. We’re now using it at a pharmaceutical grade.”
The next big thing might actually be cannabinol (CBN), the so-called ‘sleepy’ cannabinoid.
Hoyos is half way through a study into CBN as an insomnia treatment, with doses up to 300mg for people with moderate-severe insomnia.
But there is a vast difference between the cannabinoid cousins: CBD is considered safe enough to head directly to pharmacies. CBN ranks alongside cocaine, heroin and recreational marijuana, meaning it’s not the path to legal riches.