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Synthetic manufacturing

Another issue highlighted by Dr Agarwal is that standardising a botanically-derived product is “incredibly hard”.

“Today’s harvest might be different to next month’s harvest, meaning the product could have a different potency and will lead to a different effect,” he said.

This is why he believes it is likely the next generation of cannabinoids will be synthetically manufactured.

This is a controversial topic given cannabis’ appeal partially stems from the perception that it is more natural than other medications.

However, Dr Agarwal argues that hundreds of pharmaceutical products have their origins in plants, including aspirin, which used to be derived from the scraping of willow bark.

“Today, 99.9% of aspirin is made from synthetic chemistry but it acts on the same target as the willow bark extract, so it has the same effect,” he said.

Another example is digoxin, one of the world’s most common cardiac rhythm controlling drug, which used to be derived from the purple foxglove plant and is now synthetically manufactured.

Dr Agarwal said now that synthetic active pharmaceutical ingredients of common cannabinoids are easily available, novel cannabinoid research can be driven using these as a base ingredient.

Utilising the appropriate format

Interestingly, more than 99% of medicinal cannabis prescribed in Australia is in the form of oil-based products.

This is very different to the US, Canada and Germany, where combustible (i.e. smoked) and vaped cannabis formats are much more commonly used.

Both formats have their pros and cons depending on the targeted disease. While smoked product is absorbed quickly through inhalation, its effect also wears off quickly and a patient would require frequent re-dosing every couple of hours.

On the other hand, an oil-based product may take up to four hours to reach its peak effect, which is too slow if a patient suffers from acute pain that comes on suddenly.

The benefit of a novel drug developed for a specific treatment is that the most appropriate format can be determined to achieve the desired effect.

For example, patients suffering chronic pain would benefit from a fast onset delivery system such as an inhaler, while patients needing steady and prolonged treatment might take medical cannabis in an oil, which could last 8-12 hours.

“That’s the idea of this Cannabis 3.0 – it is designed to treat the disease. You’re not just taking the same drug and hoping it works for the disease, which is what is currently happening,” Dr Agarwal said.

Why has it taken so long for novel drug development to start?

There are still a lot of bureaucratic restrictions hindering companies’ abilities to branch into novel drug research.

Dr Agarwal described it as “basically impossible” to perform novel trials in California, despite the US state legalising medical cannabis almost a decade ago.

“If you want to get a cannabis research permit for a novel drug in California, you’ve still got to get an exemption permit from the DEA [Drug Enforcement Agency],” he said.

Likewise, Canadian based companies need an exemption from Health Canada, which can take up to 12 months to be approved.

Dr Agarwal said when testing drugs, researchers “hedge their bets” by evaluating several hundred combinations via high-throughput screening to determine which combination achieves the most effective action.

“If you did that in the US, you’d need an exemption permit for every single permutation of that drug, so the paperwork would take a lifetime,” he said.

However, Dr Agarwal noted that the Medical Cannabis Research Act of 2019 going through US Congress at the moment will “definitely allow things to go faster”.

He added that physician support and patient numbers in the United Kingdom were still too small to get trials up and running.

Australia as the top location for novel cannabinoid research

Until recently, Australia didn’t have the prescriber network support and patient depth to recruit adequate sample sizes for trials.

Although according to Dr Agarwal, the country is “now probably the best place in the world to get cannabis trials up and running and has some of the best pre-clinical and clinical facilities to recruit patients.”

He said in order to undertake cannabis research, a legal framework is required, along with supportive doctors, an adequate patient size and a “cannabis-naïve population”.

“Trials always need a comparison group – a placebo group – who haven’t taken cannabis. It’s pretty hard to find that in the US and Canada,” Dr Agarwal said.

He said the barriers of access in Australia are still “pretty high”, compared to North America where patients can buy cannabis from a pharmacy without a prescription. In California, you can even buy it from a bottle shop.

“For example, if you had Chron’s disease in Canada, the chances are you’ve probably tried cannabis because you can just buy it over the counter. Almost every patient with Chron’s will try it at least once,” Dr Agarwal said.

Clinical trials in Australia

Centered in Melbourne, Cannvalate and Swinburne University of Technology has a research collaboration named, Medicinal Cannabis Research Collaboration (MCRC) where an experienced team are performing clinical trials on novel cannabinoids under the supervision of Professor Con Stough and the clinical trials coordinator, Dr Sarah Catchlove.

He said seven clinical trials are in progress with a further five in the protocol writing stages. There has been significant interest in MCRC internationally. One example being Cannvalate has secured a memorandum of understanding with Cannbit based in Israel to research skin cancer under the supervision of the chairman of their scientific committee, Professor Raphael Mechoulam.

Three of the trials are for Impression Healthcare and concern treatment for sleep apnoea, traumatic brain injury and temporomandibular joint function.

Cannvalate are currently creating a library of novel cannabinoid Intellectual Property of which the details can’t be disclosed, but Dr Agarwal revealed they involved trials for autism, pancreatic cancer and one, ironically, relates to treating substance addiction.

Other companies such as GW Pharmaceuticals and Botanix Pharmaceuticals (ASX: BOT) have used Australian sites for clinical trials of their respective drugs, Epidiolex (for epilepsy) and BTX-1503 (for the treatment of severe acne).