Whole plant cannabis. We’ve all probably heard the term. Companies use it to promote their products, patient groups campaign for the right to use it, yet the majority of scientific research into medical cannabis ignores it, choosing to focus on single compounds like THC and CBD.
Globally, medical cannabis use and regulation is riddled with contradictions, inconsistencies and hypocrisy, but for many the near impossibility of bringing whole plant cannabis medication to market is the biggest travesty of all.
The FDA says there’s not enough proof that the cannabis plant has therapeutic use, but its continued schedule 1 status means it’s a bureaucratic nightmare to research.
Patients see first hand that whole plant extracts treat their symptoms better than isolated cannabinoids, yet no pharmaceutical company will invest millions researching a plant that can’t be patented.
At the heart lies a seemingly irrevocable tension between what anecdotal evidence from patient experience suggests to be effective and what ultimately will keep pharmaceutical company shareholders and government regulators happy.
Cannabis – a complex plant
So why does it matter anyway if the whole plant is researched or not? Surely if we know that certain cannabinoids have therapeutic effects, we should just concentrate on those, right?
Well, that would be the easy answer if the cannabis plant fitted in with the current single molecule model of scientific research.
But cannabis is a complex beast. With approximately 420 molecules, including 113 cannabinoids, over 200 terpenes, plus flavonoids, amino acids, proteins, enzymes, fatty acids and sugars, it’s easy to see that the cannabis plant has a whole lot of botanical stuff going on.
So far, it’s the two headline grabbing cannabinoids Tetrahydrocannabinol (THC) and Cannabidiol (CBD) that have been most widely researched, with many scientists believing they are key players in the piece.
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Difficult to get funding for whole plant studies
This tendency for single cannabinoid research is further compounded by a lack of incentive for drug companies to invest millions into researching something that is still considered a Schedule 1 controlled substance, is impossible to patent, and will bring very little financial return.
Molecular biologist and leading scientist in the field of cannabinoid research Manuel Guzmán says, “it’s currently extremely difficult to work in the clinics with cannabinoids, one has to fill in a lot of paperwork, ask for a lot of permissions, and that detracts from the attention and interests of different sponsors and companies to do clinical research on cannabis”.
He goes on, “It’s also true that they are natural compounds and so many companies are not interested in them as they cannot patent compounds that belong fortunately to humankind, which also detracts the attention of investors and funding companies to do clinical research”.
System designed to fail for whole plant medical cannabis
Indeed many universities in the United States even shy away from backing research into the plant. According to Jahan Marcu, Chief Scientist at Americans for Safe Access, “even if you get funding, your administration might not approve the study anyway. There’s a prejudice and a fear around this and the universities are considering their risks too. By engaging in any research involving cannabis, you can potentially lose funding for your institutions”.
According to Marcu, the schedule 1 status of Cannabis in the US, means that cannabis clinical trials are always destined to failure.
“If you order cannabis from the government to do a phase 1 clinical study, they’ll only approve a very short, safety study. You’d spend years getting the cannabis and the patients together, and then you run the study for 30 days. And then let’s say you have profoundly amazing effects, and you want to move forward and create dosing and formula, it would actually be impossible for you to order the same material again for a follow up study. And even if they provided the material, you would never get approved for stage 2 because it’s a schedule 1 narcotic with no accepted medical value. So how could you do a study on the medical effect?”
This system failure is further compounded by a federal bias against approving whole plant medicine.
Marcu: “All terpenes that are found on cannabis are FDA approved; THC, terpenes, they’re all available as isolated agents by the FDA. Where they don’t like it is when they’re all combined.”
So by trying to shoehorn cannabis into a biased, pharmaceutical model that’s destined to fail, it would seem much of the cannabis plant’s therapeutic is being missed.
Aristotle made the timeless observation that ‘the whole is more than the sum of its parts’, but in cannabinoid research it was Israeli pioneer Raphael Mechoulam and fellow scientist Shimon Ben-Shabat that applied it to understanding the cannabis plant, coining the term ‘The Entourage Effect’. They observed that greater therapeutic benefit was achieved from the whole plant working synergistically together than single cannabinoids taken in isolation.
This theory was further expanded by neurologist and psychopharmacology researcher Dr Ethan Russo in his seminal paper ‘Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects’. He examines the mysterious world of the cannabis plant, outlining the under-explored potential of the plant’s terpenes, which according to Russo “display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts”.
Jahan Marcu agrees with this synergistic view of the cannabis plant. “So when you’re throwing in a hundred or so compounds that are increasing and decreasing the speed of certain neurons, you definitely have a synergistic effect. And many of the compounds like the aromatics, the terpenes, the smell: they’re potent at ambient air levels, they can have an effect on physiology. And many of those compounds counteract the effects of THC on intoxication”.
THC and CBD – better together
The entourage effect can also be extended to how THC and CBD work synergistically together to bring about a greater effect than if acting in isolation.
Scientists have documented how cannabidiol can mitigate against the psychoactive effects of THC, while potentiating some more sought after benefits such as pain relief. Both are attractive qualities for anyone taking cannabis for medical reasons and not wanting to experience the sometimes uncomfortable high experienced with strains abundant in THC.
And in a study conducted in 2014 entitled ‘The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model’, scientists found “dramatic reductions” in a deadly form of brain cancer when THC and CBD were used in conjunction with radiation treatment on mice. So CBD and THC together, combined with conventional radiotherapy, were more successful than radiation combined with single cannabinoids.
Synthetic cannabinoids vs whole plant extracts
A tempting proposition for drugs companies to get round the lack of patentability of the cannabis plant is to create synthetic versions. Marinol (Dronabinol) and Cesamet (nabilone), both synthetic types of THC, are prescribed for the treatment of weight loss in HIV and nausea/ vomiting during cancer treatment.
However, patients have reported experiencing greater psychoactive effects than with natural cannabis and say effective dosing can be difficult.
In a paper written by Lester Grinspoon, MD, Professor of Psychiatry at the Harvard Medical School, called ‘On the Pharmaceuticalization of Marijuana’ he said, “I have yet to examine a patient who has used both smoked marijuana and Marinol who finds the latter more useful; the most common reason for using Marinol is the illegality of marijuana, and many patients choose to ignore the law when they believe that the difference between the two puts their health, comfort or economic well-being at risk”.
Whole plant CBD avoids synthetic dosing difficulties
Scientists have also discovered an important difference in how synthetic, single molecule CBD acts compared with a whole plant CBD rich extract.
A recent study in Israel published in Pharmacology and Pharmacy showed that using a whole plant extract could get round some of the dosing difficulties experienced in administering cannabinoids.
Researchers noted that in trials carried out on pure CBD, “healing was only observed when CBD was given within a very limited dose range, whereas no beneficial effect was achieved at either lower or higher doses.”
They set out to see if this same trend, which can make dosing difficult when administering CBD to patients, were different in whole plant CBD-rich cannabis extract. And indeed it was, with the high CBD strain providing ‘a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this plant medicine ideal for clinical uses’.
Which basically meant that there was a direct link between pain relief and the amount of CBD administered, rather than the limited window of dosing opportunity offered by the pure CBD. Not only that but scientists found that less whole extract CBD was needed to elicit an anti-inflammatory effect than the pure, synthetic variant.
They concluded, “It is likely that other components in the extract synergize with CBD to achieve the desired anti-inflammatory action that may contribute to overcoming the bell-shaped dose-response of purified CBD.”
GW Pharma – exception to the rule?
All this points towards the possibility that the current standard route taken by pharmaceutical companies of funding research into single molecules will never lead to uncovering the full therapeutic potential of cannabis.
There have however been some exceptions to the rule. GW Pharma’s Cannabis based medication Sativex has been approved in 20 countries for treating the spasticity associated with Multiple Sclerosis and is currently undergoing clinical trials for Glioblastoma.
Somehow the British pharmaceutical company specialising in cannabinoid medicine, seems to have navigated through the complex maze of regulation by differentiating between the cannabis plant and its standardized, patented CBD and THC extracts. Although in an interview with Cambridge Business Magazine Chairman, Geoffrey Guy revealed that Sativex does in fact contain the same active compounds as the cannabis plant itself.
“Most people in our industry said it was impossible to turn cannabis into a prescription medicine,” he said. “We had to rewrite the rule book. We have the first approval of a plant extract drug in modern history. It has 420 molecules, whereas every other drug has just one”.
But so far GW Pharma seem to be alone in knowing how to work the system and get a cannabis based plant extract passed as medicine.
People Power – crowdfunding to pay for whole plant studies
Frustrated by the difficulties in funding studies into whole plant cannabis extracts, some patients groups and activists are circumventing the traditional model and turning to crowdfunding to raise money for whole plant research, since they know through their own experience that the whole plant works.
€35,750 raised to test whole plant vs single cannabinoids in tumour reduction
Jeff Ditchfield, founder of Bud Buddies, the non-for-profit organisation that supplies cannabis products to the seriously ill, decided to take action when he saw that there was no impetus to study the effectiveness of whole plant extracts when treating cannabis.
Through a crowdfunding campaign Jeff raised over €35,750 for a study to be carried out at Madrid Complutense University under Dr Manuel Guzmán, Guillermo Velasco and Cristina Sanchez.
The purpose of the study is to “investigate the anti-cancer properties of cannabis and individual cannabinoids, seeking to establish the most effective cannabinoid or combination of cannabinoids. We will also investigate whether whole plant extracts or individual cannabinoids are more effective at treating breast cancer and glioma cell types than individual cannabinoids”.
“A pressing question for me is; which is more effective as an anti-cancer agent? Whole plant extracts or individual pharmaceutical grade cannabinoids (both synthetic and plant derived)? This study will hopefully answer this question.”
Israeli Mum raises money to include more whole plant strains in Autism and Cannabis clinical study
Jeff is not alone in trying to keep patients at the heart of the studies and not company shareholders. In Israel, home to some of the most ground breaking research into cannabinoid science, a mother of an autistic son is campaigning to raise funds for the first ever clinical trial into autism and cannabis.
The trial conducted by Adi Aran, has already been approved, but Abigail Dar, mum to 23 year old Yuval, is raising money for more whole plant strains to be included in the study, as she has seen first hand how single cannabinoids are less effective with autistic children.
Abigail says: “It’s going to be the first clinical research about cannabis and autism. And it must work because if they gave clean CBD or isolated cannabinoids, and it didn’t work for autism, it would be devastating. It would be devastating because people wouldn’t bother to read exactly what they gave. They would just read cannabis doesn’t work for autistic people”.
International change needed
Despite these small steps taken by patients, parents and medical cannabis activists, right now the odds remain stacked against whole cannabis plant becoming medicine. With most countries taking their lead from the United States, Jahan Marcu sees a change in the federal stance as key.
“Drugs are designed in the United States to go into schedule 1, they’re not designed to come out of it. I think that’s what we need to talk about – an international change and a change at the level of the country through appropriate congressional action”.
But with a new anti-cannabis administration about to step up to the plate in the form of Donald Trump and his team of advisors, it seems for the short term at least, whole plant cannabis will continue to have a bumpy ride.