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14 min read
Sarah Sinclair
This article will take a deep dive into the global evidence base for the medicinal use of cannabis, with a specific focus on clinical trials and emerging areas of research in the UK. We’ll explore how the findings can inform modern healthcare and potentially make a real difference to millions of patients in the UK.
Taking place from 11-15 March, the NHS-led Healthcare Science Week is an annual celebration of professionals working in healthcare science and the impact that they have on the lives of patients’.
Over the course of the week, NHS trusts around the UK will be seizing the opportunity to raise awareness of the vital role that ​​science and technology plays in modern healthcare. They’ll also be hoping to inspire the next generation of healthcare science professionals with events at schools and colleges around the country.
What better opportunity then, to delve into the ever-expanding field of cannabis science?
Cannabis has been used as a medicine for thousands of years, the earliest known usage dating back to 2800 BC in China.
Up until 1937 cannabis was actually the main treatment for more than 100 separate illnesses or diseases, according to the US Pharmacopoeia and the prescribing of cannabis was permitted in the UK until the early 1970s.
But as regulators began to shift towards more prohibitionist-based drug policies in the 60s and 70s, it became harder to carry out scientific research on the plant and its compounds.
In 1961 cannabis was moved to schedule 1 of the UN Single Convention on Drugs, placing it in the same category as morphine, heroin, and cocaine and shortly after the UK also classed cannabis as a Schedule 1 drug with the introduction of the Misuse of Drugs Act in 1971.
This means that scientists hoping to carry out research on the plant must apply for a controlled drug licence from the UK Home Office.
When medical cannabis was legalised in 2018, it was moved to Schedule 2 when prescribed by a specialist doctor. However cannabis used in clinical trials is still effectively a Schedule 1 drug requiring extensive Home Office clearances.
The barriers to running and getting approval for clinical trials on cannabinoids makes it a challenge to collect the scientific evidence which regulators such as the Medicines and Healthcare Regulatory Agency (MHRA) and National Institute for Health and Care Excellence (NICE) have repeatedly called for.
The US-based advocacy organisation, NORML, publishes an annual update on the number of researchers papers which have been published on cannabis to date. , which shows a significant increase in recent decades as its medicinal use has become more accepted.
Meanwhile, PubMed, a free resource supporting the search and retrieval of biomedical and life sciences literature, now cites over 45,900 scientific papers on cannabis or ‘marijuana’, dating back to the year 1840.
Since 2010, NORML estimates that over 32,000 peer-reviewed papers specific to cannabis have been published with the annual number increasing year on year.
In a 2018 study, which explored the trends in cannabis-related publications, investigators reported that the total number of peer-reviewed publications dedicated to medical cannabis has increased ninefold since the year 2000.
This trend was echoed in a paper published last year by the US Food and Drug Administration. which reported that around 400 new investigational drug applications for cannabis-derived products had been submitted in the last decade — the same as in the 40 years prior combined.
The majority of clinical trials on cannabinoids in the last decade have been registered in the US.
However, according to one industry report, the UK saw the second highest number of trials registered via clinicaltrials.gov, making up 13% of all trials during the last 13 years.
The majority of these have been carried out using the licensed cannabis medicines, Epidiolex and Sativex, produced by UK-based company GW Pharmaceuticals (now Jazz Pharmaceuticals), which has been conducting research in this field for over two decades.
Before we go any further, it’s important to understand the types of research that is conducted on cannabinoids and the differences between them.
Randomised control trials (RCTs) are what is usually meant when talking about a clinical trial and these are widely considered to be the ‘gold standard’ of scientific evidence. For a product or drug to be given licensing approval by the MHRA, for example, it must have demonstrated efficacy in RCTs.
In these studies, participants are randomly assigned to groups to test a specific drug, treatment or other intervention. One group will be given the intervention, while the other (the control or comparison group) will be given a placebo or nothing at all.
The groups are then followed up to see how effective the intervention was, with outcomes measured at specific times and any differences assessed statistically.
As RCTs are usually carried out on single compound pharmaceuticals, some experts argue that this type of study is not suited to research looking at the cannabis plant as a whole. Cannabis contains over 144 different cannabinoids, along with hundreds of other compounds such as terpenes and flavonoids. All of these are thought to have their own potential medicinal effects.
Some studies have suggested that the ‘entourage effect’, the synergy of all these compounds working together actually plays a crucial role in the therapeutic action of medical cannabis, exhibiting stronger effects than any of these compounds on their own. This is something which can’t be replicated in an RCT setting (or at least not easily!)
Real-world evidence is generated from data collected outside of a highly-controlled clinical trial. Sometimes referred to as ‘anecdotal evidence’ it centres around the patients’ experiences and self-reported outcomes.
Given the challenges of conducting RCTs on cannabis-based products, real-world evidence often forms an integral part of data collection.
It can be very compelling and data collected in this way is often used to inform the design of future RCTs. However, it is not considered to be robust enough for regulators to approve drugs based on this form of evidence alone.
While there are around 144 known cannabinoids in the cannabis plant, only around 11 of these are prevalent enough in most varieties of cannabis to be considered major cannabinoids.
These include cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabidiol (CBD), tetrahydrocannabivarin (THCV), cannabinol (CBN), Δ9-trans-tetrahydrocannabinol (Δ9-THC), Δ8-trans-tetrahydrocannabinol (Δ8-THC), cannabicyclol (CBL), cannabichromene (CBC), and Δ9-tetrahydrocannabinolic acid-A (THCAA).
Out of the 11 major cannabinoids, perhaps the most well-known are CBD and THC and these also feature most often in cannabis-related clinical trials.
In recent years there has been an increase in clinical trials on isolated forms of CBD, with approximately 50% of all trials registered from 2022 onwards including CBD alone.
But as well as more interest in treatments involving multiple cannabinoids, there has also been more focus on those cannabinoids that are closely related, such as CBDV, THCV and CBDA.
While cannabis has demonstrated varying levels of medicinal potential in a wide range of health conditions, there are some indications which crop up again and again in the research.
Chronic or neuropathic pain, encompassing conditions such as fibromyalgia/myofascial pain, cancer-related pain, is particularly prevalent, as well as pain associated with neurodegenerative diseases such as multiple sclerosis (MS).
Other related conditions which have been examined in research on cannabinoids include post-surgical and post-operative pain; pelvic pain (including endometriosis) knee or back pain; fractures and pain related to inflammatory bowel disease.
But research is expanding rapidly and contrary to the longstanding belief that cannabis has a negative effect on mental health, there has been an increase in the number of clinical trials examining the potential benefits of cannabinoids for various psychiatric and neurological disorders.
These include PTSD, insomnia/sleep disorders, Tourette’s syndrome and epilepsy.
Five years since medical cannabis was legalised in the UK, the NIHR recently confirmed that to date no government-funded clinical trials on cannabinoids have been given the green light Although two RCTs exploring CBD and CBD:THC in childhood epilepsy are said to be ‘under operational consideration’.
Several private organisations have made headway when it comes to building the evidence-base, receiving regulatory approval for trials involving cannabis-based products in a range of different medical conditions.
Let’s take a closer look at some of those which have been registered on clinicaltrials.gov.
ARISTOCRAT is currently recruiting patients for a phase 2, double-blind, placebo-controlled, randomised trial comparing Sativex with placebo in patients with recurrent glioblastoma in combination with the chemotherapy drug temozolomide.
Researchers recently completed an open label, phase 2 clinical trial to assess the feasibility of CBD-dominant medicinal cannabis in managing symptoms of Long Covid. The treatment was found to be ‘safe and well-tolerated’, paving the way for future studies in this area.
The CANPAIN study is investigating the safety and efficacy of inhaled cannabis flower in chronic pain patients at a private clinic. The feasibility study is expected to enrol 100 patients, with a larger study planned for a minimum of 5,000 participants.
Completed in 2015, a pilot experimental study investigated the licensed cannabinoid-based medication, Sativex in 30 adults with ADHD. Researchers found preliminary evidence ‘supporting the self-medication’ of cannabis use in ADHD and recommended further studies on the endocannabinoid system in this specific condition.
A number of clinical trials of various stages are investigating Sativex in the treatment of spasticity and pain in multiple sclerosis (MS), diabetic neuropathy, spinal cord injury and advanced cancer pain.
Other trials have looked at the recreational use of cannabis and how it may affect people differently, including the optimal dose combination of CBD and THC and the effects of these in patients with schizophrenia, and the potential of CBD as a novel treatment for cannabis use disorder.
A number of other potentially promising clinical trials involving cannabinoids are on the horizon and at various stages of the approval process.
These include the use of cannabinoids for the treatment of chemotherapy-induced neuropathy (CIPN) and pain associated with endometriosis.
Researchers at Imperial College London’s Medical Cannabis Research Group are exploring the potential of novel cannabinoid therapies targeting inflammation and cancer and pain with a current focus on pancreatic ductal adenocarcinoma (PDAC) and acute/post-surgical, neuropathic and cancer-related pain.
Alongside these clinical trials, the UK has a significant and ever-expanding database of real-world evidence collected through schemes such as T21 (formerly Project Twenty21) led by Drug Science, and the UK Medical Cannabis Patient Registry.
To date a number of papers have been published based on this evidence, supporting the use of cannabis in a wide range of chronic conditions. Speaking generally, this evidence shows that not only does the treatment help reduce symptoms but it also vastly improves patients’ quality of life.
These include:
It is clear that there is significant interest in researching cannabinoids and their therapeutic potential.
While the evidence is still in its infancy, studies have shown that cannabinoids hold promise in the management of hard-to-treat conditions where there is currently an unmet need, particularly in treating spasticity and neuropathy and various forms of chronic pain.
Many patients who report benefit from cannabis medicines have tried numerous conventional treatments and prescription drugs without success. In these cases, cannabis could offer much-needed hope and the chance for them to regain some of their quality of life.
The real-world evidence for medical cannabis is compelling and the experience of patients’ should be considered when looking at this unique form of medicine. However, it is important that more RCTs are conducted in the UK to allow for medical cannabis treatment to be rolled out more widely.
It is also hoped that government-funded trials will be rolled out in the near future, as well as data collection through the NHS Patient Registry, to help build the evidence base for the safety and efficacy of medical cannabis and inform future clinical trials.
Millions of people in the UK could stand to benefit from medical cannabis treatment. Releaf’s own research found up to 50% of the population (approximately 29.6 million people) have a condition which means they could be eligible for a medical cannabis prescription.
The data also showed that 45.6% of those reported living with significant distress and discomfort, and one in four said they were worried about their future health. However, less than 1% of patients that could potentially benefit are able to access cannabis legally.
Investing in more research and clinical trials is crucial to ensure that in the future all those who are eligible are able to access medical cannabis and to ensure more healthcare professionals are confident to prescribe.
If you have one of the conditions mentioned in this article and are interested in exploring medical cannabis, Releaf's free online eligibility checker can help you determine whether the treatment is right for you.
A team of expert clinicians will review your application and if appropriate you will be invited to schedule an appointment with a specialist consultant.
If, during the initial consultation, the clinician decides cannabis is right for you, they will issue your prescription and guide you through the next steps.
If you still have some unanswered questions, you can find out more via the FAQs page or contact a member of the team.
It is important to seek medical advice before starting any new treatments. The patient advisors at Releaf are available to provide expert advice and support. Alternatively, click here to book a consultation with one of our specialist doctors.
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Am I eligible?Sarah, a distinguished journalist with over a decade in publishing and communications, now excels in cannabis health and policy journalism in the UK, advocating for informed health decisions through her award-winning work.
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