Evolution of cannabinoids from recreation to mainstream

The proposed role for cannabis in medicine has been leveraged for some years now, with illegal sources being smoked or baked to ameliorate clinical issues such as muscle spasticity or pain. Cannabis for medical use is for sale legally in some states in the USA, and most recently in Thailand and the Isle of Man public consultation is currently underway to allow patients to buy medicinal cannabis in pharmacies.

Emerging data from the USA shows that  where medical cannabis is legal it may reduce reliance on opioids, with two studies demonstrating a reduction in opioid prescriptions, although both were population-based studies from which cause and effect are hard to derive. More detailed studies from the USA suggest medical cannabis could reduce opioid prescribing, self-reports of opioid misuse and reduced treatment admissions for opioid addiction; but more studies are needed.

Not surprisingly for a natural product, cannabis contains >100 cannabinoids some of which create the ‘high’ feeling associated with cannabis and others not. The two compounds of interest include tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the primary psychoactive compound of cannabis, whereas CBD has not been associated with psychoactive properties and they are emerging as interesting molecules for a range of conditions.

Clinical applications of cannabinoids – pain

Medicinal cannabis (CBD, CBD/THC and THC) is used widely for the treatment of pain, but data are largely equivocal. In fibromyalgia medicinal cannabis had no impact on pain that was significantly better than placebo. Only in pressure pain tolerance experiments did medical cannabis containing high levels of both THC and CBD or THC alone significantly reduce pain. However, both preparations also elicited a moderate ‘high’ in patients including reductions in alertness, mood and perception.

A meta-analysis of cannabinoids (unspecified) indicated increases in pain tolerance, reductions in unpleasantness of experimental pain, but no reliable decrease in experimental pain intensity. In a second meta-analysis selective cannabinoids subject to pharmaceutical production such as Savitex (nabiximols), dronabinol (delta-9-tetrahydrocannabinol [Δ9-THC]) and nabilone (synthetic delta-9-tetrahydrocannabinol) demonstrated a significant, but clinically small reduction in pain compared with comparators (pharmacological therapies, physical therapy or combination) p=0.002. In cancer pain unalleviated by optimised opioid therapy, Sativex failed to meet its primary endpoint of changed in pain but in a post-hoc analysis Sativex appeared to provide statistically significant pain relief in younger patients (<65 years).

Given the high levels of heterogeneity among studies for pain, large, randomised studies are required to better evaluate the role of cannabinoids in pain. It may be in these instances that cannabinoids may make pain feel less unpleasant and more tolerable rather than diminishing the intensity of pain. And it may be this effect that underlies the widely held belief that cannabis relieves pain. Case reports however, across a range of pain types continue to emerge where THC, CBD or combined THC/CBD can alleviate pain scores and reduce overall analgesic intake.

It’s not all gloomy, however. CBD has been suggested for some time as a potential analgesic. Recent data in animal models in osteoarthritis indicated that CBD reduced swelling and pain and improved weight bearing. These studies suggest that CBD may have a role in attenuating neuropathic pain and molecules are in development to explore this. Larger trials in humans are awaited.

Clinical applications of cannabinoids – THC

THC has clinical uses in increasing appetite in patients with extreme weight loss in diseases such as AIDS, and to treat nausea and vomiting associated with chemotherapy. For appetite stimulation dronabinol is available in the USA as and marketed as Marinol. Clinical studies have demonstrated a substantial improvement in appetite and trends towards improved body weight and mood. Similarly, nabilone, which is structurally distinct from naturally occurring THC in cannabis is approved for use in the treatment of nausea and vomiting associated with chemotherapy when other anti-emetics have failed. Nabilone mimics the pharmacological activity of natural THC through partial agonism at cannabinoid-1 and 2 receptors (CBR-1 and CBR-2) but is twice as active. It is marketed in Canada, USA, UK and Mexico as Cesamet.

In combination with CBD, THC derived from Cannabis sativa is used in a mouth spray to alleviate muscle spasticity in patients with multiple sclerosis (MS) with inadequate responses to previous anti-spasticity medication. It is marketed under the brand name Sativex and was first licensed in the UK in 2010. In clinical studies, Sativex has demonstrated significant improvements in spasticity compared with baseline versus placebo, but between treatment differences were not significant. As a result, NICE in the UK, do not recommend Sativex as it is not considered clinically or cost-effective.

However, several recent studies have suggested significant improvements with Sativex in MS. In one, Sativex as add-on therapy to current anti-spasticity medication ensured significantly more patients experienced >30% improvement on a spasticity numerical rating scale (NRS) 77.4% of patients vs 32.11; p<0.0001), and significantly improved parameters of mean pain (p=0.0013) and mean Ashworth’s Scale (a measure of muscle resistance during soft-tissue stretching) (p=0.0007) (Markova et al. 2018). A second smaller study demonstrated analgesic efficacy in MS particularly in improvement in cold pain threshold, thought to be via modulation of peripheral cold-sensitive TRP channels (Turri et la. 2018). NICE guidance for MS is currently being reviewed and it is not yet known what the impact of new data for Sativex will be.

Very recently published data of Sativex in 60 patients with Motor Neurone Disease (MND) [Riva et al. 2019] indicated significant improvements in spasticity compared with placebo (p=0.013) with a good tolerability profile. Authors suggest that larger studies are warranted.

Clinical applications of cannabinoids – CBD and epilepsy

CBD is not associated with a ‘high’ like THC and have been shown to have efficacy in rare epilepsy syndromes such as Dravet Syndrome and Lennox-Gastaut Syndrome. Lennox-Gastaut Syndrome is a severe form of epilepsy, that is difficult to control with currently available anti-epileptic drugs. Many children with Lennox-Gastaut Syndrome also develop learning difficulties or behavioural problems. Dravet Syndrome is a rare genetic epileptic syndrome caused by a gene mutation in ion channels. Seizures in Dravet Syndrome are refractory to treatment and children develop some level of development disability or other conditions. CBD has been evaluated in rare seizure conditions including Lennox-Gastaut and Dravet Syndromes. In Dravet Syndrome CBD was shown to reduce seizures by 17% and in Lennox-Gastaut syndrome by 23% (both compared with placebo).

GW Pharma have developed CBD for treatment of rare epilepsies – Epidolex – which was launched in the USA in November 2018, with EMA approval for Europe anticipated in early 2019. In clinical studies Epidolex has demonstrated a compelling 55% reduction in seizures associated with Dravet syndrome and Lennox-Gastaut Syndromes at high doses leading to its US approval. In a recently published study in patients with Lennox-Gastaut Syndrome Epidolex reduced seizure frequency by 48–60% over the course of 48 weeks, with a median reduction in monthly seizure frequency of 48–57% across all 12-week periods up to 48 weeks. Similarly, in Dravet Syndrome Epidolex reduced monthly seizure frequency by 38-44% for convulsive seizures and 39–51% overall. In both Lennox-Gastaut and Dravet Syndrome Epidolex had an acceptable tolerability profile, and significantly improved patients’ overall condition as reported by parents and caregivers.

CBD/THC and future applications

The future for cannabinoids is wide ranging with studies exploring their role in oncology, psychological conditions, neuropsychiatric conditions and rare epilepsies.

It is known that heavy cannabis use, particularly in adolescence may precipitate or exacerbate symptoms of schizophrenia. However, some studies of cannabidiol suggest it may improve positive psychotic symptoms and improve cognitive performance, although studies are conflicting with a recent study finding no improvement in psychotic symptoms or cognitive impairment.

THC or combination THC/CBD has been evaluated in glioma. Preclinical data indicates that THC/CBD in combination with temozolomide (TMZ) synergistically reduces glioma growth. A recent case report of two patients with high grade gliomas treated with CBD and TZ, demonstrated significant improvement with no evidence of disease progression for at least 2 years and at time of publication (February 2019) were still alive. Neither patient demonstrated alterations in blood chemistry indicating that CDB had no significant impact on the liver or the heart. These data warrant further studies to explore if cannabinoids plus TMZ can be exploited therapeutically.

GW Pharma have a robust clinical programme in place and CBDV a pro-drug of CBD (GWP42006) is being evaluated in phase 2 studies in glioma. This product is also being evaluated in a mode of RETT Syndrome (a severe behavioural and psychological condition due to mutations in the MECP2 gene). In a mouse model of RETT Syndrome doses of CBDV up to 100 mg/kg ip reduced brain and behavioural alterations restored general health status, sociability and brain weight, and provide a partial restoration of motor coordination. CBDV may also have applications in other rare orphan epilepsies with recent animal data in knock out mice

Ongoing studies are also exploring CBD in reducing phobic symptoms in patients with social phobia or panic disorder with agoraphobia which have proven to be refractory to treatment.

Cannabinoids – where are we now? Where next?

Medicinal cannabis was the subject of a high-profile case in the media in 2018 to treat a child with severe epilepsy. The outcry over this case and others led the UK’s Home Secretary decision to reschedule cannabis derived medicinal products from Schedule I to Schedule II of the 2001 Misuse of Drug Regulations Act in November 2018 so that clinicians can now prescribe medicinal as needed for patients. Indeed, in February 2019 it was announced that Australia’s Althea will supply medicinal cannabis in the UK and Grow Biotech made history in the UK in the same month with the first bulk shipment of cannabis-based medicines into the UK.

GW Pharma, based in the UK are leading the march in developing cannabinoids produced with the rigour expected of a pharmaceutical company. With research programmes in place for neuropathic pain, schizophrenia and infantile spasms, further indications for existing and new cannabinoids can be expected.

Cannabinoids are demonstrating a true clinical benefit to patients and it will be fascinating to see the field emerge and explore the future role of cannabinoids in a range of conditions. However, this applies only to medical grade preparations developed under strict pharmaceutical regulations. Cannabis oil or cannabis itself – vaped, smoked, baked etc. – cannot be considered safe or effective. In fact, the risks of cannabis per se, outweigh the benefits, so fully developed, licensed products are awaited with anticipation.

Further reading

Dall’Stella PB et al. Front Oncol 2019;8:643 doi: 10.3389/fonc.2018.00643

Devinksy O et al. Epilepsia 2019;60:294-302

Epilepsy Research UK – https://www.epilepsyresearch.org.uk/?s=cannabis&x=0&y=0 [Accessed February 2019]

Marcovà J et al. Int J Neurosci 2018;13:1-10

Philpott HT et al. Pain 2017;158:2442-51

Riva N et al. Lancet Neurol 2019;18:155-64

Thiele E et al. Epilepsia 2019; Feb 11 doi: 10.1111/epi.14670 [in press]

Turri M et al. Medicines (Basel) 2018;5:E59

Van de Tonk T et al. Pain 2018; Dec 20 doi: 10.1097/j.pain.0000000000001464 [in press]

Whiting PF et al. JAMA 2015;313:2456-73