Magic bullet or just high hopes?

There have been calls to legalise medicinal cannabis in Ireland in recent years, but pressure has recently increased due to a number of high-profile patient cases.

One of those cases is six-year-old Ava Barry from Cork, who has Dravet syndrome, an extremely rare drug-resistant form of epilepsy. She has hundreds of seizures daily and frequently spends long periods in hospital. All of the many medications that she has tried have failed to control her seizures and her parents Vera Twomey and Paul Barry believe there is now only one thing that can help her: Cannabidiol (CBD) oil, a form of medicinal cannabis, which is currently illegal in Ireland.

The couple set up an online petition to change the law, which to date has attracted almost 22,000 signatures and at the start of this month Ms Twomey planned a protest walk from Cork to the Dáil, which she called off after a personal phone call and commitment from Minister for Health Simon Harris to review Ireland’s policy on the use of cannabis for medical purposes.

The Minister also had a meeting with Ms Twomey and Mr Barry in recent weeks, where he took the opportunity to update them on the details of the review. Minister Harris has asked the Health Products Regulatory Authority (HPRA) to provide expert advice on this issue, specifically:

<p class=”listBULLETLISTTEXTMIstyles”>Recent developments in the use of cannabis for medical purposes, in particular an overview of products that have been authorised in other jurisdictions;

<p class=”listBULLETLISTTEXTMIstyles”>An overview of the wider ongoing and emerging clinical research in new indications and evidence of efficacy;

<p class=”listBULLETLISTTEXTMIstyles”>An overview of the different regulatory regimes in place in countries which allow cannabis to be used for medicinal purposes;

<p class=”listBULLETLISTTEXTMIstyles”>Legislative changes that would be required to allow use of cannabis for medicinal purposes in Ireland.

The Joint Oireachtas Health Committee will also examine the issue of cannabis for medicinal purposes. Minister Harris hopes to receive the report from the HPRA and the output from the Oireachtas Health Committee in January. He will then be in a position to move forward with any legislative changes that may be recommended.

During the summer, the People Before Profit/Anti Austerity Alliance tabled a Bill in the Dáil calling for the legalisation of cannabis for medical purposes, ie, for those with multiple sclerosis, epilepsy, and cancer. The Medicinal Cannabis Bill 2016 calls for the establishment of a Cannabis Regulation Authority and will be debated on 1 December.

Separately, Irish pharmaceutical start-up, GreenLight Medicines recently commenced its first phase of research with a number of Irish universities, as it aims to advance medicines using CBD and other plant-derived molecules to treat a variety of illnesses.

GreenLight-commissioned research is now underway in a number of universities throughout Ireland and the UK, including University College Dublin (UCD), which will be investigating cancer and a joint study between UCD and Imperial College London, which will focus on addiction. A study by the RCSI will focus on epilepsy, while Ulster University will investigate arthritis.

So is cannabis really a magic bullet for certain medical conditions?

Below Dr Des Corrigan, Chairman of the National Advisory Committee on Drugs and Alcohol and Director of the School of Pharmacy at Trinity College Dublin, outlines the evidence for the use of CBD-based medicines for epilepsy and other conditions.

<h3 class=”subheadMIstyles”>The evidence for cannabidiol-based medicines for epilepsy and other conditions</h3>

The UK medicines regulator (MHRA) recently issued a letter to suppliers of CBD-containing products instructing them to stop supplying such products without a valid marketing authorisation as they had determined that CBD met the criteria for a medicinal product. Thus only CBD-containing products licensed on the basis of the normal criteria of quality, safety, and clinically proven efficacy could in future be supplied to patients.

CBD is one of 70 phytocannabinoids produced by cannabis plants. It would be considered to be one of the major constituents of cannabis alongside Delta -9-THC. Depending on the type of plant involved, CBD may be the predominant cannabinoid, as is the case with the hemp or fibre-type, or it may be virtually absent from the genetically selected drug-type plants specifically grown nowadays to maximise THC content in the form that is now called weed or skunk in slang terms. CBD was first isolated in 1940 but its exact chemical structure was not elucidated until 1963. It is an unusual cannabinoid in that it does not bind to either the CB1 or CB2 cannabinoid receptors. As a result it is not considered to be ‘psychoactive’ in the way that THC gives cannabis users their characteristic “high”, but more importantly it is not psychotogenic as THC is and in fact it seems to have neuroprotective effects against THC in cannabis smokers. Strictly speaking CBD is psychoactive, though, because it does have demonstrable sedative and anti-convulsant activity.

Those anti-epileptic effects of CBD were among the first pharmacological actions discovered when the pure compound became available for study in the 1970s and there is an abundance of preclinical studies showing positive effects on seizure reduction in various <em>in vivo</em> models. The mechanism of action is still unclear but it is clear that it does not involve the classical endocannabinoid system. A number of small and methodologically limited studies of CBD in humans have given inconclusive results.

A 2014 Cochrane Review of CBD-enriched therapies for the treatment of epilepsy found only four randomised studies involving a total of 48 participants. One report was an abstract while another was a ‘Letter to the Editor.’ Existing anti-epileptic medication was continued alongside the CBD. One study reported that two out of four patients became seizure-free over 12 weeks but the remaining trials either reported no benefit or the treatment effect was unclear. According to Cochrane, “all the reports were of low quality. No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy”.

Anecdotal evidence reported in the media suggests that CBD may be effective in cases of intractable epileptic syndromes in infants, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS).

Dravet syndrome is also known as Severe Myoclonic Epilepsy of Infancy (SMEI) and is characterised by seizures, which are often triggered by high temperatures beginning about six months of age. It is a lifelong condition that worsens as the child ages, progressing to include psychomotor problems, learning difficulties, sleep disorders, and behavioural problems, such as hyperactivity and impulsiveness. The burden on parents and other caregivers is enormous.

Conventional treatments include clobazam, stiripentol, topiramate, and valproic acid. LGS is another childhood epilepsy that is difficult to treat. It appears between the ages of two to six years and involves multiple daily seizures, abnormal EEG patterns and moderate to severe intellectual impairment.

The best publicised case of treatment of Dravet syndrome with CBD is that of ‘Charlotte’ who had a 90 per cent decrease in seizures after three months of using an extract from a strain of cannabis now called ‘Charlotte’s Web,’ which had a CBD to THC ratio of 16 to one. One study from UCLA in the journal <em>Epilepsy and Behaviour </em>surveyed parents of children with infantile spasms (IS) and LGS who had been treated with CBD-enriched cannabis preparations. A reduction in seizure frequency was reported by 85 per cent of parents, with 14 per cent reporting complete freedom from seizures.

The authors of the study wrote, “although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy, including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by a lack of blinded outcome assessment”.

A 2015 press release from one company that previously had licensed a cannabis-based medicinal product for MS, reported on data from a clinical trial in 58 patients with treatment-resistant epilepsies, including Dravet syndrome, who had received a product containing a cannabis extract consisting of more than 97 per cent CBD and less than 3 per cent of THC for at least three months. The reported median reduction in seizure frequency was 43 per cent for all patients. Fatigue and sleepiness were the side effects reported by 80 per cent of participants. Diarrhoea and appetite changes were also reported.

At the present time there are at least 19 small-scale trials under way to study whether non-psychoactive cannabinoids may be useful as anti-epileptics. In addition, there are trials in MS patients, in schizophrenia and bipolar disorder, in social anxiety, in neuropathic and cancer pain, in anorexia in cancer patients, in Huntington’s disease, and in insomnia.

A 2016 Expert Opinion on Investigational Drugs looked at the promise of phyto-, endo-, and synthetic cannabinoids as chemotherapeutic agents in breast and prostate carcinomas, reporting that CBD may have promise in combination therapy for breast and prostate cancer due to its direct anti-tumour effects and its ability to improve the efficacy of anti-tumour drugs. Palliative effects on nausea, vomiting, pain, and appetite may also prove valuable.

Should any or all of these studies show positive benefits, which would allow the products to be licensed as medicinal products, then it is reassuring, given the fact that CBD does not act via the endocannabinoid system so abuse liability is likely to be low to non-existent, as would be dependence potential.

The final word (for now) goes to the Cochrane Review: “Further trials are needed.”

<strong>Dr Des Corrigan</strong>