feature

Cannabis and epilepsy

Benjamin J Whalley explores the potential of cannabis as a treatment for epilepsy. He describes the research and development of particular cannabis compounds and the social climate that may still be undermining their future use
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Benjamin J Whalley

cannabis and epilepsy

Cannabis contains >500 different components. Some have been historically associated with anticonvulsant effects and others with proconvulsant effects. In 2013, two isolated non-psychoactive components of cannabis entered human clinical trials as part of an anti-epileptic drug development programme. Unregulated cannabis extracts with psychoactive components are being administered outside of regulated trials to children with treatment resistant epilepsy in US states where cannabis use has been decriminalised.

t seems as though barely a week will pass without the mass media highlighting the risks of cannabis use or its potential therapeutic benefits. Or as more often seems to be the case both! However, in recent months, the risk and potential benefits of cannabis and its components in epilepsy have received more attention than has been the case in previous years. When we talk of cannabis, we refer to the plant Cannabis sativa L. Although there are two other types (Cannabis indica and Cannabis ruderalis), they rarely receive as much attention. This is largely because they produce only limited amounts of the psychoactive component, 9-tetrahydrocannabinol (THC), in which most recreational users are interested. However, THC remains only a small part of cannabis and of the cannabis story. The herb and its extracts contain more than 100 chemically similar compounds (called cannabinoids). They also contain over 400 other non-cannabinoid compounds, each with a distinct pharmacology. Interestingly, the cannabis plants closest relative is the hop. This evolutionary link can be most clearly perceived if you have ever taken a deep breath while in an oast house where hops are being kilned.
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Both plants owe their characteristic smell to their shared aromatic terpenoid components. Cannabis remains best known as a drug of recreational use and is consumed by approximately 150

Despite substantial preclinical evidence of efficacy... few cannabis-based medicines have received licenses for medicinal use
million people around the world each day. It was also probably the first non-food crop grown by man with evidence of its use for fibres dating back to 8,000 BCE. Subsequently, both recreational and therapeutic use was confined to the Far and Middle East.

The Western appropriation

The Western world remained oblivious to cannabis until the 19th Century, when several physicians experimented with it. Most notable among these was JRR Reynolds, Queen Victorias personal physician, who allegedly prescribed it as a treatment for dysmenorrhea (severe period pains). In addition to Reynolds, three

other physicians McMeens, Moreau and OShaughnessy explored potential therapeutic uses for cannabis. They suggested benefits in the treatment of a diverse range of disorders including glaucoma, cramp, gout, burns, appetite stimulation, bowel discomfort, pain, epilepsy, colic, insomnia, diabetes and a variety of mental health disorders. Turning the clock forwards to the 20th Century, a formulation for cannabis tincture was included in the British Pharmaceutical Codex. It was listed as an anodyne sedative or hypnotic in mania, spasmodic coughs, phthisis, asthma, and dysmenorrhoea. It has been used in the treatment of chorea and paralysis agitans. The listing was removed in 1971. Thereafter, it is interesting to note that, despite substantial preclinical evidence of efficacy in many of the disorders mentioned above, few cannabis-based medicines have received licences for medicinal use. Specifically, nabilone (THC) has been available for the treatment of chemotherapy-induced nausea and vomiting since the 1980s. However, it has also been used outside of this licensed indication for a number of pain-related indications. Also, in 2005, Sativex a combination treatment for pain and spasticity associated with

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multiple sclerosis was licensed. Sativex is notable since it not only contains THC but an equal amount of the non-psychoactive cannabis component, cannabidiol (CBD). As a point to which we shall return later, it is notable that both nabilone and Sativex are contraindicated in patients with a history of seizures. It is interesting to speculate about the reasons behind the existence of a significant preclinical evidence base but a lack of commercial drug development of cannabinoid compounds in the clinic. This is a common topic of heated discussion among both recreational and medicinal cannabis advocacy groups! However, more down-to-earth reasons for this apparent incongruity are clear. The conventional business model of pharmaceutical drug development allows investment costs to be recouped by providing several years of market exclusivity for a new medicine. This comes by way of the patent protection of a New Chemical Entity (NCE). As natural products, the plant cannabinoids cannot be commercially composition of each of the approximately 500 different extract componentswithout access to the proprietary cannabis strains. Rather than using conventional legal protection, this approach makes the cost: benefit for a competitor unattractive and therefore provides sufficient commercial protection. However, one limitation associated with such an approach may be that it remains viable only when targeting a niche indication with a relatively small patient population (such as late-stage multiple sclerosis). The wider the population in which a medication may be used, the lower the risk that the initial financial outlay associated with producing a generic competitor would not be recouped. In treatments for a condition like epilepsy, the potential financial return could make it worth trying to reproduce a complex mixture. In this case, a competitor might be more likely to take advantage of the lack of any legal protection over a newly developed compound. The only other cannabinoid medicine to receive a licence for clinical use was rimonabant, an anti-obesity treatment that was, in its own way, unique. Here, the discovery in the late 1980s of the mammalian endocannabinoid system (see panel) was used to develop synthetic ligands that targeted a significant component of this system, the cannabinoid (type 1) receptor (CB1). Rimonabant was developed to act as an antagonist (blocker) at CB1 receptors and thus inhibited endocannabinoid signalling. The rationale for this use was based on the well-known effect of THC a partial agonist (activator) at CB1 receptors to increase appetite. I believe this is an effect referred to by recreational users as the munchies! Hypothesising that rimonabants blockade of CB1 receptors would

Benjamin J Whalley

The endocannabinoid system

The endocannabinoid system is a largely ubiquitous biological system present in the majority of animal species. It comprises biosynthesis, receptor, signalling and degradation components associated with the two principal endogenous cannabinoids (endocannabinoids) found in our bodies. These are anandamide and 2-arachidonoyl glycerol. The receptor for these endocannabinoids appears as two subtypes, CB1 and CB2. CB1 is principally present in nervous tissue, where it dynamically modulates neurotransmission. CB2 is more prevalent in the periphery, where it mediates immune responsiveness. Rather like nomenclature of the opioid system, the cannabinoid system was so called by virtue of THC being the prototypical ligand first used to probe the pharmacology of the CB1 receptor. reduce endocannabinoid-induced appetite stimulation, the compound was developed for the treatment of obesity. However, while rimonabant was successful in clinical trials and early use, it was withdrawn from use in 2008. Concerns were raised about psychiatric side-effects, particularly suicidal ideation and depression at higher doses. Some discussion ensued surrounding whether or not rimonabants withdrawal was premature. The reported side-effects are associated with a variety of other licensed medications that remain available for use. These include selective serotonin re-uptake inhibitors (SSRIs) and benzodiazepines. Whether or not the decision to
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Sativex not only contains THC but an equal amount of the non-psychoactive cannabis component, cannabidiol
protected in this way, which necessitates the use of other approaches. Sativex illustrates one novel response to this challenge. Here, two proprietary strains of cannabis (one rich in THC, the other in CBD) were developed and the licensed medicine formulated from a 1:1 mixture of each complex extract. Any competitor would be obliged to produce a generic product that precisely matched the

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cannabis and epilepsy

potent. Meanwhile, tetrahydrocannabivarin (THCV) blocks the CB1 receptor but partially activates CB2 receptors. Turning our attention specifically to cannabis, cannabinoids and epilepsy, the plant has a longstanding but conflicted association with seizures. As long ago as 1,100CE, a scribe called al-Mayusi described its use to treat convulsions. Specific references to its use in this way were also made in the 15th Century by Ibn al-Badri. Thereafter, the 19th Century saw Reynolds, OShaughnessy, Moreau and McMeens each independently test extracts of cannabis in seizures and report beneficial effects. Reynolds went as far as writing that cannabis is the most useful agent with which I am acquainted in the treatment of attacks or violent convulsions which may recur two or three times in the hour. He later specifically identified seizures resistant to bromide as often responding to treatment with cannabis. However, since the 19th Century, evidence describing the effects of cannabis in epilepsy has remained limited and ambiguous. Numerous individual case studies have been published, the majority reporting the successful use of cannabis by patients to control drug-resistant seizures. In most cases, it was used as an adjunct to conventional treatment. A minority of reports suggest that cannabis use might exacerbate epilepsy. Several surveys have examined the relationship between recreational cannabis use and epilepsy in addition to alleged medicinal use to control seizures. The majority again found that the reported effects are anticonvulsant, but no clinical trials have been conducted. Similarly, preclinical evidence is conflicting where herbal cannabis has been tested in animal models of

withdraw was influenced by rimonabants mechanism of action by way of the endocannabinoid system and, by extension, its association with cannabis and the inevitable social stigma is still speculated upon. Nevertheless, since withdrawal, there has been no sign of any commercial

Since the 19th Century, evidence describing the effects of cannabis in epilepsy has remained limited
clinical development of other CB1 antagonists. An oft-ignored footnote to this story is the fact that preclinical studies and one clinical case study suggested that rimonabant could be proconvulsant. Thus, despite THC and Sativex both being pharmacological opposites of rimonabant, all three drugs were contraindicated for use in patients with a history of seizures.

Renewed attention

The discovery of the endocannabinoid system produced a surge in the number of synthetic endocannabinoid system modulators available, including agonists, antagonists and inhibitors of degradation. Not only that, it also hailed a resurgence of interest in plant cannabinoid pharmacology. A huge variety of plant cannabinoids have been tested for direct effects on the endocannabinoid system. Somewhat ironically, only three of the 100 present in the plant have been found to exert notable effects as physiologically relevant concentrations. Here, THC partially activates cannabinoid receptors and is responsible for cannabis psychoactivity. Cannabinol (CBN) acts in the same way, but is 50 times less
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epilepsy and seizure in a number of species. A mixed response was seen with some studies reporting anticonvulsant effects and some proconvulsant responses. Importantly, the majority of these studies were conducted several decades ago, prior to modern standardisation of species, models and housing conditions used. Although no human trials have been conducted, pure THC and a variety of synthetic CB1 agonists have more recently been tested in preclinical disease models. These preclinical tests have provided a substantial evidence base around effects in eight different species and nearly 100 unique models, conditions or experimental designs. Here, 68 per cent of studies reported an anticonvulsant effect, 22 per cent

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reported no effect, while 10 per cent reported proconvulsant effects. These results largely reflect the reports from clinical cases and surveys. Also of interest was a US National Toxicology Programme study. This reported reliable induction of seizures in otherwise healthy rats and mice after several weeks treatment with THC. However, seizure frequency diminished after several months of treatment and so does not follow a classic pattern of kindling or epileptogenesis. In comparison, a small number of other plant cannabinoids have been examined in preclinical models and found to be of limited effect (for

Benjamin J Whalley

28 different models, conditions and designs have been examined and anticonvulsant responses were reported in 81 per cent of cases
instance, CBN and THCV). However, the second most common plant cannabinoid, CBD, and more recently its propyl derivative, cannabidivarin (CBDV) have been extensively tested with promising results. Here, 28 different models, conditions and designs have been examined and anticonvulsant responses were reported in 81 per cent of cases. In the remaining cases, no effect was seen (although hindsight now tells us that a significant proportion of these studies failed because inadequate doses were used). Importantly, no published studies using pure CBD have reported proconvulsant effects. From a mechanistic perspective, CBD remains enigmatic. It can functionally modulate

the effects of THC, but does not directly interact with the endocannabinoid system at physiologically relevant concentrations. Aside from the endocannabinoid system, a host of other molecular targets have been proposed. These include TRP channels, 5HT receptors, the GPR55 orphan receptor, adenosine reuptake and modulation of intracellular calcium. However, to date, while the molecular target(s) that mediate the anticonvulsant effects of CBD and CBDV remain unknown, they both lack the psychoactivity associated with THC. Encouragingly, four small clinical trials of the use of pure CBD have been conducted. Of these, all had significant limitations (open label, under-powered, no baseline and so on) and so any conclusions drawn from their findings must remain speculative. In two, no beneficial effect of CBD treatment (of up to 300mg daily) was reported, although no adverse effects were noted. In the two others, beneficial effects of treatment with similar doses were reported, although somnolence as an adverse effect was noted.

The current climate

In recent months, CBD particularly has come to the attention of more and more people in the epilepsy community as a result of two different types of activity. The first started in 2007 with investment by GW Pharma in a preclinical drug development programme at the University of Reading. The programme specifically explored CBD and CBDV use in the treatment of epilepsy. Recapitulation of several older studies (but using modern conditions and methods), plus the addition of studies employing modern models of seizure and epilepsy, led to Phase 1 clinical trials of CBDV in 2013.
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cannabis and epilepsy

Now we must wait for public announcement of the results of both the Phase 1 CBDV trial and the ongoing Phase 2 CBD trial. Still, the unregulated use of cannabis and particularly CBD-rich extracts by patients and especially by parents of children with treatment-resistant epilepsy warrants consideration. While this activity has attracted a huge amount of media attention in the US and elsewhere, the reports remain anecdotal and thus subject to the risk of positive reporting bias. Furthermore, with only a few exceptions (see Jacobson and Porter in Further Reading), the children are receiving extracts containing significant quantities of THC. At the reported doses, this will exert psychoactive effects. The crude and unstandardised nature of these extracts also presents cause for concern. The cannabis strain, growing conditions, extraction process and storage can have a profound effect on the final composition of an extract. Also, the potential pharmacological effects of the majority of the approximately 500 components of a given cannabis extract are not known. These combined facts coupled with the knowledge that many of these children are being treated with high doses of concurrent conventional medication mean that unpredictable drug/drug interactions are a significant risk. Finally, while the evidence remains contradictory, concerns remain about the use of any material that contains THC in children. THC has been claimed to affect long-term cognitive function and susceptibility to mental health problems. Given the critical condition of some of these patients and their limited response to conventional medication, one can sympathise enormously with the circumstances in which their parents find themselves. However, acceding to the naturalistic fallacy that natural means safe could be a dangerous error in these cases. Considered, measured and wellregulated clinical trials represent the only safe and objective way to assess the potential that plant cannabinoids may hold for the treatment of epilepsy. While THC can clearly exert anticonvulsant effects, the evidence suggests its use is associated with greater risks. This further justifies the ongoing clinical investigation of non-psychoactive CBD alone in epilepsy before any consideration of whether the potential benefits of trials involving THC/CBD combination outweigh the risks.

Around the time of Phase 1 CBDV studies, reports of parents in the US who were using CBD-rich cannabis extracts for the treatment of treatment-resistant epilepsy in children began to emerge. This was largely a result of the legalisation of cannabis in some US states. This story led to specific interest in CBDs potential for clinical development and the discussion of appropriate approaches for such development. This culminated in a symposium on the topic, organised by Prof Orrin Devinsky (NYU; see Further Reading) in late 2013. Shortly thereafter, approval for development under the US Food and Drug Administration Office of Orphan Products Development (OOPD) programme was granted. OOPD advances evaluation and development of treatments that demonstrate promise in rare diseases, such as the epilepsies affecting many of these children (Dravet Syndrome, for instance). Fortunately, the Phase 1 study of CBDs safety and tolerability in healthy subjects had been undertaken during the development of Sativex which is 50 per cent CBD. As a result, an open-label safety and tolerability study in children with treatment-resistant epilepsy could begin. This study is now recruiting participants. Of particular interest is the fact that the OOPD grants

Benjamin J Whalley University of Reading

Further reading
Hill AJ et al (2012). Cannabidivarin is anticonvulsant in mouse and rat. British Journal of Pharmacology (Vol 167, Issue 8) pp.1,62942 Hill AJ, Hill TDM and Whalley BJ (2013). The development of cannabinoid based therapies for epilepsy. In: Murillo-Rodrguez E (Ed) Endocannabinoids: Molecular, pharmacological, behavioural and clinical features. [Kindle e-book] Bentham Science Publishers, pp. 164205. Available at www.amazon.co.uk Jones NA et al (2010). Cannabidiol displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo. Journal of Pharmacology and Experimental Therapeutics (Vol 332, Issue 2) pp. 56977 Jones NA et al (2012). Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure (Vol 21, Issue 5) pp. 344-52 New York University (2013). Langone Medical Center Symposium: Cannabidiol: Potential use in epilepsy [online] Available from http://faces.med. nyu.edu/research-education/cannabidiol-conference Porter BE, Jacobson C (2013). Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior (Vol 29, Issue 3) pp. 574-7 doi:10.1016/j. yebeh.2013.08.037 Whalley BJ. American Herbal Pharmacopeia Monograph on Cannabis and Seizures. [Online] Available from tinyurl.com/herbalAHP [Accessed March 2014]

The unregulated use of cannabis and particularly CBD-rich extracts by patients warrants consideration
exclusivity to approved medicines. This renders the previously highlighted challenges that face commercial protection of natural products moot.
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