Posts Tagged Cannabinoid
Purpose of review
Treatment-resistant epilepsy (TRE) is associated with severe morbidity and mortality and affects over 30% of epilepsy patients. Despite advances in epilepsy management over the last 30 years, this rate has largely remained unchanged. Through a largely patient driven movement and despite federal regulations, cannabidiol (CBD) emerged as a candidate drug for improving the management of treatment-resistant epilepsies. This review highlights the available research on CBD and its therapeutic role in the treatment of TREs.
Randomized controlled trials have established CBD as an add-on treatment option for the management of seizures in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), and there is a growing body of additional literature supporting CBD’s use as an add-on therapy in other TREs. Several studies have shown CBD to be a safe anti-seizure medication with dose-dependent mild-moderate adverse events which resolve with treatment de-escalation. CBD does affect toxicity with other anti-seizure medications including clobazam and valproate.
CBD is a safe and efficacious adjunctive therapy in the management of treatment-resistant epilepsies.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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•• Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–20. This pivotal clinical trial provided evidence of CBD efficacy as adjunctive therapy in Dravet syndrome assisting its eventual Federal Drug Administration (FDA)-approved indication for adjunctive therapy in this patient population.
•• Devinsky O, Patel AD, Cross JK, Villanueva V, Wirrell EC, Previtera M, et al. Effects of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378:1888–97. This pivotal clinical trial provided evidence of CBD efficacy as adjunctive therapy for the treatment of drop seizures in Lennox Gastaut Syndrome assisting its eventual Federal Drug Administration (FDA)-approved indication for adjunctive therapy in this patient population.
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Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.
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• Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59(8). The results from this expanded access open-label program provide the largest published cohort to date of CBD use in a population of both children and adults with TREs providing important long-term safety and treatment effect data.
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The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.
Traumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (Langlois et al., 2006). Young men are consistently over-represented as being at greatest risk for TBI (Langlois et al., 2006). While half of all traumatic deaths in the USA are due to brain injury (Mayer and Badjatia, 2010), the majority of head injuries are considered mild and often never receive medical treatment (Corrigan et al., 2010). Survivors of TBI are at risk for lowered life expectancy, dying at a 3⋅2 times more rapid rate than the general population (Baguley et al., 2012). Survivors also face long term physical, cognitive, and psychological disorders that greatly diminish quality of life. Even so-called mild TBI without notable cell death may lead to enduring cognitive deficits (Niogi et al., 2008; Rubovitch et al., 2011). A 2007 study estimated that TBI results in $330,827 of average lifetime costs associated with disability and lost productivity, and greatly outweighs the $65,504 estimated costs for initial medical care and rehabilitation (Faul et al., 2007), demonstrating both the long term financial and human toll of TBI.
The development of management protocols in major trauma centers (Brain Trauma Foundation et al., 2007) has improved mortality and functional outcomes (Stein et al., 2010). Monitoring of intracranial pressure is now standard practice (Bratton et al., 2007), and advanced MRI technologies help define the extent of brain injury in some cases (Shah et al., 2012). Current treatment of major TBI is primarily managed through surgical intervention by decompressive craniotomy (Bullock et al., 2006) which involves the removal of skull segments to reduce intracranial pressure. Delayed decompressive craniotomy is also increasingly used for intractable intracranial hypertension (Sahuquillo and Arikan, 2006). The craniotomy procedure is associated with considerable complications, such as hematoma, subdural hygroma, and hydrocephalus (Stiver, 2009). At present, the pathology associated with TBI remains refractive to currently available pharmacotherapies (Meyer et al., 2010) and as such represents an area of great research interest and in need of new potential targets. Effective TBI drug therapies have yet to be proven, despite promising preclinical data (Lu et al., 2007; Mbye et al., 2009; Sen and Gulati, 2010) plagued by translational problems once reaching clinical trials (Temkin et al., 2007; Tapia-Perez et al., 2008; Mazzeo et al., 2009).
The many biochemical events that occur in the hours and months following TBI have yielded preclinical studies directed toward a single injury mechanism. However, an underlying premise of the present review is an important need to address the multiple targets associated with secondary injury cascades following TBI. A growing body of published scientific research indicates that the endogenous cannabinoid (endocannabinoid; eCB) system possesses several targets uniquely positioned to modulate several key secondary events associated with TBI. Here, we review the preclinical work examining the roles that the different components of the eCB system play in ameliorating pathologies associated with TBI.
The Endocannabinoid (eCB) System
Originally, “Cannabinoid” was the collective name assigned to the set of naturally occurring aromatic hydrocarbon compounds in the Cannabis sativa plant (Mechoulam and Goani, 1967). Cannabinoid now more generally refers to a much more broad set of chemicals of diverse structure whose pharmacological actions or structure closely mimic that of plant-derived cannabinoids. Three predominant categories are currently in use; plant-derived phytocannabinoids (reviewed in Gertsch et al., 2010), synthetically produced cannabinoids used as research (Wiley et al., 2014) or recreational drugs (Mills et al., 2015), and the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995).
These three broad categories of cannabinoids generally act through cannabinoid receptors, two types of which have so far been identified, CB1 (Devane et al., 1988) and CB2 (Munro et al., 1993). Both CB1 and CB2 receptors are coupled to signaling cascades predominantly through Gi/o-coupled proteins. CB1 receptors mediate most of the psychomimetic effects of cannabis, its chief psychoactive constituent THC, and many other CNS active cannabinoids. These receptors are predominantly expressed on pre-synaptic axon terminals (Alger and Kim, 2011), are activated by endogenous cannabinoids that function as retrograde messengers, which are released from post-synaptic cells, and their activation ultimately dampens pre-synaptic neurotransmitter release (Mackie, 2006). Acting as a neuromodulatory network, the outcome of cannabinoid receptor signaling depends on cell type and location. CB1 receptors are highly expressed on neurons in the central nervous system (CNS) in areas such as cerebral cortex, hippocampus, caudate-putamen (Herkenham et al., 1991). In contrast, CB2 receptors are predominantly expressed on immune cells, microglia in the CNS, and macrophages, monocytes, CD4+ and CD8+ T cells, and B cells in the periphery (Cabral et al., 2008). Additionally, CB2 receptors are expressed on neurons, but to a much less extent than CB1 receptors (Atwood and MacKie, 2010). The abundant, yet heterogeneous, distribution of CB1 and CB2 receptors throughout the brain and periphery likely accounts for their ability to impact a wide variety of physiological and psychological processes (e.g., memory, anxiety, and pain perception, reviewed in Di Marzo, 2008) many of which are impacted following TBI.
Another unique property of the eCB system is the functional selectivity produced by its endogenous ligands. Traditional neurotransmitter systems elicit differential activation of signaling pathways through activation of receptor subtypes by one neurotransmitter (Siegel, 1999). However, it is the endogenous ligands of eCB receptors which produce such signaling specificity. Although several endogenous cannabinoids have been described (Porter et al., 2002; Chu et al., 2003; Heimann et al., 2007) the two most studied are anandamide (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995). 2-AG levels are three orders of magnitude higher than those of anandamide in brain (Béquet et al., 2007). Additionally, their receptor affinity (Pertwee and Ross, 2002; Reggio, 2002) and efficacy differ, with 2-AG acting as a high efficacy agonist at CB1 and CB2 receptors, while anandamide behaves as a partial agonist (Hillard, 2000a). In addition, anandamide binds and activates TRPV1 receptors (Melck et al., 1999; Zygmunt et al., 1999; Smart et al., 2000), whereas 2-AG also binds GABAA receptors (Sigel et al., 2011). As such, cannabinoid ligands differentially modulate similar physiological and pathological processes.
Distinct sets of enzymes, which regulate the biosynthesis and degradation of the eCBs and possess distinct anatomical distributions (see Figure Figure11), exert control over CB1 and CB2 receptor signaling. Inactivation of anandamide occurs predominantly through FAAH (Cravatt et al., 1996, 2001), localized to intracellular membranes of postsynaptic somata and dendrites (Gulyas et al., 2004), in areas such as the neocortex, cerebellar cortex, and hippocampus (Egertová et al., 1998). Inactivation of 2-AG proceeds primarily via MAGL (Dinh et al., 2002; Blankman et al., 2007), expressed on presynaptic axon terminals (Gulyas et al., 2004), and demonstrates highest expression in areas such as the thalamus, hippocampus, cortex, and cerebellum (Dinh et al., 2002). The availability of pharmacological inhibitors for eCB catabolic enzymes has allowed the selective amplification of anandamide and 2-AG levels following brain injury as a key strategy to enhance eCB signaling and to investigate their potential neuroprotective effects.
People with epilepsy resort to cannabis products when antiepileptic drug side-effects are intolerable and epilepsy uncontrolled.
The first Australian nationwide survey on the experiences and opinions of medicinal cannabis use in people with epilepsy has revealed that 14 per cent of people with epilepsy have used cannabis products as a way to manage seizures.
The study showed that of those with a history of cannabis product use, 90 per cent of adults and 71 per cent of parents of children with epilepsy reported success in managing seizures after commencing using cannabis products.
Published in Epilepsy & Behaviour, the Epilepsy Action Australia study, in partnership with The Lambert Initiative at the University of Sydney, surveyed 976 respondents to examine cannabis use in people with epilepsy, reasons for use, and any perceived benefits self-reported by consumers (or their carers).
The survey revealed:
- 15 per cent of adults with epilepsy and 13 per cent of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy.
- Across all respondents, the main reasons for trying cannabis products were to manage treatment-resistant epilepsy and to obtain a more favourable side-effect profile compared to standard antiepileptic drugs.
The number of past antiepileptic drugs was a significant predictor of medicinal cannabis use in both adults and children with epilepsy.
“This survey provides insight into the use of cannabis products for epilepsy, in particular some of the likely factors influencing use, as well as novel insights into the experiences of and attitudes towards medicinal cannabis in people with epilepsy in the Australian community,” said lead author Anastasia Suraev from The Lambert Initiative.
“Despite the limitations of a retrospective online survey, we cannot ignore that a significant proportion of adults and children with epilepsy are using cannabis-based products in Australia, and many are self-reporting considerable benefits to their condition.
“More systematic clinical studies are urgently needed to help us better understand the role of cannabinoids in epilepsy,” she said.
Co-author of the paper Carol Ireland, CEO of Epilepsy Action Australia, who was recently appointed to the Australian Government’s new Australian Advisory Council on the Medicinal Use of Cannabis, said: “Cannabis products are often what people turn to when they have been unable to control their epilepsy with conventional medication.”
“This highlights a growing need to educate consumers and health professionals on the use of cannabis by people with epilepsy, and to provide safe and timely access to cannabinoid medicine in order to lessen people’s reliance on illicit black market products” she said.