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27 research focus cannapatientcare.com august 2021 | cannabis patient care Nevertheless, cannabis studies have observed statistically significant decreases in seizure frequency for epileptic children, a clinically important finding (8). Cannabis for Epilepsy: Survey of the Research There is a substantial body of research on cannabis uses for treating epilepsy. A sizeable amount of preclinical research on cannabis for epilepsy has been performed. However, up until the last few years, most clinical research on cannabis for epilepsy has been low-powered, due to such problems as: small sample sizes, non-randomly selected participants, lack of control groups, lack of blinding, inconsistent interventions across participants, and poorly described cannabis products (2,8). At the same time, study participants were also generally taking a regimen of antie- pileptic therapies, with variable consistency in dosing throughout the study period. Nevertheless, reported findings for nonrandom- ized studies, though slightly larger in magnitude, were still simi- lar to findings from more recent randomized controlled trials (8). Preclinical Research Preclinical studies have shown that cannabis prevents seizures and reduces mortality in epilepsy. Studies have also shown that after chronic seizures have been experienced, the endocannabinoid system exhibits changes in homeostatic components that are both acute and chronic in nature (4). Finally, studies have shown that THC has produced both anticonvulsive and proconvulsive effects in animals (9–11), while CBD has exhibited clear antiepileptic effects (3). Clinical Research Case Studies There are a multitude of case studies on the effects of cannabis for epilepsy. Some reports suggest pro-convulsive effects of can- nabis. However, the majority of cases report either positive ef- fects or lack of effect of cannabis for controlling seizures (4,11,12). Surveys There are also a multitude of surveys on the effects of canna- bis for epilepsy. The estimated prevalence of cannabis use by epileptic patients ranges from about 4% to about 20%, with more evidence of incidence toward the higher end of the range. Again, the majority of surveys report either positive effects or lack of effect of cannabis for controlling seizures (4,11,13,14). Non-Randomized Clinical Trials As with both case study and survey research on the effects of cannabis for epilepsy, there is also a multitude of small-scale or non-randomized clinical trials on cannabis use for epilepsy. And as with both the case studies and surveys, the majority of the research reports either positive effects or lack of effect of cannabis for controlling seizures (1,2,4,6,8,15,16). More specifical- ly, four classes of positive effects were reported for patients in treated groups relative to those in control groups: • Reduction in seizures was achieved by a moderate to substantial portion of patients • More than 50% reduction in seizures was achieved by a moderate portion of patients • Freedom from seizures was achieved by a small but nonzero portion of patients • Secondary improvements were achieved in the areas of quality of life, mood, alertness, behavior/aggression, sleep, language/cognition, and motor skills Randomized Controlled Trials There are a couple of larger-scale randomized controlled trials (RCTs) on the effects of CBD for epilepsy. These RCTs are all associated with clinical trials of Epidiolex on behalf of GW Phar- maceuticals for the purpose of gaining US Food and Drug Ad- ministration (FDA) approval of this drug. The RCTs indicated that GW's CBD formulation may reduce seizures with high tolerability and low toxicity. As such, in June 2018, Epidiolex received FDA approval for the treatment of two specific DDEs, Lennox-Gastaut syndrome (LGS) and Dravet syndrome (17). Points of Concern Several points of concern, which warrant further discussion, can be gleaned from the research on cannabis for epilepsy. Pro-Convulsant Potential of THC Preclinical research and case studies indicate the potential for THC to have pro-convulsive effects (9,10,11,18,). Due to a combination of this pro-convulsive potential, together with its psychoactive nature, researchers have tended to shy away from clinical studies of the therapeutic potential of THC. Fur ther examination of this research reveals that THC may have pro-convulsive effects either when administered at "near-lethal doses" or when administered to subjects with a recessive genetic mutation (9,10,18). Other case study repor ts of cannabis causing seizure activity occurred in patients who had consumed either other drugs (for example, cocaine, LSD, amphetamines) or "street drugs" that could easily have con- tained other impurities responsible for the seizures (11). On the subject of THC being pro-convulsant in humans, not- ed cannabis researcher Ethan Russo observes, "It should be mentioned that while there are claims of seizure exacerbation