Current Literature In Clinical Science
Cannabidiol and Epilepsy: Sifting, Winnowing and Buzz
Cannabidiol in Patients With Treatment-Resistant Epilepsy: An Open-Label Interventional Trial. Orrin Devinsky, Eric Marsh, Daniel Friedman, Elizabeth Thiele, Linda Laux, Joseph Sullivan, Ian Miller, Robert Flamini, Angus Wilfong, Francis Filloux, Matthew Wong, Nicole Tilton, Patricia Bruno, Judith Bluvstein, Julie Hedlund, Rebecca Kamens, Jane Maclean, Srishti Nangia, Nilika Shah Singhal, Carey A Wilson, Anup Patel, Maria Roberta Cilio. Lancet Neurol 2016;15: 270–278.
BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. METHODS: In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Drug–Drug Interaction Between Clobazam and Cannabidiol in Children With Refractory Epilepsy. Alexandra L. Geffrey, Sarah F. Pollack, Patricia L. Bruno, and Elizabeth A. Thiele. Epilepsia 2015;56:1246–1251.
OBJECTIVE: Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug–drug interaction, which we evaluate in this article. METHODS: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB
Epilepsy Currents, Vol. 16, No. 4 (July/August) 2016 pp. 239–241 © American Epilepsy Society
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Cannabidiol and Epilepsy
doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. RESULTS: We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [−2–91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90–610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. SIGNIFICANCE: Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.
Commentary The traditional path to drug development in epilepsy has been, for the most part, a fairly predictable process. Typically, known or suspected neurophysiological targets are identified, and candidate molecules are either designed or screened for activity. More recently, molecular biology has allowed medicinal chemists to customize specific molecules to interact with specific molecular targets. Traditionally, once a candidate drug is identified, it must undergo a rigorous series of preclinical studies to confirm activity, but also tease out potential toxicity. Should said candidate present a favorable profile, it can then proceed on through the long, arduous process of human clinical safety and ultimately well-controlled efficacy trials. This process, albeit tedious, is necessary in order to acquire sufficient pharmacological and clinical evidence to allow clinicians, and patients to make rational therapeutic decisions. This is the customary path that most clinicians and consumers expect as a quality assurance measure. Then we have the cannabinoids. The topic of medical marijuana has turned this established development process on its head. Over the past few years there has been a phenomenal resurgence in the interest in the use of Cannabis sativa and Cannabis indica for the treatment of epilepsy (among many other disorders as well). Clearly, the media and the proliferation of internet sites offering advice has fueled interest not only among patients and caregivers, but clinicians as well. Mainstream and social media interest in patient testimonials have, for better or worse, created a great deal of buzz. As it turns out, marijuana is a highly complex plant. Marijuana is not simply one drug. The cannabis plant contains over 100 phytocannabinoids and terpenes that work through a number of complex signaling networks (1). The two cannabinoids that have attracted the most attention for the treatment of seizures are delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). While THC is responsible for much of the psychoactive properties of marijuana, CBD appears to lack these properties. How precisely these molecules may work, either together or independently, to treat seizures is unclear. Given the absence of an FDA approved compound, patients and families are forced to use products produced by marijuana dispensaries. A lack of product uniformity and dosing standardization only complicates our interpretation of clinical ef-
240
fects in our patients. Many of these preparations contain varying amounts of CBD and/or THC (2), and may vary by grower owing to the complex botany of this plant. While some animal models have demonstrated anticonvulsant properties (1), the available human data is quite sparse. Several small studies have suggested that while CBD does appear to have a fairly good tolerability profile in most patients, none of these were of sufficient size or design to properly assess efficacy, or to sort out pharmacokinetic or pharmacodynamics interactions (3). While CBD appears devoid of the psychoactive properties of THC, we simply don’t know the long-term effects, especially in the young, developing brain. So unlike the situation of an FDA-approved, marketed drug, we now have a situation where patients have wide access to formulations that may contain varying amounts of drug(s) of indeterminate quality, unverified effectiveness, and likely drug interaction potential. The presumption that because cannabis is natural, it must be safe, is a problematic concept that has led many to set aside evidence-based medicine (4). Given the continuing concern over generic AED formulations of regulated, approved products, this would seem to be an untenable situation. Clearly, objective, controlled studies with a standardized drug formulation are needed. Fortunately, such data is beginning to emerge. Data from a multicenter study by Devinsky and colleagues now provides us with our first systematically obtained evidence of both CBD efficacy and adverse effect profile. Using a standardized, purified CBD formulation (GW Pharmaceuticals), this study enrolled over 160 young patients with documented pharmacoresistent childhood onset epilepsy, including, but not limited to Dravet syndrome and Lennox-Gastaut syndrome. While this was a prospective, adjunctive treatment study with defined outcome measures, it was not placebo controlled, and recruited patients from 11 epilepsy centers with physician-sponsored expanded access trials. While patients had multiple seizure types, the primary endpoint selected were motor seizures, which are likely to be better documented than more subtle seizures. Unlike previous reports, baseline seizure frequency was quantified, and a relatively standardized CBD dosing strategy was employed. Despite the limitations of no placebo arm, this study does provide valuable information. First, to the answer of does CBD provide benefit, the answer appears to be yes. Median change
Cannabidiol and Epilepsy
in motor seizure frequency over the 12-week observation period was reported to be reduced by 36%. Notably, 4% of patients were seizure free during the study period. The most responsive seizure types were focal seizures (−55%), followed by atonic seizures (−54.3%), tonic seizures (−36.5%), and tonicclonic seizures (−16%). Seizure response between Dravet and Lennox-Gastaut syndrome patients did not seem to differ, but again, this study was not designed to tease out such differences. Overall, these results would seem comparable to what we might expect from our currently approved AEDs. With respect to safety perspective, CBD seemed to be well tolerated in most patients. The principle treatment emergent adverse effects are the ones we might expect, and include somnolence (25%), decreased appetite (19%), diarrhea (19%), and fatigue (13%). Status epilepticus that the investigators felt was possibly related to CBD treatment occurred in nine patients (6%). Final CBD dose did seem to correlate with the prominent CNS adverse effects. A somewhat concerning observation was that all patients with elevations in liver function tests, or reduced platelet counts had valproate (acid or salt) (VPA) as one of their background medications. One patient taking VPA also was noted to have treatment – emergent hyperammonemia that ultimately led to CBD discontinuation. Although these troubling adverse effects were uncommon in this study, they clearly merit close observation in future trials. Another cautionary observation is noted in patients receiving concomitant clobazam. Over half of the patients receiving clobazam reported treatment emergent somnolence or fatigue versus only a quarter of those not receiving clobazam reporting somnolence. While this study was not a pharmacokinetic trial, these two observations of particular adverse effects being seen more commonly in certain drug combinations does raise the issue of drug–drug interactions. First, it should be noted that pharmacokinetic or pharmacodynamics interactions are not always a bad thing. Indeed, 51% of patients in the Devinsky trial receiving concomitant clobazam had a reduction of 50% or more in motor seizures, as compared with 27% of those patients not receiving clobazam. Similarly, a more robust response was seen when CBD was added to VPA treatment. These beneficial effects may come at a cost however. The observation that adjunctive treatment with CBD may augment the clinical effects of clobazam is consistent with observations by Geffrey and colleagues. These investigators noted that the addition of a purified formulation of CBD to 13 patients receiving concomitant clobazam as part of an expanded access open trial resulted in increases in both clobazam as well as N-desmethylclobazam plasma concentrations (60% and 500%, respectively), although substantial variability was seen. Interestingly, despite clobazam dose reductions,
N-desmethylclobazam plasma levels were 2- to 6-fold greater than at baseline. Adverse effects however appeared to resolve with clobazam dose reduction. Albeit the number of patients was quite small, mean reduction in seizure frequency still appeared quite robust (–50%) in patients who had their clobazam dose decreased. Given that clobazam is chiefly metabolized by CYP3A4 to the active metabolite N-desmethylclobazam that is subsequently metabolized by CYP2C19, the observations of Geffrey would suggest that CBD is likely to present multiple drug interactions. Specifically, it would seem that CBD has the potential to inhibit both CYP3A4 and CYP2C19. Taken together, these two recent studies greatly add to the available evidence regarding this unique molecule. Still, we must be mindful of study limitations. Neither study was placebo controlled. While lack of a placebo arm does not play as much of a part in pharmacokinetic observations, it does in evaluations of both efficacy and adverse effects. Without adequate blinding and placebo control, true estimates of seizure effect or subjective experience of side effects is hampered due to a variety of factors including but not limited to observer bias, patient and family experience/expectations, and regression to the mean (5). Such confounders have indeed been reported with cannabis treatment (6). Clearly, future investigations should also be designed to provide us with more granular detail as to mechanism and time course of CBD kinetic and importantly dynamic drug interactions. Whether or not CBD, or some other cannabidiol, will ultimately prove to be an effective AED remains to be determined. At least we can finally say with some confidence to our patients, their families, and our colleagues, that there is more to this drug than media hype, and internet buzz. by Barry E. Gidal, PharmD References 1. Rosenberg EC, Tsien RW, Whalley BJ, Devisnky O. Cannabinoids and epilepsy. Neurotherapeutics 2015;12:747–768. 2. Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia 2014;55:787–790. 3. Gloss D, Vickery B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2014;3:CD009270. 4. Mathern GW, Bennisig L, Nehlig A. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: results of Epilepsia survey. Epilepsia 2015;56:1–6. 5. Goldenholz D, Goldenholz S. Response to placebo in clinical epilepsy trials. Old ideas and new insights. Epilepsy Res 2016;122:15–25. 6. Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav 2015;45:49–52.
241
Cannabidiol and Epilepsy: Sifting, Winnowing and Buzz
Cannabidiol in Patients With Treatment-Resistant Epilepsy: An Open-Label Interventional Trial. Orrin Devinsky, Eric Marsh, Daniel Friedman, Elizabeth Thiele, Linda Laux, Joseph Sullivan, Ian Miller, Robert Flamini, Angus Wilfong, Francis Filloux, Matthew Wong, Nicole Tilton, Patricia Bruno, Judith Bluvstein, Julie Hedlund, Rebecca Kamens, Jane Maclean, Srishti Nangia, Nilika Shah Singhal, Carey A Wilson, Anup Patel, Maria Roberta Cilio. Lancet Neurol 2016;15: 270–278.
BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. METHODS: In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Drug–Drug Interaction Between Clobazam and Cannabidiol in Children With Refractory Epilepsy. Alexandra L. Geffrey, Sarah F. Pollack, Patricia L. Bruno, and Elizabeth A. Thiele. Epilepsia 2015;56:1246–1251.
OBJECTIVE: Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug–drug interaction, which we evaluate in this article. METHODS: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB
Epilepsy Currents, Vol. 16, No. 4 (July/August) 2016 pp. 239–241 © American Epilepsy Society
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Cannabidiol and Epilepsy
doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. RESULTS: We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [−2–91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90–610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. SIGNIFICANCE: Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.
Commentary The traditional path to drug development in epilepsy has been, for the most part, a fairly predictable process. Typically, known or suspected neurophysiological targets are identified, and candidate molecules are either designed or screened for activity. More recently, molecular biology has allowed medicinal chemists to customize specific molecules to interact with specific molecular targets. Traditionally, once a candidate drug is identified, it must undergo a rigorous series of preclinical studies to confirm activity, but also tease out potential toxicity. Should said candidate present a favorable profile, it can then proceed on through the long, arduous process of human clinical safety and ultimately well-controlled efficacy trials. This process, albeit tedious, is necessary in order to acquire sufficient pharmacological and clinical evidence to allow clinicians, and patients to make rational therapeutic decisions. This is the customary path that most clinicians and consumers expect as a quality assurance measure. Then we have the cannabinoids. The topic of medical marijuana has turned this established development process on its head. Over the past few years there has been a phenomenal resurgence in the interest in the use of Cannabis sativa and Cannabis indica for the treatment of epilepsy (among many other disorders as well). Clearly, the media and the proliferation of internet sites offering advice has fueled interest not only among patients and caregivers, but clinicians as well. Mainstream and social media interest in patient testimonials have, for better or worse, created a great deal of buzz. As it turns out, marijuana is a highly complex plant. Marijuana is not simply one drug. The cannabis plant contains over 100 phytocannabinoids and terpenes that work through a number of complex signaling networks (1). The two cannabinoids that have attracted the most attention for the treatment of seizures are delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). While THC is responsible for much of the psychoactive properties of marijuana, CBD appears to lack these properties. How precisely these molecules may work, either together or independently, to treat seizures is unclear. Given the absence of an FDA approved compound, patients and families are forced to use products produced by marijuana dispensaries. A lack of product uniformity and dosing standardization only complicates our interpretation of clinical ef-
240
fects in our patients. Many of these preparations contain varying amounts of CBD and/or THC (2), and may vary by grower owing to the complex botany of this plant. While some animal models have demonstrated anticonvulsant properties (1), the available human data is quite sparse. Several small studies have suggested that while CBD does appear to have a fairly good tolerability profile in most patients, none of these were of sufficient size or design to properly assess efficacy, or to sort out pharmacokinetic or pharmacodynamics interactions (3). While CBD appears devoid of the psychoactive properties of THC, we simply don’t know the long-term effects, especially in the young, developing brain. So unlike the situation of an FDA-approved, marketed drug, we now have a situation where patients have wide access to formulations that may contain varying amounts of drug(s) of indeterminate quality, unverified effectiveness, and likely drug interaction potential. The presumption that because cannabis is natural, it must be safe, is a problematic concept that has led many to set aside evidence-based medicine (4). Given the continuing concern over generic AED formulations of regulated, approved products, this would seem to be an untenable situation. Clearly, objective, controlled studies with a standardized drug formulation are needed. Fortunately, such data is beginning to emerge. Data from a multicenter study by Devinsky and colleagues now provides us with our first systematically obtained evidence of both CBD efficacy and adverse effect profile. Using a standardized, purified CBD formulation (GW Pharmaceuticals), this study enrolled over 160 young patients with documented pharmacoresistent childhood onset epilepsy, including, but not limited to Dravet syndrome and Lennox-Gastaut syndrome. While this was a prospective, adjunctive treatment study with defined outcome measures, it was not placebo controlled, and recruited patients from 11 epilepsy centers with physician-sponsored expanded access trials. While patients had multiple seizure types, the primary endpoint selected were motor seizures, which are likely to be better documented than more subtle seizures. Unlike previous reports, baseline seizure frequency was quantified, and a relatively standardized CBD dosing strategy was employed. Despite the limitations of no placebo arm, this study does provide valuable information. First, to the answer of does CBD provide benefit, the answer appears to be yes. Median change
Cannabidiol and Epilepsy
in motor seizure frequency over the 12-week observation period was reported to be reduced by 36%. Notably, 4% of patients were seizure free during the study period. The most responsive seizure types were focal seizures (−55%), followed by atonic seizures (−54.3%), tonic seizures (−36.5%), and tonicclonic seizures (−16%). Seizure response between Dravet and Lennox-Gastaut syndrome patients did not seem to differ, but again, this study was not designed to tease out such differences. Overall, these results would seem comparable to what we might expect from our currently approved AEDs. With respect to safety perspective, CBD seemed to be well tolerated in most patients. The principle treatment emergent adverse effects are the ones we might expect, and include somnolence (25%), decreased appetite (19%), diarrhea (19%), and fatigue (13%). Status epilepticus that the investigators felt was possibly related to CBD treatment occurred in nine patients (6%). Final CBD dose did seem to correlate with the prominent CNS adverse effects. A somewhat concerning observation was that all patients with elevations in liver function tests, or reduced platelet counts had valproate (acid or salt) (VPA) as one of their background medications. One patient taking VPA also was noted to have treatment – emergent hyperammonemia that ultimately led to CBD discontinuation. Although these troubling adverse effects were uncommon in this study, they clearly merit close observation in future trials. Another cautionary observation is noted in patients receiving concomitant clobazam. Over half of the patients receiving clobazam reported treatment emergent somnolence or fatigue versus only a quarter of those not receiving clobazam reporting somnolence. While this study was not a pharmacokinetic trial, these two observations of particular adverse effects being seen more commonly in certain drug combinations does raise the issue of drug–drug interactions. First, it should be noted that pharmacokinetic or pharmacodynamics interactions are not always a bad thing. Indeed, 51% of patients in the Devinsky trial receiving concomitant clobazam had a reduction of 50% or more in motor seizures, as compared with 27% of those patients not receiving clobazam. Similarly, a more robust response was seen when CBD was added to VPA treatment. These beneficial effects may come at a cost however. The observation that adjunctive treatment with CBD may augment the clinical effects of clobazam is consistent with observations by Geffrey and colleagues. These investigators noted that the addition of a purified formulation of CBD to 13 patients receiving concomitant clobazam as part of an expanded access open trial resulted in increases in both clobazam as well as N-desmethylclobazam plasma concentrations (60% and 500%, respectively), although substantial variability was seen. Interestingly, despite clobazam dose reductions,
N-desmethylclobazam plasma levels were 2- to 6-fold greater than at baseline. Adverse effects however appeared to resolve with clobazam dose reduction. Albeit the number of patients was quite small, mean reduction in seizure frequency still appeared quite robust (–50%) in patients who had their clobazam dose decreased. Given that clobazam is chiefly metabolized by CYP3A4 to the active metabolite N-desmethylclobazam that is subsequently metabolized by CYP2C19, the observations of Geffrey would suggest that CBD is likely to present multiple drug interactions. Specifically, it would seem that CBD has the potential to inhibit both CYP3A4 and CYP2C19. Taken together, these two recent studies greatly add to the available evidence regarding this unique molecule. Still, we must be mindful of study limitations. Neither study was placebo controlled. While lack of a placebo arm does not play as much of a part in pharmacokinetic observations, it does in evaluations of both efficacy and adverse effects. Without adequate blinding and placebo control, true estimates of seizure effect or subjective experience of side effects is hampered due to a variety of factors including but not limited to observer bias, patient and family experience/expectations, and regression to the mean (5). Such confounders have indeed been reported with cannabis treatment (6). Clearly, future investigations should also be designed to provide us with more granular detail as to mechanism and time course of CBD kinetic and importantly dynamic drug interactions. Whether or not CBD, or some other cannabidiol, will ultimately prove to be an effective AED remains to be determined. At least we can finally say with some confidence to our patients, their families, and our colleagues, that there is more to this drug than media hype, and internet buzz. by Barry E. Gidal, PharmD References 1. Rosenberg EC, Tsien RW, Whalley BJ, Devisnky O. Cannabinoids and epilepsy. Neurotherapeutics 2015;12:747–768. 2. Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia 2014;55:787–790. 3. Gloss D, Vickery B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2014;3:CD009270. 4. Mathern GW, Bennisig L, Nehlig A. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: results of Epilepsia survey. Epilepsia 2015;56:1–6. 5. Goldenholz D, Goldenholz S. Response to placebo in clinical epilepsy trials. Old ideas and new insights. Epilepsy Res 2016;122:15–25. 6. Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav 2015;45:49–52.
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