Wednesday, December 7, 2016

Cannabidiol in patients with treatment-resistant epilepsy

Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8.

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.
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.
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).

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.


  1. Hussain SA, Zhou R, Jacobson C, Weng J, Cheng E, Lay J, Hung P, Lerner JT, Sankar R. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy Behav. 2015 Jun;47:138-41.

    There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. 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 lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

  2. Gruber SA, Sagar KA, Dahlgren MK, Racine MT, Smith RT, Lukas SE. Splendor in the Grass? A Pilot Study Assessing the Impact of Medical Marijuana on Executive Function. Front Pharmacol. 2016 Oct 13;7:355.

    Currently, 25 states and Washington DC have enacted full medical marijuana (MMJ) programs while 18 states allow limited access to MMJ products. Limited access states permit low (or zero) tetrahydrocannabinol (THC) and high cannabidiol (CBD) products to treat specified conditions such as uncontrolled epilepsy. Although MMJ products are derived from the same plant species as recreational MJ, they are often selected for their unique cannabinoid constituents and ratios, not typically sought by recreational users, which may impact neurocognitive outcomes. To date, few studies have investigated the potential impact of MMJ use on cognitive performance, despite a well-documented association between recreational marijuana (MJ) use and executive dysfunction. The current study assessed the impact of 3 months of MMJ treatment on executive function, exploring whether MMJ patients would experience improvement in cognitive functioning, perhaps related to primary symptom alleviation. As part of a larger longitudinal study, 24 patients certified for MMJ use completed baseline executive function assessments and 11 of these so far have returned for their first follow-up visit 3 months after initiating treatment. Results suggest that in general, MMJ patients experienced some improvement on measures of executive functioning, including the Stroop Color Word Test and Trail Making Test, mostly reflected as increased speed in completing tasks without a loss of accuracy. On self-report questionnaires, patients also indicated moderate improvements in clinical state, including reduced sleep disturbance, decreased symptoms of depression, attenuated impulsivity, and positive changes in some aspects of quality of life. Additionally, patients reported a notable decrease in their use of conventional pharmaceutical agents from baseline, with opiate use declining more than 42%. While intriguing, these findings are preliminary and warrant further investigation at additional time points and in larger sample sizes. Given the likelihood of increased MMJ use across the country, it is imperative to determine the potential impact of short- and long-term treatment on cognitive performance as well as the efficacy of MMJ treatment itself.

  3. Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, Laux L, Marsh ED. Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases. J Child Neurol. 2016 Sep 21.

    Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting cannabidiol, 6 of 7 patients' seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add cannabidiol as a possible treatment for FIRES.

  4. A purified oral formulation of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) significantly reduces seizures in treatment-resistant epilepsy, according to new research that included double-blind randomized controlled trials of patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), two of the most difficult-to-manage seizure conditions.

    The new research, released here at the American Epilepsy Society (AES) 2016 Annual Meeting, also highlights the relative safety of this new drug, a prescription medicine derived from the cannabis plant.

    Elizabeth A. Thiele, MD, PhD, director, Pediatric Epilepsy Program, Massachusetts General Hospital, and professor, neurology, Harvard Medial School, Boston, who contributed to many of the studies, told Medscape Medical News she is excited about the results.

    "It's exciting because at least for a portion of people with Dravet and with Lennox-Gastaut, it's going to be an effective treatment, and what I can see with my experience with the expanded-access program, it's going to be an effective treatment for other people as well."

    Dr Thiele estimates that more than 1000 patients now have access to the drug through this expanded program.

    Only once before in her career has she seen an effective epilepsy treatment come into being because of a push from the epilepsy community. The other was the very-low-carbohydrate ketogenic diet, which was at first shunned by the medical community but is now being used or tested not only in epilepsy but also in other neurologic disorders and in cancer…

    Much of the new research includes patients with LGS, an epilepsy syndrome due to many different causes, and DS, which is mostly a single-gene disorder. Both are rare seizure conditions that typically start in childhood. (continued)

  5. (continued)Researchers initially carried out a safety study in children with DS who were randomly assigned to one of three doses of CBD (5, 10, or 20 mg/kg per day) or to placebo as add-on therapy for 3 weeks.

    Safety data in 34 patients aged 4 to 10 years showed that the most common adverse events (AEs) were somnolence (19% in those taking CBD vs 14% in those receiving placebo), pyrexia (22% vs 0%), decreased appetite (19% vs 0%), and sedation (15% vs 0%).

    Serious adverse events were reported in 5 patients (a treatment-related case of status epilepticus in the 5-mg group, a treatment-related case of pyrexia and maculopapular rash and a case of pyrexia and convulsion in the 10-mg group, and a case of parvovirus and a case of viral infection in the 20-mg group)…

    The larger randomized controlled trial of CBD in DS included 120 patients. The mean age was 10 years, and 29% of patient were under age 6 years. Patients in this study had tried a median of four antiepileptic drugs and at the time of the study were taking a median of three. They were randomly assigned to receive CBD 20 mg/kg per day or placebo.

    The study showed that the median reduction in seizure frequency — the primary efficacy endpoint — after 14 weeks of treatment was 39% for those receiving CBD compared with 13% for those receiving placebo (P = .0123). The difference between CBD and placebo was established by the end of 4 weeks.

    As with any antiepileptic drug, not all patients responded. "Even if a child has an SCN1A mutation causing them to have Dravet, they're still genetically different than another kid with Dravet," noted Dr Thiele.

    Adverse events in this study occurred in 93.4% of patients receiving CBD and 74.6% of those receiving placebo. Most events in CBD recipient were mild or moderate. The most common adverse events in patients taking the active drug were somnolence, diarrhea, decreased appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection, and convulsion.

    Serious adverse events were reported in 16.4% of patients taking CBD (8.2% of these were considered treatment related) and 5.1% of placebo recipients…

    Dr Thiele also noted that the safety profile of CBD is better than that of some AEDs, which can cause cognitive side effects and require regular blood monitoring…

    She related several individual CBD success stories. One is a young man with LGS who experienced "the best seizure control that he's every had" after starting CBD and is now seizure-free (after adding a "tiny dose" of clobazam, according to Dr Thiele).

    A young girl in whom no drug had succeeded in controlling her seizures had just acquired a guide dog when she began CBD. She has now been seizure free for 2.5 years. A picture posted on the Internet depicts her dog on a beach in flip flops holding a sign saying he's happily retired.

    So far, the efficacy of the drug hasn't been lost in any of Dr Thiele's patients. "But I think we see a honeymoon period for all of our treatments…. Some people will probably lose efficacy with time."

    Drug interactions with other AEDs are a concern, however. Researchers have noted significant interactions with clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine.