A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome
Blathnaid McCoy, Laura Wang, Maria Zak, Sameer Al-Mehmadi, Nadia Kabir, Kenda Alhadid,
Kyla McDonald, Grace Zhang, Rohit Sharma, Robyn Whitney, Katia Sinopoli & O. Carter Snead III
Annals of Clinical and Translational Neurology, 2018, 5, (9), 1077–1088
Introduction : Both D9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 – a cannabis plant extract produced by Tilray, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.
Methods : Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives.
Results : Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7–16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14–0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.
Conclusions : TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.
Despite the expansion of available antiepileptic drugs (AED), dietary, and surgical therapies in the last 20 years, up to 30% of children with epilepsy continue to have seizures, termed drug-resistant epilepsy.1 Dravet syndrome is a catastrophic epilepsy syndrome impacting all developmental realms including cognition, behavior, and motor function.2–6 Typically, a mutation in the SCN1A sodium channel gene is causative. 7 The devastation caused by DRE provides impetus to explore new therapies through research.
Recently, there has been growing interest in using cannabis plant extracts in the treatment of DRE.8–14 D9 tetrahydrocannabidiol (THC) and cannabidiol (CBD) have both shown anticonvulsant properties in animal studies.15–20 THC has also been shown to be pro-convulsant in some animal models.14 The clinical use of cannabis plant extracts in epilepsy has been limited by concern of the psychotropic effects of THC, but THC-containing compounds have been studied in other indications.21 It is important to differentiate the actions of THC and CBD within the endocannabinoid system.22,23 While THC directly binds to the CB1 receptor (widely distributed in the central nervous system) to elicit its effects, CBD does not.24,25 The mechanism of action of CBD involves intermediary pathways without direct action on CB1. Therefore, it is plausible that THC-containing cannabinoid preparations may be superior to CBD-only preparations in their anticonvulsant effect, and that combination CBDTHC products may increase tolerance of THC by reducing its psychoactive properties26,27
Primetime attention by media outlets, patient advocacy groups and families concerning a mixed CBD/THC containing cannabis extract [so-called ‘Charlotte’s Web’] to treat seizures in patients with Dravet syndrome, resulted in increasing demands from advocacy groups for cannabinoids to be considered in the treatment of epilepsy.28,29
This resulted in a massive expansion of the academic literature exploring the potential of CBD (excluding THC due to the aforementioned concern, and due to THC being considered illegal in many jurisdictions) as a therapy in DRE.23,30,31 In turn, prospective studies of CBD in DRE were conducted. Specifically, a pharmaceutical-grade formulation of purified CBD in oil has been studied in epilepsy patients in several clinical trials and has been shown to be more efficacious but less tolerated than placebo in treating seizures.32–35
The cannabis oils available in Canada contain mixed extract of predominantly CBD and THC.36 While the clinical trials of pure CBD alluded to above have given us an understanding of CBD dosing, side effects and efficacy, there is a paucity of information regarding dosing and safety of cannabinoid products containing THC. However, products vary significantly in their pharmaceutical formulations (purity and constituent component stability) and have not undergone formal clinical study. Clearly, there is a gap in our understanding of these preparations.
The primary objective of this study was to establish safe dosing and tolerability of TIL-TC150, a cannabis extract containing only CBD and THC, at a ratio of 50:1 CBD: THC in children with Dravet syndrome. Secondary objectives were to assess the impact of CBD/THC therapy on seizure frequency, spike index, cognition, and quality of life.