cannabidiol and Fatigue

The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on 'Cannabinoids'.

Topics: Animals; Anticonvulsants; Biomedical Research; Cannabidiol; Drug Interactions; Epilepsy; Evidence-Based Medicine; Fatigue; Humans; Randomized Controlled Trials as Topic

The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.. In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.. The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval [CI], -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient's overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.. Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Double-Blind Method; Epilepsies, Myoclonic; Fatigue; Female; Humans; Liver; Liver Function Tests; Male; Seizures

This study explored whether symptom relief differs by sex in patients with cancer receiving medical cannabis (MC) therapy.. This is an analysis of data collected from patients with cancer enrolled in the Quebec Cannabis Registry. MC was initiated for the therapeutic management of cancer symptoms. Patients completed the revised Edmonton Symptom Assessment System (ESAS-r) questionnaire at baseline and 3-month follow-up. We examined the interaction between sex and time on each ESAS-r symptom and the interaction between time and tetrahydrocannabinol:cannabidiol (THC:CBD) ratios for each sex on total symptom burden.. The analysis included 358 patients (M: 171). There were no sex differences in baseline ESAS-r scores. Three months of MC therapy led to significant improvements in pain (M: - 1.4 ± 0.3, p < 0.001; F: - 1.1 ± 0.3, p < 0.01), tiredness (M: - 1.7 ± 0.4, p < 0.001; F: - 1.2 ± 0.4, p < 0.05), anxiety (M: - 1.1 ± 0.4, p < 0.05; F: - 1.2 ± 0.4, p < 0.001), and well-being (M: - 1.2 ± 0.4, p < 0.05; F: - 1.4 ± 0.4, p < 0.01) in both sexes. Only F perceived improved drowsiness (- 1.1 ± 0.4, p < 0.05), nausea (- 0.9 ± 0.3, p < 0.05), lack of appetite (- 1.7 ± 0.4, p < 0.001), and shortness of breath (- 0.9 ± 0.3, p < 0.05). From baseline to 3-month follow-up, THC-dominant MC significantly reduced pain (- 1.52 ± 0.52, p < 0.05) in M, whereas in F it diminished nausea (- 2.52 ± 0.70, p < 0.01) and improved well-being (- 2.41 ± 0.79, p < 0.05). THC:CBD-balanced products significantly reduced pain (- 1.48 ± 0.49, p < 0.05), tiredness (- 1.82 ± 0.62, p < 0.05), anxiety (- 1.83 ± 0.54, p < 0.05), and improved well-being (- 2.01 ± 0.56, p < 0.01) in M. CBD-dominant products did not offer significant symptom relief in either sex.. The perceived relief of cancer symptoms from MC differs between sexes. More randomized controlled trials are needed to confirm our findings.

Topics: Analgesics; Cannabidiol; Cannabis; Dronabinol; Fatigue; Female; Humans; Male; Medical Marijuana; Nausea; Neoplasms; Pain; Quebec; Registries

Topics: Cannabidiol; Child; Cognition; Fatigue; Female; Humans; Neuropsychological Tests; Quality of Life

The use of cannabidiol products in pediatric patients is becoming more frequent because of the increased ease of accessibility. This case report illustrates the potential for cannabidiol to interact with stable medication regimens. A 13-year-old girl with metastatic cancer and chronic pain presented with increased sleepiness and fatigue. She had been started on 7.5 mg of methadone by mouth twice daily 4 months earlier. Unbeknownst to her physicians, her parents had commenced her on cannabidiol and subsequently increased the dose leading up to her presentation, thinking it would result in tumor shrinkage. The initial serum methadone level was 271 ng/mL, which decreased to 125 ng/mL 14 days after discontinuing cannabidiol. The reduced serum methadone level coincided with improved sleepiness and fatigue. Cannabidiol inhibits CYP3A4 and CYP2C19, both of which are involved in the metabolism of methadone. Pediatricians should be aware of this potential interaction and inquire if their patients are receiving cannabidiol.

Topics: Adolescent; Analgesics, Opioid; Cancer Pain; Cannabidiol; Drug Interactions; Drug Therapy, Combination; Fatigue; Female; Humans; Methadone