VANCOUVER—“Neurologists are often asked to ‘certify’ patients, but should you recommend or support medical marijuana use for patients with epilepsy?”
Daniel Friedman, MD, MSc, Assistant Professor of Neurology at New York University Langone School of Medicine in New York, addressed this question in his presentation at the 68th Annual Meeting of the American Academy of Neurology.
Daniel Friedman, MD, MSc
“There is a disconnect between what the patient, families, and the public understand about cannabinoid therapies for epilepsy and what we as a neurologic community know,” he said. “Much of human evidence for the efficacy of cannabinoids for the treatment of epilepsy is anecdotal” and, of the “few controlled trials, most are small and methodologically flawed.”
A Brief History of Medical Marijuana
Cannabis sativa was first cultivated in approximately 8,000 BCE in China for rope, then medicinally for conditions ranging from menstruation to absentmindedness and, eventually, more than 100 ailments. In the early 19th century, W.B. O’Shaughnessy introduced cannabis to England, where Gowers and other Victorian neurologists used the “Indian hemp” to treat epilepsy.
Medicinal use of cannabis dwindled in the 1930s due to a move to synthetic medicine and Prohibition, which also “coincided with the beginning of the era of rigorous scientific investigation of drug claims,” said Dr. Friedman. Now, “the discovery of the endocannabinoid system in the brain has sparked new research into the therapeutic potential of cannabinoids.”
The Chemicals in Cannabis
The genus Cannabis includes C. sativa, C. indica, and C. ruderalis. A total of 85 phytocannabinoids are found in Cannabis species plants, and cannabidiol (CBD) and delta-9 tetrahydrocannabinol (THC) are the most abundant neuroactive chemicals; others include the terpenes and flavonoids.
CBD-rich oil is a concentrate made from cannabis bred to have a low level of THC and a high level of CBD. GW Pharma manufactures a solution with equal parts purified plant-derived THC and CBD (Sativex). The company also makes an investigational agent, pure CBD (Epidiolex), a 98% purified plant-derived CBD. INSYS Therapeutics is developing a synthetic CBD that is structurally identical to the plant-derived compound.
What Is the Evidence?
Experimental and human studies have provided evidence for the anticonvulsant properties of CBD and THC, and antiseizure effects have also been observed with cannabidivarin (CBDV).
Since 2014, more than 10 US centers have been using Epidiolex under an FDA expanded-access program to treat patients between ages 1 and 30 (median age, 10.5) with severe, treatment-resistant, childhood-onset epilepsy. Patients’ baseline motor seizure rate was 29.5 per month (range, 11.0–96.0 per month).
As of January 2015, 162 patients had completed 12 weeks of observation. Preliminary results showed median motor seizure reduction to be 36.5%. Patients with Dravet syndrome had a 49.8% reduction in seizures, and patients with Lennox-Gastaut syndrome had a 36.8% reduction. Serious adverse events, primarily status epilepticus, were observed in 12% of participants. Only 3% of patients discontinued treatment, however. Commonly reported adverse events included somnolence (25.3%), decreased appetite (19.1%), diarrhea (19.1%), fatigue (13.0%), and convulsion (11.1%).
In addition, children with Dravet syndrome in a phase III trial of Epidiolex had a median reduction in motor seizures of 39% versus 13% for placebo.
“Much of the safety data for chronic cannabinoid use” has come from studies of recreational use, which is “inherently confounded,” Dr. Friedman said. Acute affects include impaired memory, judgment, and motor performance. Chronic use leads to addiction in approximately 9% of users, as well as to cognitive impairment, decreased motivation, and increased risk for psychotic disorders.
Researchers examined pooled data from adults with multiple sclerosis who used cannabinoids for spasticity, pain, and dyskinesias for less than six months. The data encompassed approximately 1,600 exposures to the drugs. About 7% of participants discontinued treatment due to adverse events that included nausea, behavioral and mood changes, suicidality, hallucinations, dizziness, and weakness.
CBD and THC are inhibitors of P450 isozymes, primarily CYP2C and CYP3A, but drug–drug interaction effects are not typically seen in doses used in human studies, said Dr. Friedman. At low micromolar concentrations, CBD inhibits CYP2C19, an enzyme involved in the metabolism of N-desmethylclobazam, phenytoin, diazepam, citalopram, and some tricyclic antidepressants. The CYP2B family may also be induced, thus affecting valproate and clobazam metabolism.
Drugs that affect CBD metabolism include the CYP3A4 inducers, such as carbamazepine and phenytoin, and the CYP3A4 inhibitors such as ketoconazole.
Randomized controlled trials of CBD and CBDV are in progress in patients with Dravet syndrome, Lennox-Gastaut syndrome, and refractory focal epilepsy.
Is Cannabis Right for My Patient?
Since New York State approved the medical use of cannabis, Dr. Friedman has discussed the drug in one of every four of his clinic visits. Deciding whether to recommend medical marijuana for a patient can be difficult, however.
