COLUMBUS, OHIO—The prospect of using marijuana to treat childhood epilepsy, movement disorders, and psychiatric conditions is generating increasing interest among pediatric neurologists. But that hope must be tempered by the potential for neurotoxicity in the developing brain, according to research presented at the 43rd Annual Meeting of the Child Neurology Society.
Two of the most prevalent chemicals in cannabis are tetrahydrocannabinol (THC)—the primary psychoactive component—and cannabidiol (CBD), a nonpsychoactive phytochemical and potential treatment for epilepsy, said Francis M. Filloux, MD, Chief of the Division of Pediatric Neurology at the University of Utah School of Medicine in Salt Lake City. Because of the widespread role of the endocannabinoid system in the body and the brain, cannabis has extensive therapeutic potential and poses considerable risk. “We have the opportunity to mess up motor function and coordination, influence executive functions, and have a major impact on mood and behavioral regulation,” he said.
Francis M. Filloux, MD
Studies Are Difficult to Compare The wide array of cannabis formulations—natural or synthetic, with various combinations of THC and CBD and varied modes of administration—makes clinical studies hard to conduct and compare. A 2014 systematic review sponsored by the American Academy of Neurology is a case in point. With a focus on multiple sclerosis (MS), movement disorders, and epilepsy, the authors reviewed more than 1,700 studies from 1948 to 2013. Only a fraction met their inclusion criteria, and eight had a class I rating, noted Dr. Filloux.
Studies Support Cannabis for MS and Pain
One formulation that has been subject to close scrutiny is nabiximols, an oromucosal cannabinoid spray used to treat MS spasms. Since 2002, more than 1,000 patients have participated in well-controlled clinical studies of nabiximols, which is approved in England, Canada, and many other countries, but not the United States. In April 2014, the FDA granted the drug fast track status to treat pain in patients with advanced cancer, but not MS.
For patients with MS, smoking “medical marijuana” results in a “reproducible cognitive dysfunction affecting working memory, information processing speed, and executive function,” Dr. Filloux said. This result is identified with a particular pattern of cerebral activation on functional MRI.
Well-controlled studies have found cannabis to be beneficial for chronic pain, but the authors of a systematic review concluded that adverse events make it an unattractive option. For painful HIV–associated sensory neuropathy, medical marijuana has been shown to be effective in well-controlled clinical trials, Dr. Filloux pointed out. Gabapentin, pregabalin, and amitriptyline, “which many of us use,” have not.
In other areas, results are discouraging, said Dr. Filloux. Despite elegant work and the promising aspects of a preclinical model for the treatment of movement disorders in animals, for example, “studies in humans have simply not panned out.” The size and quality of the studies were insufficient to prove efficacy or lack of benefit for cannabis as a treatment for Huntington’s disease, levodopa-induced dyskinesia, Tourette syndrome, or cervical dystonia, he said.
What’s Ahead for Neuropsychiatric Disorders?
“It’s hard to give a neuroactive compound to people who already have disturbances in this area,” Dr. Filloux commented, but the idea that CBD may be an endogenous antipsychotic agent is generating interest. An inverse correlation between levels of anandamide in the CSF and psychotic symptoms prompted a German study to see whether CBD could enhance endogenous levels of anandamide and have beneficial results.
Researchers randomized 42 patients with acute psychotic schizophrenia to amisulpride—a D2 dopamine receptor antagonist that is a standard treatment in Germany—or CBD. The results were “relatively comparable,” but greater improvement in the negative symptom scale occurred with CBD, Dr. Filloux said.
Recent animal studies have examined fragile X syndrome and autism. The concept for fragile X is that altered metabotropic glutamate receptor 5 signaling affects the synthesis of endocannabinoids, and hence activation of CBD receptors, and in certain models, manipulation of the endocannabinoid system rectified neuropsychologic and neurobehavioral changes in mice with fragile X syndrome. “We don’t know whether this will ever be translated into clinical use, but it is tantalizing,” Dr. Filloux said.
What is happening in the realm of CBD and epilepsy probably could not have happened 15 years ago, Dr. Filloux noted, referring to videos on YouTube of a child with intractable seizures treated with an artisanal hemp oil, reportedly containing a high concentration of CBD. This video has generated “extraordinary patient-centered interest” in an area of clinical investigation in which there is rapid progress, he said.
A review of 19 patients taking such artisanal preparations in which more than 50% of the group self-reported greater than 80% improvement in seizure frequency and severity is encouraging, Dr. Filloux reported. Huge variations in dose and concerns about quality control exist, he cautioned, with the potential for cumulative exposure to THC. In addition, the availability of these “natural products” varies from state to state.