Public support for medical marijuana is at an all-time high, more states are passing laws easing restrictions, and more research is in the pipeline. That support, combined with case reports of often remarkable symptom relief, has shifted the traditional drug approval process. Research and funding for clinical trials are gaining momentum based on anecdotal reports, and newer preparations that don't contain tetrahydrocannabinol (THC), the psychoactive component of the plant, are being investigated.
Pot in the Pipeline
Currently, only two cannabis drugs are approved for medical use by the US Food and Drug Administration (FDA): dronabinol and nabilone, which use a synthetic form of THC for treating nausea associated with chemotherapy and appetite loss in HIV/AIDS patients.
Others being studied include cannabidiol (CBD), a non-psychoactive cannabis oil extract; an oral spray called nabiximols (Sativex), which contains CBD and THC; and Epidiolex, which is almost pure CBD. In fact, Epidiolex, which contains a highly purified, plant-derived form of CBD, has been granted "orphan drug" status by the FDA and is currently being tested in clinical trials in children with Dravet syndrome, a rare and severe form of childhood epilepsy. (Learn more about pediatric epilepsy.) In addition, positive reports on the effects of the THC extract tetrahydrocannabinolic acid (THC-A) have garnered support among patients with neurologic disorders and advocacy groups.
And the research continues. Randomized clinical trials of CBD in children with severe forms of epilepsy were launched last year with support from the National Institutes of Health (NIH), which is also investigating possible therapeutic uses in inflammation, pain, substance abuse disorders, and post-traumatic stress disorder (PTSD).
At the American Epilepsy Society's (AES) annual meeting in December, researchers at several institutions described the effectiveness of CBD and its derivatives in treating epilepsy, but cautioned that the studies were small and lacked the scientific rigor the FDA requires for approval.
One study conducted at Children's Hospital Colorado and the University of Colorado assessed outcomes for 58 children and adolescents with an average age of seven who had catastrophic forms of epilepsy and were given oral cannabis extracts. Although one-third of children saw their seizures diminish by 50 percent or more, their response did not correlate with improvement in electroencephalograms (EEGs), which register seizure activity in the brain. Only two children showed signs of improvement on EEG, and the responses did not change with various strains of cannabis. And 21 percent of the subjects experienced an increase in seizures or new seizures.
Two other papers have since updated the findings on Epidiolex, and the first clinical trial of the purified form of CBD—a one-year study at six research centers involving 150 patients with intractable epilepsy between one and 18 years of age—was approved last year.
Researchers at New York University and the University of California, San Francisco, who are conducting the current Epidiolex trial, presented initial data for 23 children with treatment-resistant epilepsies at the AES meeting. After three months, 39 percent of participants had 50 percent fewer seizures, with a median reduction of 32 percent.
One of the trial's lead investigators, Orrin Devinsky, MD, director of the New York University Comprehensive Epilepsy Center and a Fellow of the American Academy of Neurology (FAAN), says a second phase of the study began recruiting children with Dravet and Lennox-Gastaut syndromes in January 2015. In the completed "open-label" phase of the study, patients knew they were receiving the active drug. In the "double-blind" phase, patients will either be given the active drug or a placebo, but neither they nor the researchers will know who receives which.
Not Enough Data
The use of marijuana for medical purposes has been studied since at least 1948, but most of the studies haven't been rigorous enough, according to the American Academy of Neurology (AAN). Last year, the Academy issued guidelines on the subject after reviewing and rating all studies published from 1948 through 2013. Of 1,729 studies, only 34 met the guideline standards. The panel looked specifically at studies in multiple sclerosis (MS), Huntington's disease, epilepsy, dystonia, and Tourette syndrome. Only eight trials were rigorous enough to meet the panel's highest rating standard, including four on spasticity in MS. Another four qualified for the second-highest rating. Studies on various other conditions were given lower classifications because of the quality of the research. (Find out more about the guidelines for patients and families.)
This lack of evidence and rigor from randomized clinical trials raises concern about a number of issues. In particular, unanswered questions remain about whether smoking marijuana increases the risk of stroke and what effect cannabinoids have on the developing brains of children.
There are too many forms of cannabinoid drugs that have never been well studied and whose long-term effects are unknown, says Vijayshree Yadav, MD, an associate professor of neurology and clinical director of Oregon Health & Science University's MS Center in Portland, who is also a member of the AAN.
For people with MS and other neurologic problems, there is some good evidence that these compounds work to relieve spasticity, for example, as the AAN guidelines indicate, "but if we are using newer formulations of CBD or THC-A, it's hard to know how much and how often a patient might use them," Dr. Yadav says.
Other experts agree. "Without better data, especially standardization of dosing in children and adolescents, all we have are anecdotal trial-and-error reports from parents who have tried different preparations and dosages," says Seth Ammerman, MD, a clinical professor of pediatrics and adolescent medicine at Stanford University in Palo Alto, CA. Clinical trials must include pediatric patients, he says, but "the big issue is the potential effect on cognitive development in younger children, about which we know almost nothing. For parents, I cannot generally recommend it."
Neither can Selim R. Benbadis, MD, an AAN member, who directs the Comprehensive Epilepsy Program at the University of South Florida in Tampa. "Parents and patients are desperate and often ask for it, but I find it difficult to recommend," he says. He believes the growing demand in patient communities underscores the importance of well-designed, government-supported clinical trials.
Legalization Marches Forward
Despite doctors' concerns, the legalization of medical marijuana continues to advance. So far, 23 states and the District of Columbia permit doctors to prescribe medical marijuana and extracts like CBD, and 11 more are considering easing laws for a range of medical problems, including migraine, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), severe fibromyalgia, spinal cord injuries, and traumatic brain injury. (For the latest information about state laws regarding medical marijuana, visit the National Conference of State Legislatures' State Medical Marijuana Laws web page.)
And patients continue to lead the way in easing restrictions. In Virginia, 14-year-old Haley Smith, who has Dravet syndrome, and her parents have been central figures in the effort to ease that state's marijuana laws. During a state General Assembly hearing, Haley had a seizure that was televised and reported by the media—an event that proved to be a powerful reality check for lawmakers and others who had never seen a seizure in a child.
In February, Virginia Governor Terry McAuliffe (D) signed a law stating that patients with severe epilepsy cannot be prosecuted for possession if they can provide an "affirmative defense" for medically recommended cannabis oils. The law does not make obtaining such extracts any easier or guarantee that patients will not be arrested or have to present a defense in court, but it does offer hope for parents of children with intractable epilepsy. And while advocates, including the Smiths, say the new law leaves much to be desired, they consider it a step in the right direction.
