Clearing the haze around medicinal cannabis

Abstract

Cannabis is legal for medicinal use or is decriminalised for recreational use in more than half of the states in the USA, in more than 10 European countries, and in Australia. On July 1, 2018, the Canadian federal government will legalise recreational use of cannabis. The increased availability of cannabis following legalisation raises questions about its implications for public health, but it also opens avenues for treatment of neurological conditions. There is some evidence that various forms of cannabis could be used to treat neurological disorders—including epilepsy and some symptoms of multiple sclerosis (eg, spasticity and pain)—and for palliative care, but medical guidelines for its use are scarce. Responding to increased public interest in the use of cannabis, in November, 2017, WHO's Expert Committee on Drug Dependence (ECDD) published a preliminary report on therapeutic applications of cannabidiol (CBD)—a cannabinoid extracted from the cannabis plant. The ECDD will meet again for a full review on the medicinal use of cannabis and other cannabis-derived substances (eg, tetrahydrocannabinol [THC]) in May, 2018, at the WHO headquarters in Geneva, Switzerland. In its preliminary report, the ECDD focused on the use of CBD for reducing seizures in patients with epilepsy, for whom clinical evidence is strongest. In trials, CBD has been shown to be an effective treatment for at least some forms of epilepsy, such as Dravet syndrome, a complex childhood epilepsy associated with drug-resistant seizures and a high mortality rate. In addition to observational studies and case reports, the report reviewed findings from two trials examining the effects of CBD in patients with severe, intractable, childhood-onset, treatment-resistant epilepsy. Both trials—an open-label study of 214 patients and a randomised controlled trial of 120 patients—showed a reduction in convulsive-seizure frequency during the treatment period in patients who received CBD compared either with pre-treatment seizure frequency or with patients who received placebo. Since the publication of the ECDD's preliminary report, a trial of 171 patients with treatment-resistant Lennox-Gastaut syndrome has provided evidence supporting the efficacy of CBD as an add-on therapy for drop seizures. These findings are promising, but a number of concerns must be addressed before CBD can enter routine clinical practice, and chief among them is safety. Although often touted as a natural product, CBD is a drug like any other and has associated side effects. In the three trials of childhood-onset, treatment-resistant epilepsy, adverse events were reported in 75% to 93% of participants. It is also unclear how CBD might interact with other drugs; evidence suggests that CBD increases serum concentration of several antiepileptic drugs, including valproate and clobazam and their active metabolites. This interaction might result in an overestimation of CBD efficacy in patients who are also receiving these drugs. Additionally, although CBD does not produce the psychoactive effects that are typically seen with other cannabinoids such as THC, no controlled studies in human beings regarding the potential physical dependence effects (eg, withdrawal and tolerance) of CBD have been reported. Without such data, it is impossible to understand its long-term effects. Additional work is also needed regarding efficacy of CBD since the only positive clinical trials have been for childhood-onset, treatment-resistant epilepsy. Indeed, for people with other types of epilepsy, CBD might not be effective: in the only randomised controlled trial of CBD for focal epilepsy in adults (synthetic transdermal CBD for the treatment of epilepsy [STAR 1]), the primary endpoint of reduction of focal seizures during the treatment period was not met. Even for epilepsy disorders for which CBD has shown signs of efficacy, there is no evidence that CBD is the best available treatment. Head-to-head comparisons between CBD and approved antiepileptic drugs will be needed. In the meantime, anecdotal evidence and trial results in rare childhood epilepsy disorders will continue spur patients on to try cannabis and its derivatives, and potentially risk exacerbation of their condition or dangerous interaction with their current medications. Although neurologists can help their patients combat misinformation with medical fact, as with all emerging treatments, high-quality studies are needed to inform practice, and the medicinal use of cannabis should be clearly delineated through regulatory processes. In light of the uncertain treatment effects of medicinal cannabis on neurological disorders, the community looks forward to the ECDD's comprehensive review following their meeting in May, with the hope that it might facilitate much needed research in this growing field.