Cannabinoids

Posted by • September 11th, 2015

cannaboidsThe pharmacologic and biochemical features of cannabinoids make them candidates for antiseizure medications. At this time, anecdotes have outstripped controlled clinical trials as sources of support for their clinical value. A new review article summarizes.

Despite the availability of more than 20 different antiseizure drugs and the provision of appropriate medical therapy, 30% of people with epilepsy continue to have seizures. The approval of many new antiseizure drugs during the past two decades, including several with novel mechanisms of action, has not substantially reduced the proportion of patients with medically refractory disease. This treatment gap has led patients and families to seek alternative treatments. Cannabis-based treatment for epilepsy has recently received prominent attention in the lay press and in social media, with reports of dramatic improvements in seizure control in children with severe epilepsy.

Clinical Pearls

• How does the U.S. Drug Enforcement Agency categorize cannabinoids?

The delay between initial reports of the antiseizure efficacy of cannabinoids in preclinical models in the 1970s and the recent start of clinical studies reflects, in part, the classification of cannabis and any product derived from it as a Schedule I drug by the Drug Enforcement Agency. Schedule I drugs are defined as having no currently accepted medical use and a high potential for abuse. Synthetic cannabinoids, since they are not derived from the cannabis plant, are sometimes subject to less restrictive scheduling if clinical evidence supports medical usefulness. For instance, the synthetic Delta9-THC isomer dronabinol is a Schedule III medication and is often prescribed for the treatment of chronic nausea and vomiting in patients with the autoimmune deficiency syndrome.

• Which of the compounds that have been isolated from cannabis species are thought to have potential as antiseizure medication?

More than 545 distinct compounds have been isolated from cannabis species; the most abundant are the cannabinoids. The best studied of these cannabinoids (termed “phytocannabinoids” if derived from the plant) are Delta9-tetrahydrocannabinol (Delta9-THC) and cannabidiol and their metabolites. Most of the psychoactive effects of cannabis are mediated by Delta9-THC. Cannabidiol’s lack of psychoactive effects and the preclinical evidence of antiseizure effects have generated interest in its potential as an antiseizure drug in humans. Cannabidivarin, the propyl variant of cannabidiol, has also shown antiseizure effects in both in vitro and in vivo models. Little is known about the antiseizure effects of other phytocannabinoids.

Morning Report Questions

Q: What available evidence supports the use of cannabinoids to treat epilepsy?

A: Cannabis has been used medicinally for millennia and was used in the treatment of epilepsy as early as 1800 B.C.E. in Sumeria. The discovery of an endogenous cannabinoid-signaling system in the early 1990s rekindled interest in therapies derived from constituents of cannabis for nervous system disorders such as epilepsy. Preclinical and preliminary data from studies in humans suggest that cannabidiol and Delta9-THC may be effective in the treatment of some patients with epilepsy. However, current data from studies in humans are extremely limited, and no conclusions can be drawn. The major cannabinoid receptor in the central nervous system is cannabinoid receptor 1 (CB1R). The activation of CB1R receptors with the use of Delta9-THC or synthetic agonists in experimentally induced seizures has been studied in various animal models. In most studies, CB1R agonists reduced seizures, but in others no effect was observed, and in four studies CB1R was associated with convulsant effects at some doses. Limited epidemiologic evidence supports the view that cannabinoids have antiseizure properties in humans. Case reports support the antiseizure effects of cannabis in patients with epilepsy and show exacerbation of seizures after abrupt discontinuation. However, in a survey conducted in Germany among adults with epilepsy who used cannabis, the substance had no apparent effect on seizure control, and some case reports have shown an exacerbation of seizures among patients who used cannabis or a synthetic cannabinoid. Few prospective therapeutic trials have been performed that involve the isolated use of cannabinoids to treat epilepsy.

Figure 1. Selected Pharmacologic Features of Cannabinoids Showing Antiseizure Effects in Preclinical Models.

Table 1. Clinical Trials, Case Series, and Case Reports on Cannabinoids in the Treatment of Epilepsy.

Q: Are cannabinoids safe to use as a treatment for epilepsy?

A: Much of the available data regarding the safety and side-effect profile of cannabinoids, especially with long-term use, come from studies examining the effects of recreational use. Cannabis-based treatment for Delta9-THC may have irreversible effects on brain development. Long-term exposure to endocannabinoids, especially Delta9-THC, may lead to cognitive and behavioral changes. It is unknown whether adverse effects on the brain are mediated solely by psychoactive cannabinoids, such as Delta9-THC, or whether long-term exposure to cannabidiol and cannabidivarin also have deleterious effects. Until more data become available, the neurodevelopmental risks of cannabinoid-based therapies should be weighed against the potential benefits for seizure control, since seizures also affect brain development. Some safety concerns have been raised with regard to the pharmacokinetic interactions of cannabinoids in patients with epilepsy who are long-term users. Cannabinoids can inhibit cytochrome P-450 (CYP) enzymes. Both Delta9-THC and cannabidiol inhibit the CYP2C family of isozymes at low micromolar concentrations and CYP3A4 at higher concentrations. These enzymes help to metabolize many antiseizure drugs, and inhibition can potentiate drug toxicity and efficacy. Little is known about the effects of fetal exposure to cannabinoids.

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