A new study suggests that patients may develop a tolerance to cannabidiol (CBD) oil over time, resulting in a loss of efficacy for seizure control.
Emilio Perucca, MD, PhD
New research recently presented at the American Epilepsy Society (AES) Annual Meeting reveals that as many as one-third of patients who used cannabidiol (CBD) oil to manage epilepsy developed a tolerance to it over time.
The research, presented at the AES annual conference in an abstract and led by researchers at the Tel-Aviv Sourasky Medical Center’s Dana Children’s Hospital, Israel, revealed that in a study of 92 children and young adults with treatment-resistant seizures who used CBD oil as treatment, 32.6% developed a tolerance.1 (Editor's Note: The CBD oil used in this study was not Epidiolex.)
The US Food and Drug Administration (FDA) approved for the first time in June 2018 a CBD oral solution for children with 2 rare, severe forms of epilepsy-Lennox-Gastaut and Dravet syndromes. The approval, for children aged 2 years and older, revealed that the CBD solution was more effective in reducing seizures when used alongside other medications than a placebo.
The authors of the prospective study noted that, as with other antiepileptic medications, this research shows that CBD oil may also grow less effective over time when it comes to treating seizures. The study focused on individuals aged 1 to 37 years treated between 2014 and 2017 with CBD oil for treatment-resistant epilepsy of varying etiologies, including Lennox-Gastaut and Dravet syndromes.
Tolerance was defined by the research team as the need for a dose increase of 30% or more after efficacy declined, or a response reduction of 30% or more. Tolerance was noted in 30 patients, according to the abstract, with those patients using an average dose of 12.6 mg/kg/day. The mean time to achieve tolerance was 7.3 months.
The research team attempted to increase CBD dosing in patients who developed a tolerance, according to the abstract, and 12 of the 30 patients with tolerance were able to achieve their previous response level at an increased dose, but 15 did not. This led researchers to conclude that tolerance to CBD oil may limit its efficacy as an antiseizure treatment when considering it for long-term clinical management of epilepsy in both children and adults.
Questions arise about tolerance
Although the authors of the abstract did not respond to media requests from Contemporary Pediatrics by press time, Emilio Perucca, MD, PhD, of the University of Pavia, Italy, and former president of the International League Against Epilepsy, who was not involved in the study, offered his take on the research.
“I am not impressed by this work-at best, it raises a signal but it does not really demonstrate tolerance. The data are based on uncontrolled observations, and it is unclear how seizure frequency was assessed, and what types of seizures were being treated,” Perucca says.
“Patients typically improve after adding any treatment due to the so-called regression to the mean phenomenon-such as spontaneous fluctuation in seizure frequency, irrespective of any effect of treatment-and the loss of improvement could again be due to spontaneous fluctuation,” he says.
Perucca also questions a note in the abstract that tolerance in 9 of the patients was observed concomitant with the drug’s tapering. Perucca says it is unclear from the abstract whether this means that concomitant drugs were removed, which he says by itself could explain the worsening of seizure control in the study patients.
Perucca has previously reviewed a number of trials on the use of CBD oil for the treatment of seizures, concluding that CBD oil does work in reducing the frequency of seizures when used alongside other antiepileptic medications.
In the Journal of Epilepsy Research, Perucca wrote that interest in cannabis products for epilepsy treatment has skyrocketed in recent years. Recent evidence demonstrated in a high-quality, placebo-controlled trial of purified oil-based CBD preparation in patients with Lennox-Gastaut and Dravet syndromes showed that 10 to 20 mg/kg/day of CBD oil improved seizure control when used with other antiepileptic medications compared with when no CBD oil was used.2
“One of the reasons for the utilization of cannabis products to have become so popular among patients and their caregivers is that these products are generally regarded as causing fewer adverse effects compared with traditional antiepileptic drugs, partly out of the misperception that remedies derived from natural products are unlikely to be harmful,” Perucca notes in his report.
Perucca’s report also reveals that unlike delta-9-tetrahydrocannabinol (THC), CBD is not associated with the development of tolerance after repeated administration in various seizure models, and there is no evidence of a withdrawal when CBD is discontinued.