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NEW ORLEANS -- About one-third of patients who used cannabidiol (CBD) to manage treatment-resistant epilepsy developed tolerance to it, researchers from Israel reported here.

In a study of 92 children and young adults with treatment-resistant seizures who used cannabis oil extract for an average of 19.8 months, tolerance to CBD emerged in 32.6% of patients, reported Shimrit Uliel-Sibony, MD, of Tel Aviv Sourasky Medical Center's Dana Children's Hospital, and colleagues at the American Epilepsy Society annual meeting.

"CBD is a good option for children and adults with certain kinds of epilepsy, but as with anti-epileptic drugs, it can become less effective over time and the dose may need to be increased to manage the seizures," Uliel-Sibony said in statement. While previous research has shown that the effectiveness of cannabinoids can decrease when it is used for pain management and in the treatment of animals with seizures, this is the first large study to show it can occur with humans who use CBD to treat epilepsy, she added.

In the U.S., the FDA has approved a purified, pharmaceutical-grade formulation of cannabidiol (Epidiolex), a chemical component of the Cannabis sativa plant, for children with Lennox-Gastaut and Dravet syndromes. (The current study used a different product.)

In this prospective study, Uliel-Sibony and colleagues followed patients in Tel Aviv, ages 1-37 years (average age 11.8) from 2014 to 2017 with treatment-resistant epilepsy of various etiologies, ranging from Dravet syndrome and Lennox-Gastaut syndrome to epilepsy caused by stroke. All patients subsequently had been treated with one of two strains of CBD-enriched cannabis oil extract that had a 20:1 CBD-to-tetrahydrocannabinol (THC) ratio.

The researchers defined tolerance as either the necessity to increase dose by ≥30% after efficacy declined, or a response reduction of >30%. They saw tolerance in 30 patients, on an average dose of 12.6 mg/kg/day. The mean time until tolerance appeared was 7.3 months (range 1-24 months).

The researchers increased the CBD dose in most patients who developed tolerance; 12 patients achieved their previous response level and 15 did not.

"By definition, most patients with treatment-resistant epilepsy do not enjoy long-term benefits from a new anti-seizure therapy -- that is, a 'honeymoon effect,'" said Orrin Devinsky, MD, of New York University Langone Health in New York City, who was not involved with the study.

"This study found that tolerance develops in one-third of patients with treatment-resistant epilepsies who showed an initial reduction in seizures to a high CBD/low THC product after 7 months," Devinsky told 番茄社区app. "The observation that two-thirds of patients did benefit over a long follow-up period is a key finding."

There was no statistically significant correlation between patient's age and tolerance, but patients with shorter epilepsy duration showed a higher tendency to develop tolerance, Uliel-Sibony's group noted. Predictive factors and mechanisms are unknown, and long-term studies to better characterize the long-term efficacy and safety of CBD are needed, they added.

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