Patients with treatment-resistant epilepsy can develop a tolerance to cannabis-based therapy, a finding that may have implications for long-term management, new research suggests.

Physicians should be aware that tolerance may occur," study investigator Shimrit Uliel-Sibony, MD, pediatric epileptologist, Dana-Dwek Children's Hospital, Tel Aviv University, Israel, told Medscape Medical News.

"There's this notion that cannabis is great medicine, that it's much better regarding response rates than other interventions for patients with treatment-resistant epilepsy, but that may only be at the beginning," she added. Long-term exposure may produce a different picture. With time, efficacy may decrease, resulting in a need to increase the dose. This suggests the development of tolerance.

"We know marijuana may have cognitive consequences with long-term, chronic recreational use. I think we need to be a little more cautious on our expectations of this therapy," said Uliel-Sibony.

The study was presented here at the American Epilepsy Society (AES) 72nd Annual Meeting 2018. To assess the long-term efficacy of cannabinoids as well as the development of tolerance in the treatment of refractory epilepsy, the investigators conducted an observational, longitudinal study of pediatric and adult patients. The analysis included 92 patients (59 males) ranging in age from 1 year to 37 years (mean age, 11.8 years).

All had treatment-resistant epilepsy; two had Dravet syndrome, and three had Lennox-Gastaut syndrome (LGS). The remainder had other types of seizures and epilepsy syndromes. All patients had experienced treatment failure with numerous drug therapies, and for some, use of the ketogenic diet or vagal nerve stimulation therapy was also ineffective.

None had been previously treated with medical cannabis. Participants were initially given a cannabis oil extract in which the ratio of CBD to THC was 20:1. That amount of THC has negligible psychoactive activity, noted Uliel-Sibony. The patients had been receiving stable doses of AEDs for at least four weeks before study enrollment. All participants had at least three months of follow-up (mean follow-up, 20 months).

Honeymoon Tolerance

Tolerance was defined as a 30% or greater reduction in response rate that continued for more than three months.Patients in whom efficacy decreased during the first three months of treatments were not included. The intention was to exclude patients who showed short-lasting improvement that was possibly the result of the "honeymoon" effect.

The investigators found that about 29% of the study population experienced a reduction in seizures by 50% to 75%.Of 84 patients included in the tolerance analysis, 25% developed tolerance, which was reported with an average dosage of 12.6 mg/kg/day.