Patients with epilepsy may develop tolerance to CBD-enriched oil
NEW ORLEANS – Cannabis oil extract with a 20:1 ratio of cannabidiol (CBD) to tetrahydrocannabinol (THC) may reduce seizures in children and adults with treatment-resistant epilepsy, but about a quarter of patients develop tolerance, according to a study presented at the annual meeting of the American Epilepsy Society .
“CBD is a good option for children and adults with certain kinds of epilepsy, but as with antiepileptic drugs, it can become less effective over time, and the dose may need to be increased to manage the seizures,” said Shimrit Uliel-Sibony, MD , lead author of the study and head of the pediatric epilepsy service at Tel Aviv Sourasky Medical Center’s Dana-Dwek Children’s Hospital.
Prior studies have found that the efficacy of cannabinoids may wane when used for pain management. Efficacy also declines in animals with seizures.
To assess the tolerance rate of cannabinoids in the treatment of children and adults with epilepsy, researchers in Israel conducted a prospective review of 92 consecutive patients with treatment-resistant epilepsy. Patients were aged 1-37 years (mean age, 11.8 years) and were treated with cannabis oil extract during March 1, 2014–Dec. 31, 2017. The researchers defined tolerance as the need to increase the dose by at least 30% following a reduction in efficacy, or a more than 30% reduction in treatment response.
The patients had various forms of epilepsy (e.g., Dravet syndrome, Lennox-Gastaut syndrome, and epilepsy caused by stroke) and used cannabis oil extract for an average of 19.8 months. Of the 84 patients included in the tolerance analysis, 21 patients (25%) developed tolerance after an average of 7.3 months (range, 1-24 months) at an average dose of 12.6 mg/kg per day. After patients with tolerance received an increased dose, 4 patients returned to their previous response levels, and 10 patients had a response that was “satisfying but less than [the] prior response level,” Dr. Uliel-Sibony and colleagues said.
About a third of patients discontinued treatment because of side effects or lack of efficacy. Side effects included sleepiness, nausea, decreased appetite, and vomiting. In addition, seizures worsened in two patients, and one patient had signs of psychosis; treatment was stopped immediately in those three patients.
The investigators had no disclosures and received no funding for this study.
Novel Molecules Discovered in CBD Oils May Reduce Seizures
Three different cannabinoids acting in aggregate may reduce seizures.
- The use of cannabis plant extracts for the treatment of seizures dates back many millennia.
- CBD is often sold as a substitute cannabis treatment for epilepsy in adults and children.
- Commercial CBD products have measurable levels of THC as well as many other cannabinoids that may reduce seizures more effectively.
- Three different cannabinoids extracted from the cannabis plant acting alone or in aggregate may be reduce seizure incidence.
The use of cannabis plant extracts for the treatment of seizures dates back many millennia. Its effectiveness was imperfect; however, nothing else was available. The components of the cannabis plant that reduce the incidence of seizures are not fully known. The internet, and those hoping to make a profit on this current state of ignorance, claim that one particular molecule, CBD, can effectively reduce seizures frequently. The data to support these claims is limited and often unreliable. Caregiver bias still remains a significant problem in most clinical trials.
In recent trials that report positive outcomes, CBD has been used in addition to standard epilepsy medications. Therefore it remains to be determined whether CBD alone is antiepileptic, a potentiator of traditional antiepileptic medications, or simply a placebo. Another nagging problem has also undermined confidence in the effectiveness of CBD — contamination of samples with other molecules from the cannabis plant.
Commercially available CBD products are prepared by one of three extraction methods — using cold carbon dioxide, oils, or ethanol. These methods indiscriminately extract any molecule that is lipid-soluble; the cannabis plant contains over 160 different lipid-soluble molecules. Therefore, it should come as no surprise that commercial CBD products have measurable levels of THC as well as many other cannabinoids.
A recent pair of studies investigated the anti-epileptic efficacy of three cannabinoids that are also found in commercial extracts from the cannabis plant, including cannabigerolic acid (CBGA), cannadivarinic acid (CBDVA), and cannabigerovarinic acid (CBGVA). CBGA is the precursor molecule to the production of both CBD and THC. Cannabinoid acids are fairly plentiful in cannabis but have received much less scientific attention.
The anticonvulsant potential of each of the cannabinoid acids was tested using a mouse model of Dravet syndrome. The authors confirmed that all three cannabinoids were readily and substantially absorbed into the brain. The level in the brain was measured to be up to six times higher than in the blood. This is to be expected when using such lipid-soluble molecules.
The study reported that all three acidic cannabinoids significantly reduced seizure incidence. The authors further reported that CBGA interacts with many epilepsy-relevant drug targets and was more effective than CBD in their seizure model. These positive results need to be taken in context; the drugs were given to mice who had induced seizures. Although this animal model may be valid and predictive, much more research needs to be conducted to confirm the effectiveness of these molecules in human epilepsy patients.
In conclusion, a series of three different cannabinoids extracted from the cannabis plant acting alone or in aggregate, and that are often found in common artisanal cannabis oils, may underlie the claimed anticonvulsant actions commercial CBD preparations.
Wenk GL (2019) Your Brain on Food, 3rd Edition, (Oxford University Press)
Anderson LL et al, (2021) Cannabichromene, related phytocannabinoids, and 5-fluoro-cannabichromene have anticonvulsant properties in a mouse model of Dravet Syndrome. ACS Chemical Neuroscience. 12: 330-339
Anderson LL et al, (2021) Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy, Br J Pharmacol. DOI: 10.1111/bph.15661