What treatment-resistant epilepsy is
Epilepsy is a neurological condition defined by recurrent, unprovoked seizures caused by abnormal electrical discharges in the brain. Treatment-resistant epilepsy, also called drug-resistant or refractory epilepsy, is diagnosed when a person has not achieved sustained seizure freedom despite adequate trials of two or more tolerated and appropriately chosen anti-seizure medications. An estimated 30 per cent of people with epilepsy have treatment-resistant forms.
Two severe childhood-onset epileptic encephalopathies have been the focus of the strongest cannabinoid research: Dravet syndrome and Lennox-Gastaut syndrome (LGS). Dravet syndrome typically begins in the first year of life with prolonged febrile seizures and progresses to multiple seizure types, developmental delay, and an elevated risk of premature death. LGS is characterised by multiple seizure types including tonic and atonic (drop) seizures, cognitive impairment, and a distinctive EEG pattern. Both conditions are highly resistant to standard anti-seizure medications.
Cannabis research on Treatment-resistant epilepsy
A purified, pharmaceutical-grade cannabidiol (CBD) oral solution (Epidyolex in the UK and Europe, Epidiolex in the United States) has been studied in two separate double-blind, placebo-controlled, randomised trials for Dravet syndrome and LGS. The US Food and Drug Administration (FDA) approved this CBD formulation for both conditions in 2018, and the European Medicines Agency followed in 2019. It is the first medicine derived from cannabis to receive regulatory approval on the basis of RCT evidence.
A 2017 double-blind, placebo-controlled RCT by Devinsky and colleagues, published in the New England Journal of Medicine, studied 120 children and young adults with Dravet syndrome. Participants received either purified CBD at 20 mg per kg of body weight per day or placebo as an add-on to their existing anti-seizure medications over 14 weeks. The median frequency of convulsive seizures per month fell from 12.4 to 5.9 in the CBD group, compared with a reduction from 14.9 to 14.1 in the placebo group. The difference between groups was statistically significant. Adverse events were reported in 93 per cent of the CBD group and 75 per cent of the placebo group. The most common were diarrhoea, vomiting, fatigue, fever, somnolence, and abnormal liver function test results.
A 2018 double-blind, placebo-controlled RCT by Thiele, Devinsky, and colleagues, published in The Lancet, studied 225 children and adults with LGS. Participants received purified CBD at one of two dose levels (10 or 20 mg per kg per day) or placebo as add-on therapy over 14 weeks. The median percentage reduction in monthly drop-seizure frequency in the 20 mg per kg CBD group was 43.9 per cent, compared with 21.8 per cent in the placebo group (estimated median difference 17.2 percentage points, p=0.014). The lower CBD dose group also showed a statistically significant reduction compared with placebo.
Animal research has also examined cannabidivarin (CBDV), a cannabinoid structurally related to CBD. Anti-seizure effects of CBDV have been observed in rodent models of epilepsy, and human clinical trials of CBDV are ongoing. No published RCT results for CBDV are available. A separate animal study reported that cannabinoid receptor agonists had anticonvulsant effects in developmental rat seizure models.
Compounds studied for Treatment-resistant epilepsy
CBD carries the strongest human clinical evidence of any cannabinoid for epilepsy. Two separate RCTs in Dravet syndrome and LGS have demonstrated that purified CBD, added to existing anti-seizure medication, can reduce seizure frequency in these specific epilepsy syndromes. The precise mechanism behind this effect is not fully established; proposed mechanisms include modulation of intracellular calcium, inhibition of adenosine reuptake, and antagonism at the GPR55 receptor. See CBD.
THC activates CB1 receptors, which are found throughout the brain. Animal research has shown both pro-convulsant and anti-convulsant effects of THC depending on the model, dose, and seizure type. No RCT has tested THC alone for epilepsy outcomes in people. See THC.
THCV has been examined in animal seizure models for anti-convulsant effects through CB1 receptor modulation. No human RCT has tested THCV for epilepsy. See THCV.
CBGA, the acidic precursor to CBG, has limited published research. Laboratory studies have examined its receptor interactions, but no clinical trial evidence exists for epilepsy. See CBGA.
Linalool has been studied in rodent seizure models for anticonvulsant effects, with proposed mechanisms involving glutamate and GABA signalling. No human clinical trial has tested isolated linalool for epilepsy. See linalool.
Caryophyllene binds to the CB2 receptor and has been examined in animal models of neuroinflammation associated with seizure disorders. Human trial data for caryophyllene and epilepsy are absent. See beta-caryophyllene.
Bisabolol has been studied in limited animal research for neuroprotective effects. No human RCT has tested bisabolol for seizure outcomes. See bisabolol.
Pinene has been examined in cell and animal models for neuroprotective and anti-inflammatory properties. Human trial data for pinene in epilepsy do not exist. See pinene.
Limits of the evidence for Treatment-resistant epilepsy
The RCT evidence supports a specific, pharmaceutical-grade CBD preparation, not cannabis flower, cannabis oil, or non-standardised CBD products. The formulation studied in the trials differs from unregulated products in its purity, standardisation, and absence of THC and other cannabinoids beyond trace amounts.
The trials were conducted in specific, severe epilepsy syndromes — Dravet syndrome and LGS. The findings do not extend to all forms of epilepsy, and there is no equivalent RCT evidence for the more common focal or generalised epilepsies.
Adverse events were common in the CBD group. Liver transaminase elevations were observed, particularly in people also taking valproate. These laboratory abnormalities are a recognised safety signal that requires monitoring.
The trials were add-on studies: all participants continued their existing anti-seizure medications alongside CBD or placebo. The effects of CBD as a standalone treatment have not been tested in an RCT.
Trial durations were 14 weeks. Longer-term controlled data are more limited, and the open-label extension studies that followed do not include a placebo control.
Sources
1. Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618. PMID: 28538134. Study record
2. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096. doi:10.1016/S0140-6736(18)30136-3. PMID: 29395273. Study record
3. FDA Press Announcement. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. 25 June 2018. Study record
4. Huizenga MN, Wicker E, Beck VC, Forcelli PA. Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats. Epilepsia. 2017;58(9):1593-1602. doi:10.1111/epi.13842. PMID: 28691158. Study record
