Medical Marijuana and Epilepsy: Beyond Epidiolex

The FDA approval of Epidiolex in 2018 was a watershed moment. For the first time, a cannabis-derived medication received full federal approval, validating decades of anecdotal evidence and parent advocacy. But Epidiolex — purified CBD — is not the end of the story. It is, in many ways, the beginning.

Epidiolex works. For patients with Dravet syndrome and Lennox-Gastaut syndrome, it reduces seizure frequency significantly. But it does not work for everyone, it does not eliminate seizures entirely for most patients, and there are forms of epilepsy where other cannabinoids might prove more effective.

This article explores what lies beyond Epidiolex — the other cannabinoids showing promise, the conditions where the current standard is insufficient, and where the research is heading.

A Brief History of Cannabis and Epilepsy

The use of cannabis for seizures is not new. It was documented in ancient Sumerian and Arabic medical texts. In the 19th century, Sir William Brooke O'Shaughnessy, an Irish physician working in India, published detailed clinical observations of cannabis tincture controlling seizures in patients who had failed other treatments.

The modern era of cannabis-for-epilepsy research was catalyzed by patient stories. Charlotte Figi, a Colorado girl with Dravet syndrome, went from 300 seizures per week to nearly seizure-free using a CBD-rich cannabis extract. Her story, profiled by CNN's Dr. Sanjay Gupta in 2013, galvanized public interest and research funding.

What Epidiolex Proved

Epidiolex (cannabidiol oral solution) was evaluated in multiple randomized, double-blind, placebo-controlled trials — the gold standard of clinical evidence:

Dravet Syndrome Trials

In a 2017 trial published in the New England Journal of Medicine by Devinsky et al.:

• 120 children and young adults with Dravet syndrome were randomized to CBD or placebo.
• The CBD group experienced a median 38.9% reduction in convulsive seizure frequency compared to 13.3% in the placebo group.
• 5% of CBD patients became seizure-free during the treatment period.
• Common side effects included somnolence, decreased appetite, and diarrhea.

A subsequent open-label extension showed that benefits were maintained over 48 weeks.

Lennox-Gastaut Syndrome Trials

Two pivotal trials in Lennox-Gastaut syndrome (LGS), published in the New England Journal of Medicine and The Lancet, showed:

• Median seizure frequency reductions of 41 to 44% in the CBD groups compared to 14 to 22% with placebo.
• Improvement in drop seizures — the seizure type most dangerous and debilitating in LGS.
• Benefits were additive to existing anti-seizure medications.

What Epidiolex Did Not Prove

Epidiolex established that purified CBD can reduce seizures in specific, severe epilepsy syndromes. But:

• It does not work for all patients. In the Dravet trial, 38% is the median reduction — meaning half the patients had less benefit.
• It does not address all seizure types equally. Focal seizures, absence seizures, and myoclonic seizures may respond differently.
• The side effect profile is not negligible. Liver enzyme elevations occurred in some patients, particularly those also taking valproate. Sedation is common.
• It is a single cannabinoid. The question remains: could a different cannabinoid, or a combination, work better?

Other Cannabinoids Under Investigation

CBDV (Cannabidivarin)

CBDV is structurally similar to CBD but with a slightly shorter side chain. Research interest has been significant:

Preclinical evidence: A 2012 study by Hill et al. in the British Journal of Pharmacology demonstrated that CBDV reduced seizure severity and duration in multiple animal models of epilepsy, including pentylenetetrazole-induced and audiogenic seizures. Importantly, CBDV appeared to work through mechanisms partially different from CBD, suggesting additive effects could be possible.

Proposed mechanisms: CBDV appears to interact with TRPV1 receptors (transient receptor potential vanilloid type 1) and may modulate diacylglycerol lipase activity, affecting 2-AG synthesis. These mechanisms are distinct from CBD's primary pathways.

Clinical development: GW Pharmaceuticals (now Jazz Pharmaceuticals) initiated clinical trials of CBDV for focal seizures. Preliminary results were mixed, but the compound remains of interest for seizure types that are less responsive to CBD.

THCA (Tetrahydrocannabinolic Acid)

THCA is the raw, unheated form of THC found in the living cannabis plant. Unlike THC, it is non-psychoactive because it does not significantly bind to CB1 receptors. But it may have anticonvulsant properties:

Emerging evidence: A 2020 study published in Epilepsy & Behavior by Sulak et al. reported on treatment-resistant epilepsy patients who added THCA-rich preparations to their regimens. The study found clinically meaningful seizure reductions in a subset of patients, including some who had not responded adequately to CBD alone.

The appeal: Because THCA is non-psychoactive, it could be used in pediatric populations and in patients who cannot tolerate THC's cognitive effects. If validated, it would represent a genuinely novel mechanism.

THCV (Tetrahydrocannabivarin)

THCV has unusual pharmacology — at low doses it acts as a CB1 antagonist, while at higher doses it may become a partial agonist. In animal models:

• THCV reduced seizure incidence in a piriform cortical seizure model.
• The effect appeared to be mediated through CB1 modulation rather than direct anticonvulsant action.
• Clinical data is extremely limited.

CBG (Cannabigerol)

CBG, the precursor molecule from which other cannabinoids are synthesized in the plant, has shown anticonvulsant activity in some preclinical models:

• A 2021 study demonstrated that CBG reduced seizure severity in a Dravet syndrome mouse model.
• The mechanism may involve GABAergic modulation and TRPV1 interaction.
• No human clinical trials for epilepsy have been completed.

THC Itself

THC's role in epilepsy is controversial and complex:

• In some patients and animal models, THC has anticonvulsant properties.
• In others, particularly at high doses, it may lower the seizure threshold.
• The biphasic nature of THC makes dosing critical.
• A 2021 review in Epilepsy & Behavior suggested that low-dose THC, particularly in combination with CBD, may benefit some patients who do not respond to CBD alone.

Whole-Plant Extracts vs. Purified CBD

The Pamplona et al. analysis (2018, Frontiers in Neurology) compared outcomes in epilepsy patients using CBD-rich whole-plant extracts versus purified CBD:

• CBD-rich extracts produced a higher rate of improvement (71% vs. 46%).
• The effective doses were lower with whole-plant extracts (average 6.1 mg/kg/day vs. 25.3 mg/kg/day for purified CBD).
• Fewer side effects were reported with whole-plant extracts.

This data, while observational, suggests that the other compounds in the plant — whether minor cannabinoids, terpenes, or other phytochemicals — may enhance CBD's anticonvulsant effects. This is one of the strongest practical arguments for the entourage effect in epilepsy specifically.

Conditions Beyond Dravet and LGS

Tuberous Sclerosis Complex (TSC)

Epidiolex received a third FDA indication for seizures associated with TSC in 2020. The GWPCARE6 trial showed significant seizure reduction, expanding the evidence base beyond the original two indications.

Focal Epilepsy

Focal (partial) seizures are the most common seizure type in adults. While some observational studies suggest medical cannabis can help, the controlled data is limited. A 2022 Australian open-label trial of pharmaceutical-grade CBD in adults with drug-resistant focal epilepsy showed modest benefit in a subset of patients.

Infantile Spasms (West Syndrome)

Case reports and small series have described improvement with CBD-rich preparations, but no controlled trials have been completed. The rarity and severity of this condition make it both high-priority and difficult to study.

Status Epilepticus

Preclinical data suggests that cannabinoids could potentially be useful in status epilepticus (prolonged seizures that do not stop spontaneously), but clinical evidence is absent. IV formulations would be needed, and none are currently available.

Challenges and Unknowns

Drug Interactions

CBD inhibits several cytochrome P450 enzymes, particularly CYP3A4 and CYP2C19. This means it can increase blood levels of other anti-seizure medications:

• Clobazam: CBD significantly increases levels of norclobazam (the active metabolite of clobazam). This interaction likely contributes to both the efficacy and the sedation seen in clinical trials.
• Valproate: The combination may increase risk of liver enzyme elevations.
• Stiripentol, topiramate, rufinamide: All may be affected.

Understanding these interactions is critical, and dose adjustments of concomitant medications may be necessary.

Dosing Optimization

Optimal dosing of cannabinoids for epilepsy is still being refined. The standard Epidiolex dose is 10 to 20 mg/kg/day, but the Pamplona analysis suggests that whole-plant extracts may be effective at much lower doses. Individualized dosing based on response, side effects, and concurrent medications is the current standard.

Pediatric Considerations

Many severe epilepsy syndromes present in childhood, raising important questions about the long-term effects of cannabinoid exposure on the developing brain. The known neurotoxic effects of THC on adolescent brain development make THC-containing products more concerning in pediatric populations. CBD and non-psychoactive cannabinoids like THCA may be preferable.

What This Means for Florida Patients

Epilepsy is a qualifying condition for medical marijuana in Florida. For patients with treatment-resistant epilepsy — meaning they have tried at least two appropriate anti-seizure medications without adequate control — medical cannabis is a legitimate option.

At CORAL, Dr. Kim works with epilepsy patients to:

• Evaluate whether medical cannabis is appropriate based on your seizure type, current medications, and treatment history.
• Select appropriate products. CBD-dominant formulations are the most evidence-based starting point, but whole-plant extracts may offer advantages.
• Coordinate with your neurologist. Medical cannabis for epilepsy should complement, not replace, your relationship with your epilepsy specialist. Drug interactions need to be monitored.
• Monitor response systematically. Seizure frequency tracking, side effect assessment, and medication level monitoring help optimize treatment.

The Next Frontier

The next decade of research will likely bring:

• Controlled trials of THCA, CBDV, and CBG for specific epilepsy syndromes.
• Combination cannabinoid formulations designed for epilepsy, moving beyond CBD alone.
• Biomarkers to predict which patients will respond to specific cannabinoids.
• Novel delivery systems optimized for seizure control, including rapid-onset formulations for acute seizure interruption.

CBD opened the door. The work now is to see what else is in the room.

If you or a family member has treatment-resistant epilepsy and want to explore whether medical marijuana is appropriate, [start your evaluation at coral.clinic/start](https://coral.clinic/start).