CBD and Seizures: New Clinical Evidence Challenges Common Beliefs

Introduction

CBD and seizures research has skyrocketed in recent years, challenging traditional treatment paradigms for refractory epilepsy. Epilepsy affects approximately 50 million people globally, according to the World Health Organization (WHO). This neurological disorder, previously limited to conventional anticonvulsant therapies, now has a new evidence-based treatment option. For the first time, class 1 evidence supports that cannabidiol (CBD) improves seizure control in patients with specific epilepsy syndromes.

The relationship between cannabinoids and epilepsy gained substantial legitimacy when the FDA approved Epidiolex® in June 2018. This pharmaceutical preparation, highly purified from plant-derived CBD, received approval specifically for Dravet syndrome and Lennox-Gastaut syndrome (LGS). Studies on CBD and seizures demonstrate impressive outcomes in clinical settings. The efficacy analysis shows a mean percent reduction in seizures of 67.8%, with 68.8% of patients achieving ≥50% reduction in seizure frequency, and 11.5% attaining complete seizure freedom. However, CBD therapy isn’t without considerations. Common adverse effects include:

Drowsiness • Reduced appetite • Diarrhea • Vomiting

This article examines recent scientific studies of CBD and seizures, exploring both historical context and cutting-edge research that has transformed our understanding of cannabinoid therapeutics in epilepsy management.

Historical Use of Cannabis in Seizure Disorders

The therapeutic relationship between cannabis and seizure disorders extends back thousands of years, with archeological evidence suggesting cannabis use for medicinal purposes dating as far back as 2700 BCE in ancient China. Throughout history, various cultures documented cannabis applications for convulsive conditions, creating a rich historical foundation that modern CBD and seizures research builds upon.

Ancient medical texts referencing cannabis for convulsions

Sumerian and Akkadian tablets from approximately 1800 BCE contain some of the earliest written records of cannabis used medicinally for convulsive disorders[51]. These ancient texts specifically mention using a medicinal plant, widely believed to be cannabis, to treat “nocturnal convulsions”. This historical documentation marks the beginning of a therapeutic tradition that would continue for millennia across multiple civilizations.

The medical application of cannabis for seizure conditions appears prominently in later Arabic and Islamic literature. Notable mentions include:

Ali ibn al-Abbas al-Mayusi (circa 1100 CE), who prescribed “the juice of the leaves of cannabis instilled in the nostril” as a treatment for epilepsy
Abu Bakr Muhammad ibn Zakariyya al-Razi (865-925 CE), who reportedly documented successful cases of epilepsy treatment with hashish

Particularly compelling is the extensive reference to a condition labeled “hand of ghost” in Assyrian medical texts from the Royal Library of Ashurbanipal (668-626 BCE). An Assyriologist/neurologist team later confirmed this terminology described epilepsy, with numerous tablets detailing various seizure types including “auras, tonic extension, absence, complex partial and even gelastic spells”. These texts repeatedly recommend cannabis in their treatment protocols, administered through multiple routes including oral consumption and fumigation.

Chinese medical traditions additionally documented cannabis applications for conditions that may have included seizures. Though interpretation remains challenging due to terminology differences, archeological evidence supports cannabis’s prominent role in ancient Chinese medicine.

19th-century clinical observations of cannabis in epilepsy

Modern scientific investigation of cannabis for epilepsy began with William B. O’Shaughnessy in 1843[51]. As a physician in the Bengal Army and Professor at the Medical College of Calcutta, O’Shaughnessy conducted methodical investigations of Cannabis indica after observing its use in Ayurvedic medicine. His published findings described “remarkable anti-seizure effects” in a 40-day-old infant suffering from recurrent convulsive seizures[51][52].

O’Shaughnessy’s work catalyzed interest among European and American physicians, including:

W. Ley, who reported success treating spasmodic seizures in infants and agreed that hemp represented “an anti-convulsive remedy of the greatest value”
Robert Christison, who noted hemp’s effectiveness “in hydrophobia, tetanus, malignant cholera, and infantile convulsions, with marked relief in repeated instances”
R.R. McMeens, who documented successful treatment in four children, including a 7-week-old infant with multiple daily seizures

Two eminent English neurologists made significant contributions to early cannabinoid epilepsy treatment. Sir William Gowers explicitly documented the effectiveness of Cannabis indica against seizures that were resistant to bromides (the standard treatment of that era)[51][52]. Furthermore, Sir John Russell Reynolds, Queen Victoria’s personal physician, published detailed case studies in 1868, showing varying degrees of benefit in three epilepsy patients (two adults and one child)[52].

Despite these promising early clinical observations, cannabis-based epilepsy treatments gradually fell from mainstream use due to standardization challenges, bioavailability issues, and ultimately prohibition. Nevertheless, these historical applications laid the groundwork for modern CBD and seizures research that would resume in earnest during the 1970s.

Understanding Cannabidiol: Structure and Receptor Targets

Cannabidiol stands apart from other cannabis compounds through its unique molecular structure and diverse receptor interactions that contribute to its anticonvulsant properties. Unlike many conventional anti-epileptic medications that target single pathways, CBD interacts with multiple neuronal systems simultaneously to modulate excitability.

CBD vs THC: Psychoactivity and therapeutic potential

While CBD and Δ9-tetrahydrocannabinol (THC) share structural similarities, they differ substantially in pharmacological activity. This distinction fundamentally explains their contrasting effects on cognition and seizure threshold. Most notably:

CBD demonstrates very low affinity for cannabinoid type 1 (CB1) and type 2 (CB2) receptors, whereas THC acts as a partial agonist at these sites
THC’s psychoactive properties primarily result from CB1 activation, while CBD’s lack of significant CB1 binding explains its non-psychoactive profile
CBD may function as a negative allosteric modulator at CB1 receptors, potentially moderating THC’s effects

In contrast to THC’s limited medical applications due to psychoactivity, CBD’s broad receptor profile underlies its therapeutic versatility. Moreover, CBD exhibits unique properties through its interactions with ion channels, neurotransmitter transporters, and non-cannabinoid G-protein-coupled receptors.

GPR55 antagonism and TRPV1 activation

G protein-coupled receptor 55 (GPR55) represents a crucial target in CBD’s anticonvulsant mechanism. Initially characterized as a novel cannabinoid receptor, GPR55 is widely distributed throughout the central nervous system, with notable concentrations in the caudate, putamen, hippocampus, thalamus, pons, cerebellum, and frontal cortex.

GPR55 activation by its endogenous ligand, lysophosphatidylinositol (LPI), triggers intracellular calcium release from endoplasmic reticulum stores via a pathway dependent on RhoA, phospholipase C, and inositol 1,4,5-trisphosphate receptor. This process ultimately enhances excitatory neurotransmission. Conversely, CBD acts as a GPR55 antagonist, blocking LPI’s pro-excitatory effects.

Essentially, CBD’s GPR55 antagonism appears particularly significant in epilepsy treatment because:

GPR55 function becomes enhanced in epileptic brains compared to non-epileptic tissue
LPI production increases during epileptic seizures, as catalyzed by phospholipase A2
CBD remains fully potent in blocking GPR55-mediated effects even in epileptic tissue

Simultaneously, CBD acts as an agonist at transient receptor potential vanilloid type 1 (TRPV1) channels. Although initial TRPV1 activation transiently increases calcium influx, prolonged exposure to CBD subsequently desensitizes these channels, preventing activation by endogenous ligands. This biphasic action ultimately reduces neuronal excitability, contributing to CBD’s anticonvulsant profile.

Interestingly, TRPV1 knockout studies demonstrate that CBD’s ability to increase the seizure threshold is markedly reduced in TRPV1-deficient mice, confirming the importance of this channel in CBD’s anticonvulsant effects.

CBD’s effect on adenosine and serotonin pathways

Another critical mechanism underlying CBD’s anticonvulsant properties involves the adenosine signaling pathway. Adenosine functions as the brain’s endogenous anticonvulsant and neuroprotectant. CBD inhibits the equilibrative nucleoside transporter 1 (ENT1), thereby preventing adenosine reuptake and increasing extracellular adenosine levels.

This elevated adenosine activates inhibitory adenosine A1 and A2 receptors, which then:

Inhibit presynaptic calcium influx
Enhance postsynaptic hyperpolarization through inwardly rectifying potassium channels
Modulate striatal CB1 receptors

At micromolar concentrations, CBD also inhibits fatty acid amide hydrolase (FAAH), the enzyme responsible for breaking down anandamide (an endogenous cannabinoid). This inhibition elevates anandamide levels, further enhancing endocannabinoid signaling.

Furthermore, CBD acts as an agonist at 5-hydroxytryptamine 1A (5-HT1A) serotonin receptors. This interaction activates G-protein-coupled inwardly rectifying potassium (GIRK) channels while inhibiting voltage-gated calcium channels, ultimately dampening neuronal excitability. CBD’s serotonergic effects also modulate presynaptic vesicle release by inhibiting adenylyl cyclase pathways.

This multimodal pharmacological profile distinguishes CBD from conventional anti-epileptic drugs and helps explain its effectiveness in treatment-resistant epilepsy syndromes. Rather than targeting a single pathway, CBD appears to modulate neuronal excitability through complementary mechanisms that collectively restore balance to hyperexcitable neural circuits.

Preclinical Evidence of CBD’s Anticonvulsant Effects

Laboratory investigations consistently demonstrate CBD’s potent anticonvulsant properties across diverse experimental models. Preclinical research has established foundational evidence that ultimately supported clinical trials in treatment-resistant epilepsy syndromes. These animal studies provide critical insights into CBD’s mechanisms, extending beyond receptor interactions, including practical anticonvulsant applications and neuroprotective capabilities.

Maximal electroshock and PTZ models

Early investigations into CBD’s anticonvulsant potential utilized classic seizure paradigms established for screening anti-epileptic compounds. Through these standardized models, researchers have thoroughly evaluated CBD’s efficacy profile:

In the maximal electroshock (MES) model, which primarily assesses compounds against generalized tonic-clonic seizures, CBD consistently demonstrates protection against seizures induced by transcorneal or transauricular electrical stimulation. Notably, CBD exhibits an ED50 (median effective dose) of 120 mg/kg in mice, indicating substantial potency in preventing the tonic extension phase characteristic of this model. This protection occurs without the development of tolerance upon repeated administration, unlike many conventional anticonvulsants.

For chemically-induced seizures, pentylenetetrazol (PTZ) remains the gold-standard agent. CBD shows remarkable efficacy against PTZ-induced seizures across multiple species, with these key findings:

CBD significantly elevates the seizure threshold in mice administered PTZ intravenously
At doses of 100 mg/kg, CBD completely prevents the expression of tonic-clonic seizures
Unlike THC, CBD produces anticonvulsant effects without accompanying psychoactivity or behavioral impairment

Beyond these standard models, CBD demonstrates effectiveness against seizures induced by other chemoconvulsants, including:

3-mercaptopropionic acid
Bicuculline
Picrotoxin
Isoniazid
Strychnine

This broad-spectrum activity suggests that CBD works through multiple mechanisms, rather than targeting a single pathway, which distinguishes it from many traditional anticonvulsants.

CBDV and THCA in animal seizure models

While CBD receives primary attention, other phytocannabinoids exhibit promising anticonvulsant properties. Cannabidivarin (CBDV), a propyl analog of CBD, shows particular promise in preclinical testing. Structurally, CBDV differs from CBD only in its side chain length, yet demonstrates independent anticonvulsant activity.

In acute seizure models, CBDV effectively suppresses seizures across multiple paradigms:

In audiogenic seizures, CBDV (at 100-200 mg/kg) significantly reduces seizure severity
Against MES-induced seizures, CBDV demonstrates dose-dependent protection
CBDV suppresses PTZ-induced seizures while simultaneously normalizing epilepsy-associated gene expression changes in the hippocampus

THCA (tetrahydrocannabinolic acid), the non-psychoactive precursor to THC, likewise exhibits anticonvulsant properties in preliminary studies. In the 6-Hz psychomotor seizure model, THCA demonstrates efficacy at significantly lower doses than CBD, suggesting potentially higher potency against certain seizure types.

Interestingly, research on cannabinoid combinations reveals entourage effects whereby certain phytocannabinoid mixtures produce enhanced anticonvulsant effects compared to isolated compounds. This finding supports the investigation of whole-plant extracts alongside purified CBD formulations.

Neuroprotective effects in hippocampal slices

Ex vivo studies using hippocampal brain slices provide crucial insights into CBD’s cellular neuroprotective mechanisms. In these preparations, researchers can precisely control experimental conditions while maintaining the neural circuit architecture.

In organotypic hippocampal cultures exposed to oxygen-glucose deprivation (simulating ischemic conditions), CBD treatment before exposure significantly reduces neuronal death. Furthermore, CBD demonstrates powerful inhibitory effects on neuronal hyperexcitability in the following ways:

First, in magnesium-free conditions that enhance NMDA receptor activation and mimic excitotoxic states, CBD reduces epileptiform activity. Second, CBD significantly decreases the amplitude and frequency of epileptiform local field potentials in hippocampal slices exposed to 4-aminopyridine (a potassium channel blocker).

Perhaps most compelling, CBD exhibits activity in the high-Mg²⁺, low-Ca²⁺ model of spontaneous epileptiform activity—a condition resistant to many conventional anticonvulsants. It suggests CBD’s unique ability to modulate neuronal excitability through non-traditional mechanisms, potentially explaining its efficacy in treatment-resistant epilepsies.

Regarding cellular mechanisms, these hippocampal slice models confirm CBD’s ability to stabilize neuronal membranes through multiple interactions with ion channels, reduce presynaptic glutamate release, and enhance inhibitory neurotransmission. Collectively, these actions preserve the delicate balance between excitation and inhibition within hippocampal networks, providing a mechanistic basis for CBD’s neuroprotective effects.

Overall, these preclinical findings establish CBD as a unique anticonvulsant compound with broad-spectrum activity, multiple mechanisms of action, and significant neuroprotective properties that distinguish it from traditional anti-epileptic drugs.

Clinical Trials That Changed the Landscape

Rigorous clinical trials have solidified CBD’s role in epilepsy treatment, establishing concrete evidence that moved cannabidiol from theoretical treatment to FDA-approved medicine. These landmark studies provided the first methodologically sound evidence supporting CBD therapy for specific seizure disorders.

GWPCARE1: Dravet syndrome outcomes

The GWPCARE1 trial represented a watershed moment for CBD and seizures research. This double-blind, placebo-controlled study enrolled 120 children and young adults with Dravet syndrome and drug-resistant seizures. Participants received either CBD oral solution at 20 mg/kg/day or placebo for 14 weeks (including a 2-week dose escalation and 12-week maintenance).

The results were compelling:

Median monthly convulsive seizures decreased from 12.4 to 5.9 with CBD compared to 14.9 to 14.1 with placebo
The median percent reduction in convulsive seizures was 39% with CBD versus 13% with placebo
43% of CBD-treated patients achieved ≥50% seizure reduction compared to 27% with placebo

Perhaps most strikingly, 5% of patients in the CBD group achieved complete seizure freedom during the treatment period, while no patients in the placebo group became seizure-free. The CBD group also experienced substantial improvements in overall condition, with 62% showing enhancement on the Caregiver Global Impression of Change scale, compared to 34% in the placebo group.

GWPCARE3/4: Lennox-Gastaut syndrome results

Following success in Dravet syndrome, researchers conducted two pivotal trials in Lennox-Gastaut syndrome (LGS). GWPCARE3 examined 225 patients randomized to receive CBD at 10 mg/kg/day, 20 mg/kg/day, or placebo. GWPCARE4 included 171 patients receiving either CBD 20 mg/kg/day or placebo.

The outcomes clearly demonstrated CBD’s effectiveness:

In GWPCARE3, the median percent reduction in drop seizures was 41.9% in the 20 mg/kg group, 37.2% in the 10 mg/kg group, and 17.2% in the placebo group. The higher-dose group showed an adjusted reduction of 21.6% compared with the placebo group. GWPCARE4 yielded similar results, with a median 43.9% reduction in monthly drop seizure frequency from baseline in the CBD group.

Beyond drop seizures, CBD demonstrated broad effectiveness against multiple seizure types. The median reduction in total seizures across both LGS trials was 38.4% for the 20 mg/kg group, 36.4% for the 10 mg/kg group, and 18.5% for the placebo.

Alongside reduced seizure frequency, patients experienced meaningful increases in seizure-free days. CBD-treated LGS patients gained approximately 5.6-6.5 additional seizure-free days per month, representing a tangible improvement in quality of life.

Responder rates and seizure freedom statistics

Responder rates—patients achieving predetermined thresholds of seizure reduction—reveal the clinical magnitude of CBD’s effects across trial populations.

In LGS trials, CBD consistently outperformed placebo:

≥50% reduction in drop seizures: 39% (20 mg/kg), 36% (10 mg/kg), and 14% (placebo)
≥75% reduction: 25% (20 mg/kg), 11% (10 mg/kg), and 3% (placebo)

For Dravet syndrome, corresponding figures showed:

≥50% reduction: 43% with CBD versus 27% with placebo

Complete seizure freedom, albeit rare in these highly treatment-resistant populations, occurred primarily with CBD therapy. In LGS, five patients (7%) receiving 20 mg/kg CBD and three patients (4%) receiving 10 mg/kg CBD became seizure-free during the maintenance phase, compared to just one patient (1%) on placebo.

Long-term extension studies have subsequently validated these findings. After 156 weeks of treatment, median reductions ranged from 45% to 71% for drop/convulsive seizures and 48% to 78% for total seizures. Approximately 10% of patients ultimately achieved complete seizure freedom, exceeding the 3-6% rates observed in the initial randomized trials.

These landmark clinical trials provided sufficient evidence for regulatory approval. In 2018, the FDA approved Epidiolex (cannabidiol oral solution) for the treatment of treatment-resistant epilepsy, initially for Dravet and Lennox-Gastaut syndromes, followed by European Medicines Agency approval in 2019.

CBD and Clobazam: A Complex Interaction

Among the critical considerations in CBD therapy for epilepsy stands its interaction with clobazam (CLB), a benzodiazepine commonly prescribed for treatment-resistant seizure disorders. The relationship between these medications reveals both pharmacokinetic and pharmacodynamic components that impact clinical outcomes, side effect profiles, and dosing strategies.

CYP2C19 inhibition and N-desmethylclobazam elevation

The primary mechanism driving the interaction between CBD and clobazam occurs through CBD’s inhibition of cytochrome P450 pathways. Specifically, CBD potently inhibits CYP3A4, which metabolizes clobazam to N-desmethylclobazam (nCLB), and CYP2C19, which converts nCLB to inactive metabolites. This dual inhibition creates a metabolic bottleneck with measurable clinical consequences:

CBD increases clobazam levels by 60±80% at 4 weeks of treatment
More dramatically, nCLB levels rise by 500±300% during the same period
The interaction appears dose-dependent, with increasing CBD doses corresponding to higher clobazam and nCLB concentrations

Interestingly, this interaction necessitates a dose reduction of clobazam in most patients. In one study, 77% of subjects required CLB dose adjustments despite experiencing improved seizure control. This seemingly paradoxical outcome—better efficacy with lower clobazam doses—highlights the complexity of this drug interaction.

Pharmacodynamic synergy in GABAergic modulation

Beyond pharmacokinetics, CBD and clobazam exhibit direct pharmacodynamic cooperation. Both compounds enhance inhibitory neurotransmission through distinct mechanisms at GABAA receptors. Laboratory investigations reveal:

CBD alone enhances GABA-evoked currents by 106% with an EC50 of 2.4 μmol/L, whereas clobazam demonstrates greater potency (EC50 of 662 nmol/L) and efficacy (369% enhancement). Upon combination, the effect exceeds what either compound achieves independently—289±54% enhancement compared to 204±33% with clobazam alone and 82±11% with CBD alone.

This additive effect at GABAA receptors provides a mechanistic explanation for both enhanced efficacy and increased side effects. Indeed, somnolence—the most frequently reported adverse event in CBD clinical trials—occurs predominantly in patients receiving both medications. Of 22 patients reporting somnolence in the cannabidiol group of one trial, 18 (82%) were taking clobazam concurrently.

Post-hoc analyses separating CBD’s independent effects.

The pronounced interaction between CBD and clobazam has prompted debate regarding whether CBD’s anticonvulsant effects might reflect augmented clobazam action rather than independent therapeutic activity. Multiple analyses address this question:

A pooled analysis of GWPCARE3 and GWPCARE4 trials determined that responses to CBD were independent of clobazam co-prescription. Furthermore, Gaston’s prospective study of 132 participants revealed no difference in seizure frequency reduction between patients receiving clobazam and those without, even at high CBD doses (50 mg/kg/day).

Most compelling, preclinical studies demonstrate that while CBD consistently increases plasma clobazam concentrations, this pharmacokinetic effect alone cannot account for the improved seizure control. Anderson et al. found that subthreshold CBD doses failed to enhance clobazam’s anticonvulsant effects, despite increasing plasma clobazam levels; only anticonvulsant CBD doses produced synergistic benefits.

Moreover, CBD shows efficacy in multiple seizure types where clobazam alone typically demonstrates limited benefit. The distinct receptor profile of CBD, including actions at GPR55 and other targets unrelated to benzodiazepine mechanisms, supports its independent therapeutic role.

Clinical practice increasingly recognizes that while monitoring this interaction remains essential, CBD demonstrates intrinsic anticonvulsant properties extending beyond simply enhancing clobazam effects. This understanding enables optimized combination therapy that capitalizes on both pharmacokinetic and pharmacodynamic synergies between these medications.

Real-World Evidence Beyond Dravet and LGS

While pivotal trials established CBD’s efficacy in specific syndromes, real-world evidence has expanded our understanding of cannabidiol’s potential across broader epilepsy populations. The transition from controlled studies to clinical practice has yielded valuable insights into the effectiveness of CBD beyond the narrow parameters of randomized trials.

Expanded access programs and observational studies

The United States Expanded Access Program (EAP) for cannabidiol, initiated in 2014, provided pharmaceutical-grade CBD (Epidiolex®) to patients with various treatment-resistant epilepsies across 35 epilepsy centers. This compassionate use program generated crucial long-term data through the structured observation of 892 patients, who were followed for a median of 694 days. The final pooled analysis revealed sustained effectiveness, with CBD treatment associated with a 46%-66% reduction in median monthly total seizure frequency.

Patient retention offers the strongest testament to real-world utility – after nearly four years of observation, 64% of patients remained on therapy. Among those who discontinued, lack of efficacy (19%) and adverse events (7%) constituted primary reasons for withdrawal. Top CBD doses averaged 25 mg/kg/day, demonstrating practical dosing patterns outside trial protocols.

Unlike controlled trials, the EAP captured outcomes across diverse seizure types, revealing:

Convulsive seizure types: 47%-100% median reduction across 144 weeks
Nonconvulsive seizure types: 50%-100% median reduction
Epileptic spasms: Similar 50%-100% reductions

Approximately half of the patients achieved ≥50% reduction in seizure frequency at almost all assessment intervals throughout the program.

Efficacy in focal epilepsies and genetic syndromes

For focal epilepsies specifically, which often remain challenging to treat, data from 151 EAP participants with confirmed focal etiology demonstrated a remarkable response. CBD treatment produced median reductions of 54%-77% in focal seizures and 54%-75% in total seizures over 144 weeks. Notably, responder rates remained consistent, with 51% to 72% of patients achieving a≥50% reduction in focal seizures.

In adults specifically, an analysis of 193 patients aged 18-74.5 years revealed median percent reductions of 45%-64% in convulsive seizures and 41%-63% in total seizures over the course of treatment. Henceforth, even severe, long-standing epilepsies showed sustained response.

Beyond focal epilepsies, CBD showed effectiveness in monogenic epilepsies, with one cohort study reporting 47.5% of patients achieving ≥50% seizure reduction. Separate observations in tuberous sclerosis complex revealed that 78% of patients achieved greater than 50% seizure reduction, surpassing the 36%-40% rates observed in controlled trials.

Seizure reduction in non-syndromic drug-resistant epilepsy

Thereupon, the broader category of non-syndromic drug-resistant epilepsy – representing most treatment-resistant cases in clinical practice – showed comparable benefits. A retrospective, multicenter study involving 311 patients found that 61.7% experienced reduced seizure frequency with CBD, including 30.5% achieving >50% reduction. Seizure freedom, albeit rare in treatment-resistant populations, was attained by 6.4% of patients.

For certain seizure types, complete seizure control appears more attainable. In patients experiencing tonic-clonic seizures, 16.7% achieved complete seizure freedom. Equally noteworthy, 55.6% of patients in one cohort demonstrated behavioral improvements, highlighting benefits extending beyond seizure control.

The safety profile in these extended populations matched earlier findings, with diarrhea (33-49%), somnolence (21-24%), and seizure events (24-25%) representing the most common treatment-related adverse events. Primarily, liver-related events occurred in approximately 5% of patients, reinforcing the need for monitoring liver function during therapy.

Collectively, these real-world findings extend CBD’s demonstrated efficacy beyond the initial approved indications, supporting its consideration across a broader spectrum of epilepsy syndromes and etiologies.

Safety Profile and Adverse Events in CBD Therapy

Clinical data indicate that CBD’s therapeutic benefits must be weighed against its associated adverse events. Controlled trials demonstrate a structured safety profile that helps practitioners anticipate and manage potential complications.

Somnolence, diarrhea, and appetite changes

Pharmaceutical-grade CBD consistently produces more adverse events than placebo, with the risk ratio for any-grade adverse events being 1.12 (95% CI, 1.02-1.23). The most frequently reported adverse effects include:

Somnolence (22.0% vs 9% with placebo)
Decreased appetite (19.5%)
Diarrhea (occurring in 33-49% of patients in long-term studies)

In real-world settings, adverse events appear less prevalent, with 79% of users not reporting any side effects in some observational studies. Typically, CBD-related somnolence resolves with clobazam dose reduction, as the interaction between these medications contributes substantially to this effect. Irritability (20.9%) emerges as another common adverse effect in pediatric populations.

Liver enzyme elevations with valproate co-use

Hepatic enzyme elevations represent a crucial safety consideration with CBD therapy. Clinical data reveal that CBD treatment increases the risk of ALT/AST elevation 12.29-fold (95% CI, 4.22-35.80) compared to placebo. Within controlled studies, 5.6% of participants experienced ALT elevations exceeding three times the upper limit of normal after just four weeks of CBD dosing.

Notably, the co-administration of valproate substantially increases this risk. In pivotal trials, 79% of patients with significant transaminase elevations were receiving concomitant valproic acid. Hence, regular liver function monitoring becomes essential, particularly during the initiation of treatment and dose adjustments.

This interaction appears mechanistically complex, as quantitative systems toxicology models suggest the increased incidence of CBD-associated liver enzyme elevations with valproate likely involves pathways beyond direct hepatotoxicity. Fortunately, most cases resolve either spontaneously during continued treatment or with dose adjustment.

Long-term tolerability and withdrawal rates

Long-term data suggest CBD maintains an acceptable safety profile with extended use. Discontinuation rates due to adverse events range from 3.6% to 8% across various studies. Given that, withdrawal rates remain lower than might be expected considering the frequency of adverse events.

Treatment discontinuation primarily results from lack of efficacy (16.5%) rather than tolerability issues. Within the clinical trial setting, AEs leading to dose reduction occurred 9.87 times more frequently with CBD than placebo, indicating that dose adjustment often successfully mitigates adverse effects.

Importantly, no evidence of physical withdrawal syndrome emerges following abrupt CBD discontinuation, distinguishing it from many conventional anti-seizure medications that require tapering.

Remaining Questions and Future Research Directions

Despite promising advances in cannabidiol research, critical knowledge gaps persist regarding its optimal clinical application. Current evidence underscores several areas requiring focused investigation to refine CBD’s role in seizure management.

CBD efficacy in adult focal epilepsy

Adult epilepsy patients remain distinctly underrepresented in most CBD trials. Common focal epilepsy etiologies in adults—including post-stroke epilepsy, traumatic brain injury, and focal cortical dysplasia—lack proper representation in existing studies. A recent trial investigating transdermal CBD for adult focal epilepsy without concomitant clobazam found no statistical advantage over placebo. This absence of treatment effect may stem from inadequate dosing, as higher doses (500-1000 mg daily) have shown efficacy in developmental epileptic encephalopathies with median focal impaired awareness seizure reductions of 44.5%. Ongoing research with extended treatment periods shows promise, with median reductions of 54% to 88% in overall focal seizures across 144 weeks in some populations.

Need for clobazam-free RCTs

The cannabidiol-clobazam relationship remains a confounding factor in interpreting CBD’s independent efficacy. Recent phase 4 evidence challenges previous assumptions, as data from patients using CBD without clobazam demonstrated:

Median percentage reductions of 16.7% in seizure frequency at 10-12 months in LGS patients
30% of LGS patients achieved≥50% seizure reduction at 12 months
Complete seizure remission in 4% of patients after 12 months

These findings support CBD’s intrinsic anti-seizure activity independent of clobazam’s effects.

Standardization of CBD formulations and dosing

Presently, considerable variability exists among CBD products. One study examining 84 different artisanal CBD extracts found only 31% were accurately labeled, with 42% underlabeled and 25% overlabeled. Beyond pharmaceutical preparations, synthetic CBD may offer solutions to legal obstacles and cost barriers. For standardized products, the “start low, go slow” principle remains foundational—pediatric dosing typically begins at 5 mg/kg/day, while adults often start at 10-20 mg daily. Still, the maximum effective doses remain debated, with trials reporting efficacy at doses ranging from 5 to 50 mg/kg/day.

Conclusion

Thus, the evidence supporting CBD’s role in epilepsy management has evolved from historical anecdotes to robust clinical data. Previously considered merely an alternative therapy, CBD now stands as a legitimate treatment option backed by rigorous clinical trials and real-world evidence. The FDA approval of Epidiolex marks a watershed moment in recognizing cannabidiol’s therapeutic value for seizure disorders.

Clinical data consistently demonstrate CBD’s effectiveness across multiple epilepsy syndromes. Though initially explicitly approved for Dravet and Lennox-Gastaut syndromes, CBD shows promise beyond these indications:

Mean seizure reductions of 39-67% across various studies
Responder rates (≥50% seizure reduction) between 36-43% in controlled trials
Complete seizure freedom achieved in approximately 5-11% of patients
Sustained benefits during long-term treatment extending beyond two years

The complex pharmacology underpinning CBD’s anticonvulsant effects distinguishes it from conventional anti-epileptic medications. Rather than targeting a single pathway, CBD modulates neuronal excitability through multiple mechanisms, including antagonism of GPR55, desensitization of TRPV1, and enhancement of adenosine. This multitarget approach likely explains its efficacy in treating cases that are resistant to treatment.

Nevertheless, CBD therapy carries critical clinical considerations. The interaction between CBD and clobazam demands particular attention due to both pharmacokinetic and pharmacodynamic synergies. Additionally, co-administration of valproate increases the risk of transaminase elevations, necessitating regular monitoring of liver function. Common adverse effects—primarily somnolence, decreased appetite, and diarrhea—generally prove manageable through dose adjustments.

While evidence strongly supports CBD’s anticonvulsant properties, several questions remain unanswered. The efficacy of CBD in adult focal epilepsy requires further investigation through dedicated trials. Likewise, studies examining CBD without concomitant clobazam would help clarify its independent therapeutic contribution. Standardization of CBD formulations presents another challenge, as artisanal products frequently contain inconsistent cannabinoid concentrations.

Despite these limitations, CBD represents a valuable addition to the epilepsy treatment arsenal. The impact extends beyond mere seizure reduction to improvements in quality of life, with patients experiencing more seizure-free days and potential behavioral benefits. Accordingly, healthcare providers should consider CBD therapy for appropriate patients with treatment-resistant epilepsy while maintaining realistic expectations about its efficacy and side effect profile.

The therapeutic paradigm for epilepsy has undoubtedly shifted with CBD’s emergence as an evidence-based treatment. Future research will likely expand our understanding of optimal dosing strategies, identify additional responsive epilepsy syndromes, and clarify long-term outcomes. Indeed, the integration of cannabinoid therapies into mainstream epilepsy management represents a remarkable advancement in neurological care, offering new hope for patients previously deemed treatment-resistant.

Key Takeaways

Recent clinical evidence has transformed CBD from an alternative therapy to an FDA-approved epilepsy treatment, challenging traditional beliefs about cannabinoid medicine and establishing new treatment paradigms for drug-resistant seizures.

CBD demonstrates proven efficacy across multiple epilepsy syndromes, achieving 39-67% seizure reductions and 36-43% responder rates in controlled trials, with some patients achieving complete seizure freedom.
Unlike conventional drugs, CBD works through multiple pathways simultaneously, including GPR55 antagonism and TRPV1 activation, explaining its effectiveness in treatment-resistant cases.
The CBD-clobazam interaction requires careful management due to 500% increases in active metabolite levels, necessitating dose adjustments and liver function monitoring.
Real-world evidence extends beyond initial approvals, showing sustained benefits across focal epilepsies and genetic syndromes with 64% patient retention after four years.
Safety profile is manageable but requires monitoring, with somnolence, appetite changes, and liver enzyme elevations being primary concerns, especially with valproate co-use.

The transition from historical cannabis use to pharmaceutical-grade CBD represents a remarkable advancement in epilepsy care, offering evidence-based hope for patients with previously intractable seizures while establishing rigorous safety protocols for clinical practice.

Frequently Asked Questions:

FAQs

Q1. How effective is CBD in treating seizures? Clinical trials have shown that CBD can reduce seizure frequency by 39-67% in patients with certain types of epilepsy. Approximately 36-43% of patients experience a 50% or greater reduction in seizures, and 5-11% achieve complete seizure freedom. CBD has proven particularly effective for treatment-resistant epilepsies like Dravet syndrome and Lennox-Gastaut syndrome.

Q2. What are the main side effects of CBD treatment for epilepsy? The most common side effects of CBD treatment include somnolence (sleepiness), decreased appetite, and diarrhea. Some patients may also experience irritability. Additionally, CBD can cause elevations in liver enzymes, especially when used with certain other medications like valproate. Most side effects are manageable through dose adjustments.

Q3. How does CBD interact with other anti-epileptic medications? CBD has a significant interaction with clobazam, a commonly prescribed anti-epileptic drug. It can increase clobazam levels in the blood by up to 60% and its active metabolite by 500%. This interaction may enhance seizure control but also increase side effects, such as drowsiness. CBD also interacts with valproate, potentially increasing the risk of liver enzyme elevations.

Q4. Is CBD effective for all types of epilepsy? While CBD has shown efficacy in several types of epilepsy, its effectiveness can vary. It’s FDA-approved for Dravet syndrome and Lennox-Gastaut syndrome, and real-world evidence suggests benefits in other forms of treatment-resistant epilepsy. However, more research is needed to fully understand its efficacy in adult focal epilepsy and other specific seizure types.

Q5. How is CBD dosing determined for epilepsy treatment? CBD dosing typically follows a “start low, go slow” approach. For children, treatment often begins at 5 mg/kg/day, while adults may start at 10-20 mg daily. Doses can be gradually increased based on response and tolerability. In clinical trials, effective doses have ranged from 5-50 mg/kg/day, but optimal dosing can vary between individuals and epilepsy types.