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. 2026 Jan 26;138(2):e70194. doi: 10.1111/bcpt.70194

Antiseizure Effects of Cannabidiol in Combination With Cannabigerol in the Maximal Electroshock Seizure Model

Han Zhong Zhou 1, Brian Wayne Scott 1,✉, Yagoda Izabela Oleksak 1, Willets McIntyre Burnham 1
PMCID: PMC12835462  PMID: 41588555

ABSTRACT

Current antiseizure therapy for epilepsy is only effective in about 70% of the patient population. Previous studies had shown that the addition of small amounts of tetrahydrocannabinol (THC) made cannabidiol (CBD) much more potent in the maximal electroshock seizure (MES) model. The psychotoxic effects of THC make it unsuitable as an antiseizure therapy. The current study investigated the effects of combining CBD with the non‐psychotoxic cannabinoid cannabigerol (CBG) in the MES model in mice. Mice were administered (i.p.) CBD or CBG or a combination of both before undergoing the MES procedure. Dose–response and dose–toxicity curves were generated for each compound and combinations. It was found that CBG has antiseizure properties and that it potentiates the effects of CBD. By using a 1:1 ratio combination of CBD and CBG, the ED50 for CBD was reduced by over 50% and the TD50 for CBD was reduced by 40%, indicating increased toxicity. This suggests that the interaction between CBD and CBG may be additive in nature. Both drugs showed little toxicity at therapeutic doses. This is the first study to provide detailed dose–response data for CBG as well as CBG in combination with CBD in a seizure model and suggests that the two drugs could act in a similar manner to suppress seizures.

Keywords: cannabidiol, cannabigerol, cannabis, entourage, epilepsy

Plain Language Summary

Cannabinoids have been examined as potential antiseizure drugs but psychotoxic effects and low potency have been problematic. The present study determines dose–response and dose–toxicity relationships for the non‐psychotoxic cannabinoids CBG and CBD in the MES model and finds that CBG has antiseizure effects on its own and can potentiate the antiseizure effects of CBD, possibly in an additive manner. This suggests that CBG and CBD could use similar mechanisms for their antiseizure effects. This study is the first to present antiseizure effects of CBG as well as provide detailed dose–response and dose–toxicity data of CBG in combination with CBD.

Cannabidiol and cannabigerol suppress maximal electroshock seizures. Cannabidiol and cannabigerol show similar dose–response properties. Both cannabinoids show no toxicity at effective doses.

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Abbreviations

CBD

cannabidiol

CBG

cannabigerol

CBGA

cannabigerolic acid

MES

maximal electroshock seizure

THC

tetrahydrocannabinol

1. Introduction

Epilepsy is a neurological disorder characterised by recurrent, spontaneous seizures that affects approximately 50 million people globally [1]. Although antiseizure drugs remain the first‐line treatment, 20%–30% of patients remain treatment‐resistant [2]. This therapeutic gap necessitates further investigation into alternative treatments targeting novel mechanisms, including those involving cannabinoids.

Among the more than 100 phytocannabinoids identified, CBD and THC have been the most extensively studied. Randomised, placebo‐controlled trials have established the efficacy of purified CBD as an adjunctive treatment for Lennox–Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex [1, 3]. However, CBD's clinical efficacy varies considerably between seizure types and syndromes, and adverse effects such as somnolence or transaminase elevation remain limiting factors [4]. Moreover, CBD has low oral bioavailability, and its relatively modest potency necessitates high therapeutic doses [5, 6].

Evidence for THC as an antiseizure agent is less consistent. Preclinical studies have reported both anticonvulsant and pro‐convulsant effects at higher doses and in specific preclinical models [7, 8]. While some animal work suggests seizure suppression via CB1 receptor activation, others demonstrate seizure exacerbation or cognitive impairment. Consequently, the clinical utility of THC is limited by its psychoactive properties, inconsistent efficacy and safety concerns [9]. Given these limitations, recent research has turned toward non‐psychotoxic cannabinoids that may retain anticonvulsant efficacy without the drawbacks associated with THC.

Interest has since expanded to non‐psychotoxic cannabinoids such as cannabigerol (CBG), cannabidivarin (CBDV) and cannabigerolic acid (CBGA). CBG is the decarboxylated derivative of CBGA, which is the biosynthetic precursor to both CBD and THC [10]. It exhibits unique pharmacological actions, including partial agonism at α2‐adrenergic and 5‐HT₁A receptors, PPARγ activation and inhibition of voltage‐gated sodium channels [11, 12]. Preclinical evidence for CBG's antiseizure potential remains sparse and inconsistent, with some studies reporting no effect in the pentylenetetrazol (PTZ) model [13], while others observed mixed anticonvulsant and pro‐convulsant actions of CBGA across models [14]. These discrepancies highlight the need for comprehensive dose–response and toxicity analyses in standardised paradigms such as the maximal electroshock seizure (MES) test.

Multiple factors can further modulate cannabinoid efficacy. Formulation and route of administration can substantially influence pharmacokinetics, pharmacodynamics and therapeutic outcome. Whole‐plant or broad‐spectrum preparations containing minor cannabinoids and terpenes sometimes exhibit greater seizure reduction at lower total CBD doses; this observation is often attributed to an entourage effect; however, causality remains uncertain [15]. Similarly, oral bioavailability of CBD increases when administered with dietary fats, and intraperitoneal routes in rodents produce higher, more consistent plasma levels [5, 16]. Such variables likely contribute to the heterogeneity of clinical and preclinical findings, underscoring the need to clearly define formulation, route and matrix effects when evaluating cannabinoid combinations.

Despite progress in clinical translation, animal studies remain indispensable. They enable controlled exploration of dose–response relationships, toxicological thresholds and mechanistic interactions that are difficult to isolate in heterogeneous patient populations. They also allow formal quantification of drug‐interaction models, thereby providing mechanistic rigor to claims of potentiation.

The present study was therefore designed to determine whether combining CBD with the non‐psychotoxic cannabinoid CBG could enhance CBD's antiseizure efficacy in the MES model, similar to the previously reported CBD + THC interactions but without psychoactive liability [6, 17]. We additionally evaluated CBG alone to assess its intrinsic antiseizure activity. Complete dose–response and dose‐toxicity curves were generated for both compounds and combinations, and their interaction was assessed. This approach directly addresses prior gaps in the literature regarding CBG's anticonvulsant and toxicity profile as well as provides information about the interactive relationship between CBD and the non‐psychotoxic cannabinoid CBG.

2. Materials and Methods

The protocols for these studies were approved by the Local Animal Care Committee at the Faculty of Medicine of the University of Toronto. The procedures took place in the Division of Comparative Medicine facility located in the basement of Terrence Donnelly Centre for Cellular and Biomolecular Research. All experiments complied with the guidelines of the Canadian Council on Animal Care. The study was conducted in accordance with the Basic and Clinical Pharmacology and Toxicology policy for experimental and clinical studies [18].

2.1. Subjects

The subjects of these experiments were adult, male CF‐1 mice, obtained from Charles River (Saint‐Constant, Quebec, Canada) and weighing between 18 and 25 g (25 to 32 days old) at the time of delivery. Subjects were allowed to acclimate to the animal facility for at least 7 days before testing. Exclusively male subjects were used in this study in order to reduce the variability in seizure response that is known to occur in female rodents as a result of cycling reproductive hormone levels [19, 20, 21]. Subjects were housed in groups of four in plastic transparent cages with dimensions of 29 cm × 17 cm × 17 cm (Ecoflo, Allentown Inc., Allentown, NJ, United States). The cages were provided with corncob bedding, and a red polycarbonate safe harbour was placed in each cage as environmental enrichment. Food (2018 Teklad Global 18% Protein Rodent Diet, Envigo, Madison, Wisconsin, United States) and water were available ad libitum. The animal facility was kept at a temperature range of 20°C–26°C, with humidity at 40%–60% and a 14‐h light–dark cycle (lights on at 6:00 and off at 20:00). All experiments were conducted during the light cycle. The subjects' weights were between 30 and 35 g (32 to 39 days) at the day of testing. Subjects, MES parameters and injection‐test interval (see below) were chosen to mimic that of Klein et al. [5] in order to better compare results among studies.

2.2. Drug Preparation

Separate formulations of CBD and CBG were provided as (99% pure) isolates by Avicanna Inc. (Toronto, Canada). CBD and CBG solutions in a standard 1:1:18 vehicle were prepared by first dissolving the 99% pure isolates in a 1:1 ratio of 95% ethanol and Koliphor EL, creating a 400 mg/mL stock concentration. Different doses were then prepared by diluting the stock solutions with a 1:1:18 ratio of 95% ethanol, Kolliphor EL and 0.9% saline.

2.3. Drug Administration

Subjects were randomly assigned to each treatment group and drug dose immediately before injections were begun. The order in which drugs were tested was randomised each testing day. Random assignment was performed using an online random number generator (random.org). Eight subjects (n = 8) were tested for each drug dose. All drugs were injected intraperitoneally (i.p.) at a constant injection volume of 10 mL/kg.

The doses and subject numbers were chosen based on past MES studies examining CBD in our laboratory [6]. These were initially selected based on the range of CBD doses used in Kein et al. [5] (50 to 150 mg/kg). Since the ED50 of CBD was found to be somewhat higher in our hands, the range of doses chosen was altered accordingly and, in most cases, doses ranged from 0 to 400 mg/kg. Since, at the time of initiation of this study, no appropriate CBG ED50 data in the MES model had been available, the range of CBD doses was used as a guide for CBG doses. In some cases, further doses were added to improve the dose–response curves when the ED50 or Emax was not adequately captured. The doses used for the combination studies were derived from the individual dose–response curves for each drug.

The injection‐test interval for all the drug doses was 2 h. This injection‐test interval was chosen to align with the reported time of peak effect for both CBD and THC in the MES [5] and kindling [22] seizure models. Each subject was tested only once and received one injection with either drug for single drug tests or one injection with each drug for combination drug tests. Injections (and MES procedure) were performed by a single experimenter who was not blind to treatment groups. Toxicity assessments were visually confirmed by at least two other non‐blind experimenters.

2.4. The MES Model—Procedure and Scoring

After drug administration—and the 2‐h injection‐test interval—each subject received a 50‐mA, 0.2‐s train of 60 Hz sine‐wave current via corneal electrodes moistened with 0.9% saline prior to use. The mice were pre‐treated with eye anaesthetic (0.5% tetracaine hydrochloride dissolved in 0.9% saline solution) in both eyes 5–10 min before stimulation.

The presence or absence of hindlimb tonic extension was determined. ‘Tonic extension’ (no protection) was defined as a full extension of hind limbs (> 135° from the torso). ‘Protection’ was defined as the absence of a full tonic hindlimb extension during the 15 s after the delivery of the electric stimulus. Subjects that did not receive full stimulation—as indicated by the MES stimulator—were excluded from analysis.

2.5. Toxicity Evaluation

Immediately prior to the delivery of the MES stimulus, mice were individually placed into an observation cage for examination of possible neurological impairments. Neurological status was evaluated visually using Löscher's 0–5 point ataxia scoring system [23]. Ataxia was scored as ‘present’ when Stage 2 or higher was seen.

2.6. Euthanasia

Immediately after MES testing, mice were euthanised with carbon dioxide followed by cervical dislocation.

2.7. Data Analysis

Seizures were scored quantally, with the absence of hindlimb extension being scored as ‘protection’ and the presence of hindlimb extension being scored as ‘non‐protection’. The percentage of animals protected, as well as the percentage showing toxicity, at each dose was calculated (% protection and % toxicity). Dose response curves, ED50, TD50 and 95% confidence intervals (CIs) were calculated using the Litchfield and Wilcoxon method as implemented in RStudio with the LW1949 package [24, 25].

In this method, a log10 transformation of each dose tested, as well as a probit transformation of the proportion of subjects protected from seizure, is obtained [24]. Minimisation of the chi‐squared statistic (difference between observed and expected data) on a simple linear regression relative to the observed data is then performed in order to find the best fit. Since 0% and 100% effects provide less information from which to derive EDs and may skew and distort the curve fit, they are not weighted the same as partial effects and are corrected based on the expected data [24, 25]. Therefore, the curves may provide more accurate ED estimates than if extreme effects were weighted equally. The ED50 and 95% CIs are then derived from this line. The chi‐squared statistic serves as an indicator of goodness of fit. All chi‐squared statistics were found to be below the critical chi‐squared value at the p = 0.05 level. The data are then reverse transformed in order to generate the familiar sigmoid dose–response curve.

The open circles on the graphs represent either 0% or 100% response. The closed black circles on the graphs represent responses that are neither 0 nor 100. ED50 are presented with the upper and lower bounds of the 95% CI. Significant differences between ED50 were determined using the z‐test method with a proportional overlap of 95% CIs. z‐test values larger than 1.96 are considered significantly different (p < 0.05) [26]. The therapeutic index (TI) was calculated as TI = TD50/ED50.

The additive isobole line on the isobologram was constructed by using the ED50 of each drug as the intercepts on the appropriate axis and represents a hypothetical assumed relationship of constant relative potency between the two drugs at the 50% effect level (i.e., an additive relationship). From the combination dose–response experiment, the dose of each component of the 1:1 ED combination of both drugs required to attain a 50% effect level (ED50) was then plotted on the isobologram.

3. Results

3.1. Dose Response and Toxicity Data

Figure 1A shows a dose–response curve for effects of CBD in 1:1:18 ratio of 95% ethanol, Kolliphor EL and 0.9% saline on MES seizures. Seizure protection was observed at doses of 100 mg/kg and above. Maximal effects of 100% MES seizure protection were seen at 150 mg/kg. The ED50 was calculated to be 133 (CI: 108–162) mg/kg.

FIGURE 1.

FIGURE 1

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Dose relationships for CBD and CBG alone and in combination in the MES model. (A) Dose–response relationship for CBD alone, n = 8 per drug dose (chi‐squared = 1.91, df = 3). (B) Dose–response relationship for CBG alone, n = 8 per drug dose (chi‐squared = 1.03, df = 3). (C) Protective effects of CBD and CBG in different ratio combinations, n = 8 per drug dose. (D) Dose–response relationship for 1:1 ED ratios of CBD and CBG in combination, n = 8 per drug dose (chi‐squared = 0.08, df = 2). Solid lines represent best fit curve; dashed lines represent 95% confidence interval. Black dots represent values that are neither 0% nor 100%, which are represented by white dots. Yellow bar in C represents CBD in vehicle alone (CBG dose = 0), while blue bars represent CBD + CBG in combination.

Figure 2A shows a dose‐toxicity response curve for the effects of CBD in 1:1:18 ratio of 95% ethanol, Kolliphor EL and 0.9% saline on MES seizures. Toxicity was observed at doses of 500 mg/kg and above. Toxicity was observed in 100% of the subjects at 700 mg/kg. The TD50 was calculated to be 560 (Cl: 487–641) mg/kg. The TI for CBD was calculated to be TI = 4.2.

FIGURE 2.

FIGURE 2

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Toxicity of CBD and CBG alone and in combination in the MES model. (A) Dose–toxicity relationship for CBD alone, n = 8 per drug dose (chi‐squared = 1.42, df = 3). (B) Dose–toxicity relationship for CBG alone, n = 8 per drug dose (chi‐squared = 2.12, df = 3). (C) Dose–toxicity relationship for 1:1 ED ratios of CBD and CBG in combination, n = 8 per drug dose (chi‐squared = 1.49, df = 2). Solid lines represent best fit curve; dashed lines represent 95% confidence interval. Black dots represent values that are neither 0% nor 100%, which are represented by white dots.

Figure 1B shows a dose–response curve for the effects of the formulation of CBG in 1:1:18 ratio of 95% ethanol, Kolliphor EL and 0.9% saline on MES seizures. Seizure protection was observed at doses of 150 mg/kg and above. Maximal effects of 100% seizure protection were seen at 400 mg/kg. The ED50 was calculated to be 149 (CI: 118–189) mg/kg.

Figure 2B shows a dose‐toxicity response curve for the effects of CBG in 1:1:18 ratio of 95% ethanol, Kolliphor EL and 0.9% saline on MES seizures. Toxicity was observed at doses of 500 mg/kg and above. Toxicity was observed in 100% of the subjects at 700 mg/kg. The TD50 was calculated to be 544 mg/kg (Cl: 463–639) mg/kg. The TI for CBG was calculated to be TI = 3.6.

Figure 1C shows different combinations of CBD and CBG on the MES seizures. CBD was administered at a fixed dose of 100 mg/kg, which was approximately the ED20 dose from the prior CBD dose–response curve (Figure 1A). CBG was administered at doses of 80 mg/kg (ED5), 100 mg/kg (ED10), 120 mg/kg (ED25) and 140 mg/kg (ED43). There was a potential synergistic effect of combined CBD and CBG, with minimally effective doses of either drug becoming much more effective when combined. As the dose of CBG increased, the % protection greatly increased. The best protection was achieved at a 1:1 ratio (100 mg/kg of CBD + 100 mg/kg of CBG).

Figure 1D shows a dose–response curve for the effect of CBD + CBG at a 1:1 ED ratio (i.e., combined doses were given at CBD ED10:CBG ED10, CBD ED5:CBG ED5, CBD ED2.5:CBG ED2.5 and CBD ED1.25:CBG ED1.25, as derived from the corresponding dose–response curves for each drug). MES seizure protection was seen at CBD 60 mg/kg (ED1.25) + CBG 68 mg/kg (ED1.25). Maximal protection was seen at CBD 100 mg/kg (ED10) + CBG 100 mg/kg (ED10). The ED50 for CBD (in combination with CBG) was calculated to be 60 mg/kg (Cl: 53–69).

Figure 2C shows a dose‐toxicity response curve for effects of CBD + CBG at a 1:1 ED ratio dissolved in 1:1:18 ratio of 95% ethanol, Kolliphor EL and 0.9% saline on MES seizures. Toxicity was observed at doses of CBD (in combination with CBG) at 250 mg/kg and above. Toxicity was observed in 100% of the subjects at 400 mg/kg. The TD50 was calculated to be 320 mg/kg (Cl: 271–377) mg/kg. The TI for the combination was calculated to be TI = 5.3.

The ED50 for CBD and CBG alone were similar (133 and 149 mg/kg respectively) and did not differ significantly from each other (z‐test = 1.266). However, by using a 1:1 ratio combination of CBD and CBG, the ED50 for CBD was reduced by over 50% (from 133 to 60 mg/kg, z‐test = 3.763), whereas the TD50 for CBD was also reduced by roughly 40% (from 560 to 320 mg/kg, z‐test = 3.595), indicating an increased toxicity relative to CBD alone.

3.2. Isobologram

Figure 3 shows the isobologram for the 1:1 CBD:CBG combination at the 50% effect level. The ED50 for the combination was found to be located close to and slightly below the theoretical additive isobole line, suggesting an additive relationship between the two drugs.

FIGURE 3.

FIGURE 3

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Isobologram for the 1:1 CBD:CBG combination. Line represents the additivity isobole for the combination of CBD and CBG at the 50% effect level. Black dot represents the experimentally derived ED50 for the 1:1 CBD:CBG combination. Error bars represent the 95% confidence interval.

4. Discussion

The current experiment was designed to examine the antiseizure activity of CBG in the MES model and to see whether it could potentiate the antiseizure effects of CBD.

CBD and CBG were first tested separately to produce dose–response curves in the MES model. They were then combined in varying ratios in order to investigate whether potentiation was seen. Finally, a combined dose–response was determined with the most effective combination.

This study is the first to provide detailed antiseizure effect and toxicity dose–response data for CBG in a seizure model as well as to examine synergistic relationships with CBD.

4.1. CBD and CBG Tested Individually

The ED50 for CBD was found to be 133 mg/kg, which is within the range of those reported for CBD in previous studies in the MES model [5, 6]. The TI for CBD reported here (4.2) is much higher than that reported by Dlugosz et al. [6] (2.4) and is likely due to differences in testing parameters, such as stimulating current and method for evaluating toxicity.

CBD and CBG were found to have similar dose‐toxicity profiles as well as similar ED50. Therefore, CBG shows comparable effectiveness to CBD in the MES model. The TI of CBG was 3.6 and is slightly lower than that of CBD (4.2) but still shows good potential for a therapeutic candidate drug.

4.2. CBD and CBG in Different Ratios

When CBD and CBG were combined at different ratios, there was an apparent synergy between the two compounds, such that ineffective doses produced great seizure suppression. Starting with the ED20 (100 mg/kg) for CBD, the addition of an ED5 (80 mg/kg) for CBG produced 75% suppression of MES seizures and the addition of an ED10 for CBG produced 100% suppression. The use of two doses that would produce little suppression of seizures produces great suppression when combined.

Interestingly, no toxicity was seen at all during these tests of different ratios. Therefore, the lowest ratio that produced 100% suppression was selected for use in the combination dose–response curve test.

4.3. The Combination Dose–Response Curve

The combination dose–response curve showed a clear left shift when compared with that of CBD alone, demonstrating that CBG does have antiseizure effects and reduces the amount of CBD necessary to achieve equivalent seizure suppression. The ED50 for CBD alone had been 133 mg/kg, whereas the ED50 for CBD in combination with CBG was about 60 mg/kg. Thus, the effective dose of CBD was lowered by about 55%. Although the administration of ineffective doses produced greater levels of seizure suppression than would be expected, this might not be a supra‐additive synergistic relationship. A 1:1 ratio of CBD to CBG reduced the ED50 of CBD by about 50%, where the individual ED50 of both drugs are similar. This might be expected with an additive relationship, with the combination of CBD and CBG being the equivalent of doubling the CBD dose and producing the results expected if a double dose of CBD was administered. Further, the combination ED50 was found to be located close to the additivity isobole line in the isobologram, suggesting an additive relationship between the two drugs.

The line of additivity in the isobologram represents an assumed relationship of constant relative potency between the two drugs at the 50% effect level. All points on this line represent dose combinations that would result in the 50% effect response. The observed deviation from this line by combinations of the two drugs may indicate a synergistic or antagonistic relationship, whereas points closer to this line may indicate a simple additive relationship [27]. If more dose combinations were examined and plotted on the isobologram (e.g., 1:3, 3:1), an upward concave or downward concave relationship would be expected if a superadditive or subaddtive relationship exists, respectively [27]. Since the 1:1 combination is so close to the isobole line (and the ED50 of both drugs are similar), this argues against the likelihood that a nonadditive (convex) relationship would be present. A limitation of this study is that only one drug combination (1:1) is provided for the isobologram. Although we argue against the likelihood of a significant synergistic relationship, a more extensive study with multiple drug combinations would be required to confirm this.

From these data, a synergistic relationship between CBD and CBG does not seem likely. This is in contrast to the synergistic relationship seen between CBD and THC. An additive relationship suggested here, as well as the similarity between the dose–response curves of CBD and CBG, could reflect a similar mechanism of action for the two compounds [28]. A more detailed analysis with determination of ED50 of more ratios could be performed in future studies to determine whether the effects are, indeed, additive or supra‐additive [27].

No toxicity at all was seen at the doses of 0–200 mg/kg. Toxicity was only observed with combination CBD doses above 250 mg/kg. TD50 was calculated to be 320 mg/kg, which is about 43% lower than that of CBD alone. Therefore, although the ED50 for CBD is greatly lowered when the combination with CBG is used, the toxicity is also increased, though not to the same extent; therefore, the TI increased.

4.4. Relation of Our Findings to the Previous Studies of CBG

Little work has been done to examine CBG in seizure models, particularly the MES model. To our knowledge, the present study is the first to present a detailed dose–response relationship for CBG in a seizure model, as well as determine its effectiveness in the presence of another cannabinoid.

CBG has been tested by Hill et al. [13] in rats using the maximal PTZ model. Hill et al. stated that CBG had no antiseizure properties using doses that would be expected to have at least some effect on seizure severity (50–200 mg/kg). Unlike this previous report, the present study found that CBG had clear antiseizure effects and was almost as potent as CBD. It is hard to compare our work to that of Hill et al., since their study used a different species, different seizure model and a shorter injection‐test interval. It is possible that Hill et al.’s classification of seizure severity may be too crude to detect some changes in seizure severity caused by CBG. For example, in the MES model, seizure severity is classified as the presence or absence of tonic hindlimb extension, while the clonic convulsions may continue to occur. Although Hill's seizure scoring method does appear to include a tonic component, perhaps Hill's classification scheme might not adequately detect this change, whereas in the MES model scoring scheme, it is profound. Future studies might attempt to replicate the findings of Hill et al. in rats, possibly with a 2‐h injection‐test interval.

CBGA, the acidic form of CBG, has been studied in several rodent seizure models, including a variation of the MES model [14]. In that study, CBGA was found to have mixed effects among models—no effect, antiseizure and pro‐seizure. In their ‘MES threshold’ test, CBGA was found to have a small antiseizure effect. Unfortunately, only three doses were used, and those were well below that of the effective CBG doses used in the present study. It is possible that if higher doses were used, a more robust antiseizure effect might have been seen. Curiously, an ‘inverted U’–shaped dose relationship was seen in that study, which is sometimes seen in studies of cannabinoids but was not found in the present study. A detailed dose–response study using CBGA would be useful.

Dlugosz et al. [6] found that much higher doses of CBD were necessary to block seizures than with THC alone and that the combination of the two showed toxicity of CBD greatly increased in the presence of a small amount of THC. Since the current data suggest that CBG appears to show similar effectiveness to CBD, it is possible that this could also be true if CBG were combined with THC. This reduced effectiveness compared with THC and increased toxicity of CBD in the presence of THC in the MES model—a model of primary generalised tonic–clonic seizures—could indicate that the use of CBD or CBG in combination with THC may be more appropriate clinically for the treatment of focal impaired awareness seizures (FIAS; treatment‐resistant complex partial seizures of limbic origin). Particularly, the combination of CBD and THC has been shown to be effective in the kindling seizure model against the limbic focal seizure—a model of FIAS—with low toxicity [17].

CBG has not been tested in a model of FIAS. CBG and combinations with THC and other cannabinoids should be tested in the kindling model, where effectiveness can be determined against both the treatment‐resistant limbic focal seizure as well as the generalised motor seizure, thus determining effectiveness against two models of clinical seizures in the same preparation.

The MES model is often used as a primary screen of antiseizure activity in order to provide candidate targets for more intensive testing. The current study in the MES model provides a rationale for proposing further testing in the labour‐intensive and expensive limbic kindling model as well as chronic spontaneous seizure models such as kainic acid [29] or long‐term electrical kindling [30].

4.5. Possible Mechanisms of Antiseizure Effects

This was the first study examining the combination of CBD and CBG for synergistic effects. The data appear to show an additive relationship between the two drugs in the MES model, but the exact mechanisms of action of both CBD and CBG against MES seizures are still unclear. We can speculate on some potential targets that might be involved in CBD and CBG antiseizure effects.

The agonistic effects of both CBD [12] and CBG [31] on the PPARγ receptor and its potential involvement in cannabinoid antiseizure effects [32] make it a good candidate mechanism to explore. Similarly, CBD and CBG have both been shown to stimulate and desensitise human transient receptor potential cation channel subfamily V member 1 (TRPV1) [33]. The actions of combinations of CBD and CBG on the antiseizure effects related to TRPV1 should be considered [34]. CBD and CBG have both been shown to block the voltage gated sodium channels (NaV) in human neuroblastoma and mouse cortical neurons in culture [13]. NaV channels are a common target for antiseizure drugs such as phenytoin. If CBD and CBG can engage the NaV channels together, they might combine their seizure protection actions.

The predominantly additive interaction observed between CBD and CBG in the MES model is possibly explained by convergence on shared excitability‐limiting mechanisms, particularly the blockade of voltage‐gated sodium (NaV) channels. Both CBG and CBD have been shown to inhibit NaV currents, including in human neuroblastoma cells and rodent cortical neurons, at concentrations relevant to anticonvulsant activity [13]. The MES paradigm is classically sensitive to sodium channel‐blocking antiseizure drugs, and additive interactions are expected when agents of similar intrinsic efficacy engage a common molecular target [27]. Consistent with this framework, CBD and CBG exhibited similar ED50 values when administered individually, and the ED50 of the 1:1 combination fell close to the theoretical additive isobole. Under conditions of constant relative potency, the combination of two agents acting at the same target would be predicted to yield a dose‐sparing but non‐synergistic interaction, as observed here. While CBD and CBG also modulate additional targets, including TRPV1 channels and PPARγ receptors, the quantitative interaction profile in the MES models supports shared NaV channel inhibition as a sufficient and mechanistically coherent explanation for the observed additivity.

Importantly, Hill et al. [13] demonstrated that NaV channel blockade by cannabinoids alone does not universally predict anticonvulsant efficacy across seizure models, indicating that sodium channel inhibition may be necessary but not sufficient for seizure protection in all contexts. However, within the MES paradigm, where seizure expression is strongly dependent on sustained neuronal firing, shared NaV modulation provides a biologically plausible basis for the additive interaction between CBD and CBG observed in the present study.

The action of these or other potential mechanisms simultaneously could be resulting in the antiseizure effects in the MES model. Further studies are needed to determine the precise nature of the mechanisms involved.

4.6. Pharmacokinetic Interactions Between CBD and CBG

Potential pharmacokinetic interactions between CBD and CBG may also contribute to their combined antiseizure efficacy. Both cannabinoids undergo extensive hepatic biotransformation that is mediated by cytochrome P450 (CYP) enzymes, which modulate their systemic bioavailability, serum concentrations and clearance. CBD is a potent inhibitor of several CYP isoforms, particularly CYP2C19, CYP2C9 and CYP3A4 [35, 36]. Inhibition of these enzymes by CBD has been shown to elevate serum concentrations and plasma levels of co‐administered substrates such as Clobazam and its active metabolite N‐desmethylclobazam, as well as other anti‐epileptic agents, including Topiramate and Zonisamide [37]. CBG is metabolised predominantly by CYP2C9 and CYP3A4 via oxidative and hydroxylation pathways [38]. These metabolic transformations occur primarily in hepatic microsomes and represent the principal route of CBG clearance from systemic circulation [35, 36, 38]. Given their shared enzymatic activities, co‐administration of CBD may competitively inhibit the hepatic metabolism of CBG, resulting in reduced clearance, elevated serum concentrations and prolonged systemic exposure. Increased serum bioavailability of CBG may enhance its central nervous system penetration and consequently, its pharmacological efficacy. CYP‐mediated inhibition likely represents a key pharmacokinetic interaction between CBD and CBG, potentially contributing to the additive or mildly potentiated antiseizure effects observed in the present study.

Pharmacokinetic data for CBG remains limited, particularly concerning its absorption and distribution within the central nervous system. However, given the well documented inhibitory effects of CBD on CYP‐mediated metabolism, it is possible that altered hepatic clearance and extended systemic exposure of CBG contribute to the combined efficacy of the two cannabinoids. Unfortunately, bioanalysis of brain and plasma levels of CBD and CBG were not conducted in this study. Therefore, a conclusive statement about the contribution of PK and PD factors influencing interactions cannot be made. However, since the current data do not appear to show a significant interaction between CBD and CBG—at least at near the ED50—with the effects of both appearing to be additive in nature, the influence of PK or PD mechanisms should not be emphasised here. Future bioanalytical studies measuring brain and plasma levels of both drugs while examining antiseizure activity would be useful in assessing any PD and PK contributions and should follow up from this study demonstrating similar antiseizure potentials.

4.7. CBG and Other Minor Cannabinoids

To contextualise our findings, we reviewed prior studies investigating CBG and other lesser‐studied cannabinoids in epilepsy and related neurological disorders. Very few studies have investigated the protective effects of CBG in epilepsy models, and even fewer have examined other minor cannabinoids such as cannabinol (CBN), cannabichromene (CBC), or CBDV [39]. Existing research has primarily focused on evaluating CBG in various animal models of neurological diseases, including Huntington's disease [40], Parkinson's disease [41] and autoimmune disorders [11]. Across these studies, CBG demonstrated neuroprotective actions, mitigating neuromotor degeneration associated with both Parkinson's and Huntington's disease [39, 40].

By contrast, evidence for other minor cannabinoids remains sparse and largely inconclusive. CBC and CBN have been evaluated in animal models of epilepsy and amyotrophic lateral sclerosis (ALS), respectively, but neither has shown robust neuroprotection. In particular, CBC failed to confer protection in the MES model [42], while CBN provided only minimal protection in an ALS model [43]. Unlike CBC and CBN, which show limited efficacy and poorly defined mechanisms of action, CBG exhibits activity across multiple receptor systems, including PPARγ, 5‐HT₁A and α₂‐adrenergic pathways. This may contribute to its broader neuroprotective and anticonvulsant effects.

Although the precise mechanism underlying CBG's neuroprotective and antiseizure effects remains unclear, its reproducible efficacy across diverse models suggests greater translational potential than other minor cannabinoids. Taken together, these findings provide mechanistic context for the additive effects observed in the present study when CBG is combined with CBD and support its further evaluation as a candidate adjunct therapy for epilepsy and other neurological disorders.

4.8. Clinical Implications

The present work was designed as an attempt to potentiate CBD with another non‐psychoactive cannabinoid. These results suggest that CBD could be used at much lower doses if it were combined with CBG. The large therapeutic window of the combination is important for clinical use. However, from the data presented, CBG appears to be about as effective as CBD, and a strong synergistic effect does not appear to be present.

From a translational perspective, the primary implication of the present findings is the marked reduction in the effective dose of CBD when administered in combination with CBG. Using standard body surface area–based allometric scaling, the CBD doses examined here fall within a range broadly consistent with clinically relevant exposure levels, recognising that such conversions provide only an approximate framework and do not substitute for human PK‐PD data [44]. Importantly, the approximate 50% reduction in the CBD ED50 observed with co‐administration suggests a potential dose‐sparing strategy that may be clinically meaningful.

In clinical epilepsy trials, CBD efficacy is often constrained by dose‐dependent adverse effects, including somnolence, GI symptoms and elevations in liver transaminases, particularly at higher doses or in combination with other antiseizure medications [1, 3, 4]. A reduction in the required CBD dose could therefore plausibly improve tolerability and reduce adverse event burden, even if the interaction between CBD and CBG is additive rather than synergistic.

Although the TD50 for CBD was also reduced in the combination condition, the greater proportional reduction in ED50 resulted in an increased TI, indicating a net improvement in the balance between efficacy and toxicity. While these findings support further evaluation of CBD‐CBG combinations as a potential strategy to optimise CBD‐based therapies, definitive conclusions regarding safety and tolerability will require clinical studies incorporating direct pharmacokinetic and adverse‐reaction assessments. Further, the similar relative potencies of CBG and CBD may negate any beneficial reductions in CBD side effects from a monetary cost perspective since a relatively large dose of CBG may be necessary to produce equivalent antiseizure effects of CBD alone.

It might be that CBG alone would be a better drug than CBD or a CBD + CBG combination. Since CBD is already in clinical use, however, it is probably more practical to consider CBG as an additive to CBD rather than as an anticonvulsive drug in its own right.

Author Contributions

Willets McIntyre Burnham: conceptualisation, funding acquisition, supervision, methodology, writing – original draft. Han Zhong Zhou: investigation, writing – review and editing, formal analysis. Yagoda Izabela Oleksak: investigation, writing – review and editing. Brian Wayne Scott: methodology, formal analysis, investigation, writing – review and editing, visualisation, supervision, project administration.

Funding

This study was conducted with the support of EpLink—the epilepsy research program of the Ontario Brain Institute. The Ontario Brain Institute is an independent nonprofit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors, and no endorsement by the Ontario Brain Institute is intended or should be inferred. H.Z.Z. was partly supported by a fellowship from the Toronto Cannabis and Cannabinoid Research Consortium.

Ethics Statement

These studies were approved by the Local Animal Care Committee at the Faculty of Medicine of the University of Toronto under the animal use protocol# 20012765. All experiments complied with the guidelines of the Canadian Council on Animal Care.

Conflicts of Interest

W.M.B. has received past project funding from Avicanna Inc. No other conflict of interest is declared by the authors.

Acknowledgements

The authors are grateful to Avicanna Inc. for generously providing the cannabinoids used in this study. We are also grateful to Lukasz Dlugosz for his comments on the manuscript.

Zhou H. Z., Scott B. W., Oleksak Y. I., and Burnham W. M., “Antiseizure Effects of Cannabidiol in Combination With Cannabigerol in the Maximal Electroshock Seizure Model,” Basic & Clinical Pharmacology & Toxicology 138, no. 2 (2026): e70194, 10.1111/bcpt.70194.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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