The Potential Proconvulsant Effects of Cannabis: a Scoping Review

Abstract

Introduction

Cannabis’ effect on seizure activity is an emerging topic that remains without consensus and merits further investigation. We therefore performed a scoping review to identify the available evidence and knowledge gaps within the existing literature on cannabis product exposures as a potential cause of seizures in humans.

Methods

A scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews guidelines. The PubMed and Scopus databases were searched over a 20-year period from the date of the database query (12/21/2020). Inclusion criteria were (1) English language original research articles, (2) inclusion of human subjects, and (3) either investigation of seizures as a part of recreational cannabinoid use OR of exogenous cannabinoids as a cause of seizures.

Results

A total of 3104 unique articles were screened, of which 68 underwent full-text review, and 13 met inclusion/exclusion criteria. Ten of 11 studies evaluating acute cannabis exposures reported a higher seizure incidence than would be expected based on the prevalence of epilepsy in the general and pediatric populations (range 0.7–1.2% and 0.3–0.5% respectively). The remaining two studies demonstrated increased seizure frequency and/or seizure-related hospitalization in recreational cannabis users and those with cannabis use disorder.

Conclusions

This scoping review demonstrates that a body of literature describing seizures in the setting of cannabis exposure exists, but it has several limitations. Ten identified studies showed a higher than expected incidence of seizures in populations exposed to cannabis products. Based on the Bradford Hill criteria, delta-9 tetrahydrocannabinol (THC) may be the causative xenobiotic for this phenomenon.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13181-022-00886-3.

Introduction

Although cannabis is far from a new drug, our understanding and perspective of this classic botanical is rapidly changing alongside its availability, delivery, and content in the USA and around the world. Over the last 25 years, cannabis availability has dramatically increased due to medicalization, decriminalization, and legalization of recreational use in some regions [1]. In addition, cannabis ingestion methods are now more diverse than traditional smoked cannabis preparations [2, 3], and vary widely in delta-9 tetrahydrocannabinol (THC) concentrations, which can be significantly higher in edibles, vape (e-cigarette) preparations, or concentrates (e.g., “dabs”) compared to their predecessors [4–6]. Perhaps even more challenging is the developing variation in product cannabinoid composition. While THC has been thought of as the traditional psychoactive and sought-after cannabinoid, other plant-based and synthetic cannabinoids are gaining popularity. Much of the research on this changing landscape has focused on synthetic cannabinoid receptor agonists (SCRAs), as they have clearly been associated with unique toxicity including arrythmias and seizures [7, 8]. However, plant-based compounds such as cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and delta-8 tetrahydrocannabinol (delta-8 THC) are also being concentrated and distributed in an increasing variety of products easily found on the internet. This increased variety of high-concentration, poorly studied xenobiotics consumed through novel routes of exposure has opened the door for a new adverse effect profile for this not-so-new drug. As this field continues to evolve, we may need to change the way we think of cannabis products and their potential effects. One such adverse effect is the potential proconvulsant and/or epileptogenic nature of cannabis. Unfortunately, such adverse effects have been difficult to study due to the natural complexity of the cannabis botanical, the imprecise nomenclature used to describe cannabis and its derivative compounds, and the heterogeneity of the cannabis products commercially available.

The word cannabis is a collective term that can refer to both the plant genus including the species Cannabis sativa and Cannabis indica, and the bioactive substances produced from these plants [9]. There are over 100 bioactive substances derived from these plants, which are referred to as cannabinoids [9, 10]. Many of these cannabis-derived compounds are known to have affinities for multiple receptor sites in the human body, including the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors [11–14]. The term cannabinoid is also used to describe other substances with intrinsic activity at the CB1/CB2 receptors, including a variety of synthetic compounds and endogenous compounds that are chemically distinct from those found in the cannabis plant [15]. The heterogeneous and inconsistent use of the terms “cannabis” and “cannabinoids” in the literature makes it challenging to assign a specific effect profile. In this review, the term “cannabis” will refer to a component of, or substance derived from, the cannabis plant and the term “cannabinoid” will refer to a substance that has intrinsic activity at the CB1/CB2 receptors.

A “cannabis product” is a collective term that refers to substances that contain cannabinoids found in the cannabis plant [10]. These products include the cannabis plant material itself, extracts made from this plant material, and naturally occurring compounds that are artificially synthesized. While there are several regulated cannabis-based pharmaceuticals now on the market [16], these make up only a small portion of the cannabis products that exist today. Many legally available commercial products are marketed as containing individual cannabinoids (e.g., CBD, delta-9 THC, or delta-8 THC), but the lack of uniform quality control standards for these products makes the actual contents unclear [4, 17–20]. Given the difficulties with poorly regulated legal products, it is almost impossible to know the contents of illegal products unless an independent analysis is performed. If we are to determine an adverse event profile, it is clearly important to know if a cannabinoid of interest (THC, CBD, etc.) is present and in what concentration. However, it is also critically important to know if any other cannabinoids are present, as in addition to their individual effects, cannabinoids behave differently and perhaps synergistically when present together at the cannabinoid receptor. This cumulative phenomenon is called the entourage effect [21, 22] and can pose as a serious confounder when studying these compounds.

These uncertainties in the cannabis nomenclature and available cannabis products have generated a level of complexity that has made it difficult to perform the high-quality research necessary to fully investigate adverse effects such as seizures. This is particularly evident in the case studies, case series, and a poorly designed case–control series that report seizures in young children after edible cannabis product ingestions [23–29], seizures associated with chronic cannabis use [30, 31], and a decreased risk of seizures in those reporting cannabis use [32]. Of these studies, five could not definitively identify the cannabis product to which the subjects were exposed [23, 25–28] and five were only able to describe the products in generic terms such as “edible marijuana,” “resin,” and “marijuana” [24, 29–32]. None listed a specific product name that could be used to investigate product content. Even when studies control for this complexity by using pharmaceuticals like Epidiolex or Dronabinol, they are limited by the fact that they are using populations with a confounding disease state that is being treated. Epidiolex (CBD) has been studied as an anticonvulsant in populations of patients with epilepsy [33]. Dronabinol (THC) has been studied in patients with cancer [34, 35], human immunodeficiency virus (HIV) [36, 37], chronic pain conditions/chronic opioid use [38–40], and a variety of neurodegenerative disorders [41–43]. While knowledge about the effects of these xenobiotics in these populations is helpful, it is not necessarily generalizable.

To our knowledge, the topic of cannabis product exposure in humans and its relationship to seizures has not yet been explored in a large-scale review. Due to the complexity of this field of study as detailed above, it is unclear if there are any high-quality original research studies evaluating the effects of cannabis products in the general population. To identify the available evidence and knowledge gaps within the existing literature, we performed a scoping review [44, 45] on cannabis product exposures as a potential cause of seizures in humans.

Methods

Search Strategy

This scoping review protocol was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for scoping reviews [46] (Supplemental Table 1). The review protocol and search algorithm were developed based on consensus from the entire investigator team with support from a medical research librarian. A search of relevant articles was conducted using the PubMed and Scopus databases. The search was conducted on 12/21/2020 using the following search string:

Table 1.

Data abstracted from included articles

Exposure chronicity	Author(s); Year, Type	Study goal/description	Data source	Location Clinical setting Timeframe	Cohort age range (y) (Mean/median), % male, % female	Routes of exposure	Biomarker testing	Description of cannabis exposure group	Seizure incidence (N); n = # of cannabis exposures (single: poly-substance)	Other relevant findings/takeaways
Acute cannabis exposures	Anderson et al. (58); 2019, RC	Characterize neuropsychiatric presentation of cannabinoid exposures to the ED	ToxIC Registry	USA, 23 states ED ‘10– ‘18	13–19 y 74% M, 26% F	NR	No	Adolescents presenting to the ED for synthetic or traditional cannabis exposure	5.8% (5^); n = 348 (86: 262)	SC-only and SC-polydrug exposures had higher rates of seizures than cannabis-only and cannabis-polydrug exposures, respectively
	Heizer et al. (50); 2018, RC	Explore dose–response relationship in THC-naïve vs. non-naïve children after THC exposure	Medical charts	CO, USA, 1 hospital Inpatient ‘09– ‘14	0–20 y (9.5 y) 60.5% M, 39.5% F	Oral = 30 (39%), INH = 35 (46%), U/O = 11 (14%)	Yes 2	Hospital presentations related to acute THC toxicity, excluding co-ingestions	3.9% (3^); n = 76 (76: 0)	Clinical effects differed for naïve vs. non-naïve patients. Naïve patients exhibited more CNS effects and a direct relationship between dose ingested, hospital disposition, and level of medical intervention required
	Noble (53); 2019, RC	Describe clinical effects of acute recreational cannabis exposures during early legalization period	Oregon/Alaska Poison Center	OR and AL, USA PCC ‘15– ‘17	0–96 y (20 y) 54.2% M, 45.8% F	Oral = 187 (74%), INH = 57 (23%), U/O = 9 (3.6%)	Yes 3	PCC calls for acute exposure to cannabis, excluding co-ingestions	3.6% (9^); n = 253 (253: 0)	Neurotoxicity is common after acute cannabis exposures Concentrated products such as resins and liquid concentrates were associated with greater toxicity than other cannabis products
	Onders et al. (57); 2015, RC	Provide information about pediatric exposures to MJ	NPDS	USA, 50 states PCC ‘00– ‘13	0–6 y (1.81 y) 50.7% M, 49.3% F	Oral = 1477 (75%), INH = 286 (14.5%), U/O = 206 (10.4%)	NR	All single-substance MJ exposures involving children < 6 years old	0.51% (10^); n = 1,969 (1969: 0)	N/A
	Schmid et al. (52); 2020, RC	Characterize the acute toxicity of cannabis with and without co-substances	Euro-DEN Plus	Switzerland, 3 hospitals ED ‘12– ‘18	14–68 y (26 y) 77.4% M, 22.6% F	Oral = 40 (6%), INH = 356 (50%), U/O = 321 (45%)	Yes 4	ED presentations due to acute toxicity related to self-reported cannabis recreational use	4.8% (9^); n = 717 (186: 531)	No significant difference found in rate of seizures with cannabis alone vs. cannabis combined with other substances
	Wang et al. (54); 2016, RC	Compare incidence of pediatric MJ exposures before and after recreational MJ legalization	Medical charts	CO, USA PCC ‘09– ‘15	0–9 y (2 y) 48% M, 52% F	Oral = 121 (74%), INH = 18 (11%), U/O = 24 (15%)	Yes 5	ED/urgent care presentations, inpatient hospitalizations, and RPC cases for single-substance MJ exposures	3% (5^); n = 163 (163: 0)	N/A
	Wolfe et al. (51); 2019, RC	ID the recreational substances most implicated in seizures, their RR, and differences in presentations with and without seizure	Euro-DEN Plus	Europe, 21 countries ED ‘14– ‘17	NR (31 y) 76% M, 23% F	NR	No	ED presentations with acute recreational drug toxicity and self-reported cannabis use	3.1% (61^); n = 22,919 (1954: 20,965)	Drugs associated with higher seizure incidence include fentanyl and synthetic cannabinoids Heroin, clonazepam, and cannabis were associated with a lower seizure incidence than other drugs
	Claudet et al. (55); 2017, RC	Assess characteristics of cannabis exposure in young children admitted from the ED	Medical charts	France, 1 hospital ED ‘04– ‘14	0–3 y (15.1 m) NR	Oral = 23 (79%), U/O = 6 (21%)	Yes □	Children admitted to a pediatric ED due to unintentional cannabis exposure	14% (4); n = 29 (NR)	N/A
	Graham et al. (59); 2020, RC	Describe trends of illicit drug exposures in young children, their incidence and outcomes	NPDS	USA, 50 states PCC ‘06– ‘16	0–10 y (2 y) 52% M, 48% F	NR	NR	Pediatric exposure calls to all US Poison Centers that include acute cannabis exposure	2.3% (76); n = 3365 (NR)	N/A
	Guidet et al. (48); 2020, RC	Present bio-concentrations of THC and metabolites in infants after cannabis intoxication	Medical charts	France, 1 hospital ED ‘16– ‘18	0–3 y (16 m) 20% M, 80% F	Oral = 8 (80%), U/O = 2 (20%)	Yes 1	ED presentations for cannabis poisoning with available data on [THC] and [metabolites] in plasma and/or urine	20% (2); n = 10 (10: 0)	No correlation between plasma concentrations and symptoms, but [THC-COOH] in the 2 patients who experienced seizures was > 3000 (ng/mL)
	Liakoni et al. (56); 2015, RC	Describe the acute toxicity of recreational drugs	Medical charts	Switzerland, 1 hospital ED ‘13– ‘14	> 16 y (31 y) 69% M, 31% F	NR	Yes □	ED presentations with acute toxicity due to self-reported recreational cannabis use	4.4% (3); n = 68 (NR)	N/A
Non-acute cannabis exposures	Desai et al. (61); 2018, RC	Assess the most frequently identified causes of hospitalization and independent predictors of in-hospital mortality in recreational MJ users	NIS	USA, > 40 states Inpatient ‘10– ‘14	18–44 y (37 y) 63.2% M, 36.8% F	NR	NR	All hospitalizations in patients with a history of recreational MJ usage *	1.8% (41,972) +; n = 465,959 (NR)	Hospital presentation for epilepsy among MJ users increased in recent years Epilepsy and convulsions were the most common primary presentations at the time of MJ-related admission
	Patel et al. (60); 2019, RC	Investigate the relationship between CUD and hospitalization for epilepsy	NIS	USA, > 40 states Inpatient ‘10– ‘14	15–54 y 50.2% M, 49.8% F	NR	NR	All hospitalizations with a primary diagnosis of epilepsy and an ICD-9 diagnosis of CUD	5.77% ϕ; n = 37,945 (NR)	CUD is independently associated with a 56% increased likelihood of epilepsy hospitalization. Odds of epilepsy hospitalization were higher in cannabis, tobacco, and alcohol use disorders, but lower with cocaine, amphetamine, and opioid use disorders

ToxIC Registry, Toxicology Investigators Consortium Registry; NPDS, National Poison Data System; Euro-DEN,European Drug Emergencies Plus Network; NIS, National Inpatient Sample; RC, retrospective cohort; PC, prospective cohort; SC, synthetic cannabinoids; CUD, cannabis use disorder; RPC, regional poison center; UDS, urine drug screen; THC, tetrahydrocannabinol; MJ, marijuana; RR, relative risk; NR, not reported; ID, identify; y, years; PCC, poison center calls; INH, inhaled; U/O, unknown or other; N/A, not applicable

¹ = only included cases with quantifiable serum and/or urine THC levels; ² = positive THC was part of inclusion criteria. Also used to rule out co-ingestions. ³ = 23 (9%) had a positive UDS immunoassay; ⁴ = used in 54% (n = 387) of the cases; among these, THC was detected in 294/387 cases; ⁵ = subjects were identified either by a positive UDS for THC or having one of a list of ICD-9 codes; ⁶ = UDS, positive in all; ⁷ = 83% confirmed with immunoassays and liquid chromatography/mass spectrometry (LC–MS/MS)

^*Only 13 subjects identified themselves as “active cannabis users”

⁺Rate (n = total #) of admissions due to epilepsy in recreational cannabis users

^ϕCUD incidence in epilepsy patients

^{^}Seizure events (N) come from the single-substance ingestion group

^[]Concentration

("Cannabis"[Mesh] OR cannabis[tiab] OR Marijuana[tiab] OR "Cannabinoids"[Mesh] OR cannabinoid*[tiab] OR phytocannabinoid[tiab] OR "Cannabidiol"[Mesh] OR Cannabidiol[tiab]OR CBD[tiab] OR THC[tiab] OR "delta-9 tetrahydrocannabinol"[tiab] OR "synthetic cannabinoid"[tiab] OR "Dronabinol"[Mesh] OR Dronabinol[tiab] OR Epidiolex[tiab] OR Nabiximols[tiab]).

And

("Seizures"[Mesh] OR seizure*[tiab] OR "Epilepsy"[Mesh] OR Epilepsy[tiab]).

Eligibility

Eligible articles met the following inclusion criteria: (1) English language, (2) original research articles, (3) human subjects, and (4) seizures mentioned as an effect of recreational cannabinoid toxicity OR exogenous cannabinoids studied as a cause of seizures. Articles were excluded based on the following criteria: (1) studies published greater than 20 years before the search date (outside the date range 12/21/2000–12/21/2020), (2) case studies, case series, letters to the editor/comments, or reviews, (3) cannabinoid products studied as therapeutics, (4) endocannabinoid studies, (5) synthetic cannabinoid only studies, OR (6) studies with epilepsy only populations.

Data Extraction/Study Selection

A single reviewer (EK) manually screened the initial list of titles and abstracts for eligibility. The full text of remaining studies was reviewed, and inclusion and exclusion criteria were again applied. A standardized data collection tool was used to abstract data from remaining full-text articles by a second author (KG), and abstracted data was reviewed by EK for completeness. A third author (SC) adjudicated any conflicts related to application of inclusion/exclusion criteria or data abstraction.

Collected Data

The following data were abstracted from eligible studies: study type, data source, timeframe of data collection, location and clinical setting from which data was extracted, routes of cannabis exposure, details on the type of cannabis products reported, if/how the presence of seizure activity was defined, biomarker testing use and its role in inclusion/exclusion of subjects, definition of cannabis exposure, total number of cannabis exposures, primary and secondary objectives of each study, and the rate of seizures and/or hospitalizations among study subjects. We also evaluated potential study confounders and key findings with respect to the relationship between cannabis exposure and seizure activity. The three reviewers jointly determined the most appropriate organizational structure for presentation, and included studies were ultimately divided into two sub-groups based on the exposure studied: acute cannabis exposures and non-acute cannabis exposures.

Results

Study Selection

The search algorithm defined above identified 1438 results from the PubMed database and 2928 results from the Scopus database (Fig. 1). After removing duplicates, there were 1433 PubMed citations and 1671 Scopus citations for a total of 3104 unique studies. Titles/abstracts were manually screened, and 3036 were removed due to not meeting initial eligibility or by the presence of exclusion criteria, resulting in 68 full-text articles. Fifty-five of these studies were excluded after full-text review for failing to meet inclusion criteria or containing exclusion criteria. Thirteen studies were included in the final analysis.

Fig. 1.

CONSORT diagram of article selection process

Characteristics of Included Studies

Table 1 highlights data from the thirteen included studies. Publication dates ranged from 2015 to 2020 with most of the articles published in 2018 or later. Seven studies were exclusive to pediatric populations (< 20 years old), four from a largely adult population (two have cutoffs of > 14 and > 15 years old), one study included all ages (0–96 years), and one study reported a mean age of 31 without providing an age range. Sample size for cannabis exposures varied from N = 10 [47] to N = 465,959 [48], with a median of N = 348.

Data collection was done retrospectively in all thirteen studies. Five studies collected data from medical charts, four from poison center call data, two from the National Inpatient Sample (NIS), and two from the European Drug Emergencies Network (Euro-DEN Plus Network). Of the eight US-based studies, all except one [49] were multi-center. The remaining five studies were conducted in Europe: two were multi-center [50, 51] and the remainder presented data from a single site.

Acute Exposure Studies

Eleven of the included studies evaluated a relationship between acute cannabis exposure and seizure activity. Cannabis exposure history was most commonly self-reported by the patient, a friend, or family member. Seven studies used cannabis biomarker testing as part of inclusion criteria [47, 49, 51–55], three of which limited their cohorts exclusively to those with positive biomarker testing [47, 49, 54]. Additionally, seven studies specified the route of cannabis exposure, the two most common being ingestion and inhalation. Four studies went further to categorize the type of product used [49, 52–54]; however, each of these included an “unknown” category for data that was not gathered at time of presentation.

Poly-substance exposures were an oft-mentioned confounder in the included studies when evaluating the relationship between cannabis products and the reported symptoms or outcomes of interest. Seven of the eleven acute exposure studies specify the rate of seizures in single-substance cannabis exposures either exclusively or as a subgroup in their results sections [49–53, 56, 57]. Of the four acute exposure studies that do not distinguish single vs. poly-substance data, the largest study, by Graham et al. (N = 3,365), is a pediatric cohort (0 to 10 years old) and does not include any confirmatory testing as to whether other substances were involved [58]. Another study expressly states that only two of 29 subjects had poly-substance exposures, but it does not indicate whether these two are part of the group who experienced seizures [54]. The third study mentions that 60% of patients endorsed use of cannabis alone but reports seizure data for the entire cohort without subgroup analysis for the single-substance presentations [55]. The final study did not explicitly state that they excluded subjects with co-ingestions; however, they used GC/MS/MS (gas chromatography-tandem mass spectroscopy) to confirm cannabis exposure and note that immunochemical, HPLC/DAD (high-performance liquid chromatography/diode array detector), and GC/MS analyses were used to screen for co-intoxication [47].

Seizure occurrence in acute cannabis exposure ranged from 0.51 to 20% in the included studies. The two largest studies that specify single-substance cannabis exposures report seizure rates of 3.1% (N = 61) [50] and 0.51%, (N = 10) [59]. The three studies that reported single- and poly-substance exposures together experienced seizure rates of 2.3% [58], 4.4% [55], and 14% [54]. Two acute exposure studies specified that all seizure activity had been witnessed prior to hospital arrival [54, 55], whereas the others did not specify when seizures occurred or how they were diagnosed. None of the studies included data on electroencephalography studies or specialist consultation.

Non-acute Exposure Studies

Two included studies did not focus exclusively on acute cannabis exposures, but rather described the relationship between seizures and cannabis use in general [48, 60]. Both examined rates of hospitalization for seizures in those who either use cannabis recreationally [48] or have a diagnosis of cannabis use disorder (CUD) [60]. These two studies had the largest cohorts of all the articles that met our inclusion criteria.

Desai et al. examined the most frequent causes of hospitalization in patients with a history of recreational marijuana use [48]. These patients were identified using relevant ICD-9 CM codes for recreational marijuana use, based on a prior study by the same author [61]. “Epilepsy; convulsions” was found to be the primary cause of hospitalization in 1.8% of this cohort. They also reported an increasing trend of epilepsy (as well as stroke and major cardiovascular events) in recreational marijuana users over the 5-year study period. While this study offered an objective report of the most frequent causes of hospitalizations in recreational marijuana users, there is no comparison data in non-cannabis users to point towards a clear positive or negative correlation between recreational cannabis use and seizure activity. They do report that “epilepsy and convulsions” were found to be the most common primary (nervous disorder) presentations at the time of marijuana-related admission. The authors do not specify whether presentations were related to acute or chronic cannabis exposure, so it is possible that there exists a combination of presentation types.

Patel et al. sought to investigate the relationship between CUD and hospitalization for epilepsy [60]. They searched the nationwide inpatient database (NIS) using a range of ICD-9 codes to create epilepsy/non-epilepsy cohorts and CUD/non-CUD cohorts. In one of their sub-analyses, they compared two cohorts of patients who were hospitalized with a primary diagnosis of epilepsy/convulsions: those with CUD and those without CUD. As above, the CUD group does not specify whether cannabis use occurred preceding the seizure event. The authors concluded that patients with CUD had significantly higher seizure rates with 56% higher odds of hospitalization for epilepsy. Rates of hospitalization for epilepsy in cannabis users were comparable to patients with alcohol use disorder and higher than rates seen in other substance use disorders such as stimulants and opioids.

Discussion

Results from this scoping review demonstrate a wide range of seizure incidence in acute cannabis product exposures (range 0.51–20%), an increase in epilepsy diagnoses in those hospitalized with a history of recreational cannabis use over a 5-year period, and 56% higher odds of being hospitalized for epilepsy in those with CUD compared to those without. Ten out of eleven studies that examined acute cannabis exposures demonstrated an incidence of seizures higher than would be expected based on the reported incidence of seizures found among US emergency department (ED) presentations (0.7–1.2%) [62–65], and higher than could be explained by the background prevalence of epilepsy in the general population (1.2% in the USA and 0.6–0.9% globally) [66, 67] or general pediatric population (0.4–0.6% in the USA, and 0.3–0.5% in Europe) [68]. Unfortunately, diagnostic criteria for what constituted a seizure event were notably absent in the cohort of included studies. As all of the acute exposure studies included data collected from ED visits, the determination of seizures was likely heavily dependent on witness reports. None of the included studies mentioned the use of electroencephalography data or specialist consultation to confirm seizure diagnoses, nor did they specify that seizure activity was witnessed by medical professionals. It is also worth noting that some of the included studies may have overlapping data, in particular those curated from US national poison center data [49, 53, 56, 57] and the European Drug Emergencies Plus (Euro-DEN Plus) Network [50, 51]. Given the heterogeneity and limitations of the available studies, the data on seizure incidence cannot be used to establish a causal relationship; however, these findings can be used to generate hypotheses.

The toxicologic exposure history was heavily dependent on either patient or witness reports in a substantial number of included studies. Only seven studies used cannabis biomarker testing as part of their inclusion criteria [47, 49, 51–55], three of which limited their cohorts exclusively to those with positive biomarker testing [47, 49, 54]. The seizure incidences of these studies were 20%, 3.9%, and 14% respectively. While it is possible that there were other cannabinoids or substances that were not detected on basic screening assays in these products, we do know that THC metabolites, and in some cases THC itself [47], were present at the time these seizure events occurred. Over the years, the cannabis plant has been bred to have a higher ratio of THC to other cannabinoids [69, 70], and edible products are now being specifically marketed for their high THC content. Authors of other studies have also noted these trends and have cited them as the likely explanation for why they have found severe symptoms like profound altered mental status, respiratory depression, and seizures in their studies of cannabis product exposures [54, 56]. These findings prompt the question as to whether THC acts as a proconvulsant or epileptogenic agent.

Since cannabis was classified as a schedule I drug in 1970, rigorous research has been difficult to perform. Before the year 2000, most scientific studies used animal models to measure the effect of cannabis on seizure occurrence. These studies used various methods to induce epilepsy including genetic variations [71–73], cerebral implants [74–76], electrodes [77–79], or chemicals [73, 77, 80]. Typically, cannabis products (usually THC and CBD) were given to the seizure-prone animals, and the effect on seizure activity was recorded. These studies produced a variety of contradictory results regarding THC’s effect on seizure activity. Some researchers showed THC decreased the incidence of seizures [73, 76, 79], and others demonstrated that while THC decreased seizure incidence, this protective effect diminished with tolerance [75]. Ham et al. found a decreased incidence of seizures with THC exposure, but also found a high rate of subject mortality due to “inanition” in animals receiving THC injections compared to controls [71]. Turkanis et al. found that THC caused an increased rate of seizure at low doses but a decreased rate at high doses [78]. Conversely, some researchers have found THC lowers the so-called seizure “threshold” for a given stimuli or toxin-induced convulsion [77, 80]. Additional researchers have demonstrated that THC increased seizure frequency [74] and incidence [72] depending on the animal model. This early animal data is a morass of different animal models and experimental designs which makes it difficult to interpret the implications of the conflicting results.

More recently, there has been a growing body of literature that supports an association between THC exposure and seizures. Animal data not only includes case reports [81, 82] and poison center data [83], but several more compelling experimental models [84–86]. The study by Malyshevskaya et al. used intraperitoneal injections of the SCRA JWH-018 and THC in a standard mouse model and a study by Breivogel et al. used intraperitoneal injections of various SCRAs, THC, CBD, and an endocannabinoid analog in a standard mouse model, in order to evaluate the proconvulsant potential of various cannabinoid types [84, 85]. Both studies found that while SCRAs produced a higher rate of seizures compared to THC, THC still caused seizures confirmed by EEG and video evidence of convulsions rated on the Racine scale respectively. For human data, several case studies, case series, and retrospective studies report seizures in young children after exposures to THC containing cannabis products [23–29, 87] and seizures associated with chronic cannabis use in adults [30, 31]. Several studies specifically note markedly elevated concentrations of THC or its metabolites on quantitative confirmatory testing [26–28].

While the cumulative human and animal data presented thus far may lend support to the hypothesis that THC is proconvulsant [84, 85], there is a lack of objective criteria evaluating the potential causative relationship between THC exposures and seizures. The Bradford Hill criteria is a frequently cited framework for causal inference used in epidemiologic studies, and it consists of 9 criteria: strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy [88]. When applied to the data presented thus far: (1) the incidence data found in this scoping review suggests a potential strength of association, (2) the multiple case studies, case series, and retrospective studies cited above detailing seizures occurring after THC exposure demonstrate the consistency and temporality of this phenomenon, and (3) the animal studies by Breivogel and Malyshevskaya demonstrate this phenomenon can be reproduced through experimentation, with higher doses of THC causing more seizures suggesting a biologic gradient. Missing from the Bradford-Hill criteria are specificity, plausibility, coherence, and analogy. To fulfill these criteria, we will need to look into the potential pathophysiology of this adverse effect.

The primary receptor within the endocannabinoid system, CB-1, is most concentrated on pre-synaptic neurons throughout the brain. These receptors are activated by endocannabinoids released from the post-synaptic neurons and appear to act as a negative feedback mechanism through pre-synaptic inhibition of both excitatory and inhibitory neurons [89, 90]. The CB-1 receptors are also the primary site of action for most cannabinoids found in the cannabis plant, with THC being a partial agonist. To better study this receptor, researchers developed a series of synthetic cannabinoid receptor agonists (“SCRAs”). These “synthetic cannabinoids” are a heterogeneous group of compounds, several of which act as full agonists at the CB-1 receptor [91]. They have been widely abused as recreational drugs with a variety of acute toxic effects, one of the most prominent being seizures [85, 92, 93]. While we know that CB-1 receptor agonists can cause seizures, and there is some evidence to suggest that activity at the CB-1 receptor itself mediates this effect [93], the underlying pathophysiology is still unclear. At a basic level, we understand that seizures occur when excitatory impulses outweigh inhibitory impulses within the brain. Pro-excitatory neuronal firing is thought to predominantly arise from voltage-gated sodium channel dysfunction but may also be associated with abnormal activity at calcium channels, NMDA receptors, and GABA receptors, to name a few [94, 95]. Since the CB-1 receptor may be involved in negative feedback mechanisms for several of these pathways [15, 89, 90], varying concentrations of exogenous cannabinoids like THC and JWH-018 may result in maladaptive inhibitory modulation of inhibitory and excitatory neuronal pathways, leading to an acute proconvulsant effect. This physiologic framework provides a plausible, coherent, and specific mechanism by which THC, and analogs like JWH-018, could cause seizures.

We now know that the cannabis plant contains hundreds of cannabinoids that have their own individual biochemical effects when isolated, and an aggregate, entourage effect when introduced together. Therefore, the classic presentation we have historically expected when cannabis plant material (with its slurry of cannabinoids) is smoked may not apply to those vaping/ingesting high-concentration THC or single cannabinoid products. In addition to seizures, other atypical adverse events such as respiratory depression [29, 53, 87, 96], profound altered mental status [29, 53, 87, 96, 97], and cardiovascular ischemic events [98, 99] have also been mentioned in more recent literature on cannabis product exposures. Just as SCRAs changed our perspective on what cannabinoids can do, cannabis products with high concentrations of individual cannabinoids may be shifting the paradigm once again. As medicinal and recreational cannabis product use continues to grow and diversify, the research performed to investigate it will need to become more nuanced. Moving forward, study designs will need to pay close attention to which cannabinoid products are being used, which of these products are associated with novel effects, and in which populations these effects are occurring.

Limitations

This scoping review has several important limitations in addition to those already described. The main goal of this study was to evaluate the relationship between cannabis products and seizures in the general human population, and as such, our search algorithm specifically excluded studies that evaluated cannabis products as therapeutics for epilepsy and studies that focused on epilepsy populations only. Since much of the existing literature on the effects of cannabis products on seizures in humans is focused on therapeutics for epilepsy, this review may miss studies showing worsening seizure outcomes in the epilepsy population. Also, the studies in this review were all published in the English language and are retrospective in nature, which can cause, and be limited by, incomplete data collection respectively. In addition to the limitations discussed above, patients that were included may have multiple confounding medical conditions, and the associated therapeutics, for which we could not account.

Conclusions

The results of this scoping review show that a body of literature describing seizures in the setting of cannabis product exposure exists, but it has several limitations. Thirteen relevant studies were identified in the existing literature. In studies investigating acute cannabis exposures, ten out of 11 studies that examined acute cannabis exposures demonstrated an incidence of seizures higher than would be expected based on studies looking at the incidence of seizures found in US ED presentations or could be explained by the background prevalence of epilepsy in the general or pediatric populations. Using the Bradford Hill criteria as an objective measure, there is evidence to suggest that THC may be the proconvulsant xenobiotic responsible for this phenomenon; however, more research is needed to better establish such a causal relationship. Gaps in our current knowledge on this topic include verifying a mechanism by which THC or other cannabinoids may induce seizures, any underlying pathophysiology that may predispose some individuals to this effect, and whether THC truly is proconvulsant, epileptogenic, or both. As the usage and variety of cannabis products expands, we should be cognizant of other novel effects that would continue to shift the paradigm for this seemingly familiar drug.

Previous presentations: Data in this manuscript were previously presented at the North American Congress of Clinical Toxicology, Virtual Meeting, 2021.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This work was partially funded by NIH/NIDA K23DA045242 (PI: Carreiro).

Declarations

Conflict of Interest

Dr. EK, Dr. KG, Dr. JZ, and Dr. MN declare that they have no conflict of interest.

Dr. LT has received honoraria for speaking and consultation fees for expert testimony both unrelated to this work.

Dr. SC is funded by the NIH/NIDA (K23DA045242).