The EMA designated CBD, with the commercial name Epidyolex, as an “orphan drug” (a medicine used in rare diseases) for the following indications: Dravet syndrome, 15/10/2014; Lennox-Gastaut syndrome, 20/03/2017; Tuberous sclerosis, 17/01/2018. Currently, safety information on CBD use as an antiepileptic is primarily based on data obtained from clinical studies that were analyzed for market authorization.

In general, clinical trial results indicate that CBD is a safe compound that causes only rare adverse reactions; however, concerns about safety have been raised, which are supported by experiments on laboratory animals. Nevertheless, the importance of this uncertainty in the clinical use of CBD has not been clearly defined (Ewing et al., 2019). CBD can produce direct adverse effects, as it has been observed in children treated for seizures resistant to other drugs. Some of these negative effects include elevated temperatures but also convulsions (Devinsky et al., 2019). These symptoms, together with temporary diarrhea and a loss of appetite, were confirmed by other studies, but the long-term effects of CBD are not definitively known (Laux et al., 2019; Wu et al., 2022).

The present work displays pharmacovigilance data from the EudraVigilance database. They are real-world data derived from pharmacovigilance signals about the use of CBD as an antiepileptic in the EU.

Descriptive data analysis indicates that in the context of the antiepileptic use of CBD, serious ICSRs are prevalent in male patients, when CBD is taken with other concomitant drugs, and in the age groups of adults 18–64 years (48.8%), followed by children aged 3–11 years (30.2%). The most common serious adverse reactions reported in ICSRs are “aggravation of epilepsy” and “hepatic disorders,” followed by “lack of effectiveness” and “somnolence.” Furthermore, 12.8% of cases result in death.

Multiple aspects of CBD pharmacology are associated with drug interactions potentially linked to its use with other medications, in particular with those able to influence CYP450 isoenzyme activity (Manikandan et al., 2018; Foster et al., 2019). In fact, CBD is an inhibitor of CYP450 enzymes such as CYP3A4 and CYP2C19 (Beers et al., 2021). To a lesser extent, CBD also has an inhibitory effect on the activity of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP3A5, CYP2D6, CYP2C9, and on the glucuronidation enzymes UGT1A9 and UGT2B7 (Qian et al., 2019). In this regard, it is important to note that in some cases, when high doses of CBD were used to treat childhood epilepsy, it was necessary to reduce the dose of co-administered synthetic antiepileptics. In particular, it has been observed that increasing the CBD dose reduces seric clobazam concentration and, at the same time, produces a 4–5–fold increase in its major active metabolite, N-clobazam (Karaźniewicz-Łada et al., 2021). Moreover, the enzymes CYP2C19 and CYP3A4 catalyze the formation of the metabolite 7-Hydroxy-CBD (7-OH-CBD) from CBD. This is the primary active metabolite that is equipotent with CBD and is directly conjugated by UDP-glucuronosyltransferases (Stout and Cimino, 2014). As previously stated, the occurrence of adverse reactions to CBD can also be attributed to drug-drug interactions, which are generally caused by the mechanism of CYP enzyme induction or inhibition (Patsalos et al., 2020).

The frequency of combinations of three drugs most commonly prescribed to those with serious CBD-related conditions indicates that the most common association involved in SARs is the prescription of CBD with clobazam and valproic acid, followed by the prescription of CBD with clobazam and lamotrigine.

EMA approved CBD for use as adjunctive therapy for seizures in conjunction with CLB; however, the combination of CBD with other drugs is common in epilepsy therapy. In this regard, it is worth noting that CBD was responsible for 31.9% of serious cases of SARs when used as monotherapy, which is an off-label use because CBD has only been authorized as an add-on therapy with clobazam for epilepsy. On this basis, the use of CBD in conjunction with valproic acid should also be considered an off-label prescription. However, the prescription of valproic acid with CBD for epilepsy seems to be frequent. Its use is most likely based on the safety profile of this combination emerging from clinical studies published after EMA approval (Patel et al., 2021; Scheffer et al., 2021). The majority of serious problems associated with CBD treatment can be attributed to interactions that this molecule may have when co-administered in polytherapy. The analysis of EudraVigilance data suggests that more attention be paid because, even though previous clinical studies showed a safer profile, the safety of this association in the real world has not been confirmed. Therefore, in patients receiving concurrent CBD/valproic acid therapy, the dose of these drugs may need to be adjusted.

Frequent aggravation of pre-existing conditions and lack of efficacy have yet to be reported in clinical studies with CBD, and in any case, they have not received the attention they deserve, while somnolence and potential hepatic impairment have already been detected together with potential drug-drug interactions (Devinsky et al., 2017; Devinsky et al., 2018). For a better understanding of the origins of these observed effects, it is possible to hypothesize that CBD’s multi-target pharmacological properties, such as stimulation of serotonergic and dopaminergic neuron firing, could explain them (French et al., 1997; De Gregorio et al., 2019). CBD has been shown to have a partial agonistic action on dopamine D2-like receptors, an action that may block the D2 receptors when they are overreactive or activate them when they are underactive (Shrader et al., 2020).

According to EudraVigilance data, “aggravation of epilepsy” is the most frequent SAR observed among serious ICSRs related to CBD. Epilepsy aggravation is a cause for concern because it increases the chance of physical injury and is also a risk factor for sudden unexpected death in epilepsy (Devinsky, 2011). Seizure aggravation has been mainly attributed to an “inverse pharmacodynamic effect,” in which specific effects of the drug on its antiseizure target lead to seizure worsening rather than improvement (Rogawski, 2020). Evidence from preclinical studies strongly indicates that CBD’s effects on seizure reduction involve neuronal excitability modulation via different mechanisms, making it difficult to explain how it could cause an inverse pharmacodynamic effect (Zavala-Tecuapetla et al., 2022). According to the Summary of Product Characteristics of CBD released by EMA as an antiepileptic drug, an increase in seizure frequency, as with other anticonvulsants, may occur during treatment with CBD, even though in phase three clinical trials, the frequency of status epilepticus was similar between the CBD and placebo groups (Epidyolex, 2022) (https://www.ema.europa.eu/documents/product-information/epidyolex-epar-product-information_en.pdf).

It has recently been suggested that using CBD in epilepsy without clobazam may result in reduced efficacy and seizure aggravation (Rogawski, 2020). Clobazam, a 1,5-benzodiazepine, is a positive allosteric modulator of synaptic GABA_A receptors that are widely used to treat focal and generalized seizures, and it is part of the treatment for epileptic encephalopathies such as Dravet syndrome and Lennox-Gastaut syndrome (Leahy et al., 2011; NG et al., 2011). Concerning aggravation, it should also be noted that several currently available antiepileptic drugs are contraindicated in Dravet syndrome and Lennox-Gastaut syndrome because they may cause a worsening of seizures. Dravet syndrome is a chronic pediatric epilepsy syndrome that begins in early childhood. Patients affected by Dravet syndrome generally have medically refractory epilepsy, and polytherapy is often required. First-line agents include valproate and clobazam, while sodium channel-blocking anticonvulsants such as carbamazepine and lamotrigine (the latter prescribed in some CBD-related ICSRs) are generally contraindicated in this syndrome (Wallace et al., 2016). Lennox-Gastaut syndrome is a severe epileptic and developmental encephalopathy. Several currently available antiepileptic drugs are contraindicated in Lennox-Gastaut syndrome because they may cause a worsening of seizures (Genton, 2000), including carbamazepine, oxcarbazepine, and pregabalin, which have been detected occasionally in single serious CBD-related ICSRs in the EudraVigilance database.

In our analysis of EudraVigilance data, no significant quantitative difference was found between the frequency of seizure aggravation and reduced efficacy observed in ICSRs where CBD was prescribed without CLB and ICSRs where both drugs were prescribed. However, our discovery of a high prevalence of ICSRs associated with epilepsy aggravation signaled by CBD use in clinical practice seems to be relevant because this issue had not previously emerged through clinical studies.

Death was reported as SAR in six cases, accounting for 12.8% of the total number of serious ICSRS to CBD in EudraVigilance. Death, particularly Sudden unexpected death in epilepsy (SUDEP), seems to be the leading cause of premature death in people affected by epilepsy, especially in those patients with refractory epilepsy, and its exact etiology is not known. However, research in animal models revealed that multiple neurotransmitters, including serotonin (5-HT) and adenosine, both of which are targets of CBD biological activity, may be involved in the pathophysiological mechanisms of SUDEP (Zhao et al., 2022).

Anyway, in general, CBD itself is a compound characterized by a low-risk profile, even when higher doses are prescribed (Chesney et al., 2020). Concerns about CBD medical use, on the other hand, may be related to potential interactions with the concurrent use of other drugs. This seems to be caused by CBD’s enzymatic inhibitory activity, particularly when high doses are used in conjunction with antiepileptic drugs, resulting in lower blood concentrations of these drugs (Gilmartin et al., 2021). Another aspect that needs to be further investigated is the possible CBD liver toxicity and its occurrence in clinical practice (Ewing et al., 2019).

The limitations of this pharmacovigilance study are represented by the restriction of data available in the public EudraVigilance database, and by the typical problems of the spontaneous reporting system, which are mainly related to under-reporting and potential information inaccuracies. However, knowledge can be obtained through the analysis of very large sample size data, which provides information on treatment practices in specific populations that are usually excluded from randomized clinical trials, in addition to the appropriateness of the prescription.

Finally, despite the fact that they are limited to the European area, real-world data from EudraVigilance indicate that serious adverse effects of CBD are prevalently affecting adults and children. Based on the data and concepts shown and expressed in this article, it is possible to assert that the clinical use of CBD as an antiepileptic agent requires more caution than previously applied. Precautions should be taken regarding the adoption of CBD in clinical practice, with greater awareness of its use with other drugs, avoiding off-label use when possible, appropriate surveillance of potential adverse effects, increased knowledge and attention to the possible aggravation of epilepsy, and the occurrence of potential and known CBD drug interactions.