Pharmacovigilance of unlicensed cannabidiol in European countries

Cannabidiol (CBD) is a multitarget agent possessing anti‐inflammatory and antioxidant properties. Unlicensed CBD gained public favor for the care of general health and well‐being as well as to get comfort from inflammatory complaints, pain, anxiety, mood, and sleep disorders. Safety profile of unlicensed CBD has been not sufficiently described. For this reason, suspected adverse reactions (SARs) to CBD unlicensed products were analyzed. Serious SARs to unlicensed CBD products in EudraVigilance, a system purchased by the European Medicines Agency, were analyzed for age, sex of the patient, adverse reactions, indication for use, and concomitant drugs. Serious SARs were 18.9% of all adverse events to unlicensed CBD; they were more frequent in men and adult people and, to a less extent, in children (3–11 years). About sex, in EudraVigilance serious Individual Cases Safety Reports of SARs to CBD in men are in the largest number (58.8%) with respect to women. Unlicensed CBD was used in the 38.8% of cases for treatment of epilepsy; more frequent adverse effects were: mental disorders, hepatic disorders, and aggravation of pre‐existing epilepsy. Drugs or substances more frequently associated with SARs were the antiepileptics clobazam and valproic acid, followed by cannabis. Results suggest that precautions and appropriate surveillance of adverse effects should be taken when unlicensed CBD is used.

legislation to legalize it, others are still limiting the access to CBD derived products (https://www.legalreader.com/cbd-in-europe-legalstatus-of-cbd-country-by-country).A medicinal product based on highly purified (≥98%) CBD (licensed as Epidyolex) has been marketed in Europe and other countries.It contains CBD 100 μg/mL of THCfree sesame oil (Arzimanoglou et al., 2020).This medicinal product was authorized by European Medicines Agency (EMA) in 2019 for the following therapeutic indications: "use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, in conjunction with clobazam, for patients 2 years of age and older; use as adjunctive therapy of seizures associated with tuberous sclerosis complex for patients 2 years of age and older" (https://www.ema.europa.eu/en/documents/productinformation/epidyolex-epar-product-information_en.pdf).

CBD has not been licensed as a drug for medical use in all
European countries, furthermore, some non-EU authorities expressed concerns due to the limited safety information.An unlicensed medicine is a not officially approved ("licensed") product for treating your health condition at present (de Wilde et al., 2018).Food and Drug Administration in the United States authorized CBD for therapeutic indications for seizures overlapping to the EMA indication, but asserted in 2020 that the safety profile of CBD was still limited and additional data related to CBD were needed (Britch et al., 2021).
However, on the basis of data from clinical studies, CBD could be considered a very safe molecule having poor toxic effects.It is also well tolerated at high doses (orally up to 6000 mg) as it has been proven through data collected by phase 1 studies (Taylor et al., 2018).
Generally, results obtained with clinical trials indicate that CBD causes rarely severe adverse reactions, even though, apprehension about hepatic safety raised and this concern is also supported from experiments carried out on laboratory animals, but the relevance of this aspect in people consuming CBD has not yet been defined (Ewing et al., 2019).In November 2020, in case C-663/18, the Court of Justice of the European Union concluded that CBD should not be considered as a narcotic drug within the meaning of the 1961 Single Convention on Narcotic Drugs.As a consequence, the European Commission considered that CBD could be qualified as a food, at the same time it was clear that the existence of knowledge gaps that need to be addressed, are an obstacle to reach a definitive conclusion on its safety (EFSA Panel on Nutrition, Novel Foods and Food Allergens; NDA et al., 2022).
Generally, CBD is known as a compound characterized by a lowrisk profile, being considered for years well tolerated, also when higher doses are prescribed (Chesney et al., 2020).Beyond the potential toxicity of CBD itself, pharmacokinetic interactions can take place when this substance is taken concomitantly with other drugs, especially with those modulating CYP450 isoenzymes activity.In addition, sometimes CBD is present in products not approved by the health regulatory authorities, so it is not easy to assess the purity of the substance (Corroon et al., 2020).
Most of the concern about its medical use could be related to potential interactions due to the contemporary use of other drugs.
These seem to be caused by the enzymatic inhibitory activity of CBD, in particular when high doses are used in association with antiepileptics, thus causing lower blood concentrations of these drugs (Gilmartin et al., 2021).Another aspect that has been signaled to be further investigated is the potential CBD liver toxicity and its real occurrence in clinical practice (Ewing et al., 2019).
Currently, some European countries try to push through legislation to legalize CBD, while others are still limiting access to CBDderived products (Brunetti et al., 2020).Moreover, it was not licensed as a drug for medical use in all European countries, consequently, there is not a wide pharmacovigilance system collecting all signals for adverse reactions.
Recently, we conducted a research on spontaneous reports of adverse reactions to CBD licensed as a drug.The safety profile emerging from the results suggested to adopt appropriate monitoring of potential adverse effects in patients with epilepsy, caused by pharmacological interactions, aggravation of epilepsy or insufficient drug effectiveness.Unlicensed CBD products are widely used for different disorders, such as pain, anxiety, sleep by consumers, and prescribed for the same uses by physicians in absence of any information on risk profile.
Since no systematic study has been published on safety of unlicensed CBD often used as food and, as it is not known the risk profile of CBD used for conditions other than childhood epilepsies, with the present study, a descriptive analysis of data was performed on suspected adverse reactions (SARs) linked to unlicensed CBD.Reports were collected from the database EudraVigilance, a database containing SARs to licensed drugs but also on single chemicals (https://www.ema.europa.eu/en/human-regulatory/research-development/pharmacovigilance/eudravigilance).

| Methodology
The EudraVigilance database is directed and controlled by EMA in the name of EU.In this data bank, SARs to CBD are described in Individ-

| Results
ICSRs reporting CBD as possible cause of SARs, during the period between January 2017 and December 2022, were retrieved from EudraVigilance (checked on December 31, 2022).Currently, the total number of ICSRs of SARs linked to unlicensed CBD from EEA countries traceable in EudraVigilance for the years 2019-2022 is 539 (checked on December 31, 2022).Most of ICSRs have been signaled by France, followed in descendent order by those signaled by United Kingdom, Germany, Italy, Spain, Netherlands, Austria, Norway, Sweden, and Denmark.Serious ICSRs were 18.9% of the total number of ICSRs related to CBD use in unlicensed products in EEA.In Table 1 are shown the total number of not serious SARs and number of serious SARs listed by country of origin (Table 1).Distribution of age groups indicates that the age more affected is represented by adults aged 18-64 years (58.8%),followed by children aged between 3 and 11 years (19.6%),people aged between 65 and 85 years (10.8%),adolescents 12-17 years (7.8%), children aging between 2 months and 2 years (2.0%), and subjects aging >85 years (1.0%) (Figure 1).About sex, in EudraVigilance serious ICSRs of SARs to CBD in men are in the largest number (58.8%) with respect to women.ICSRs in which CBD was taken without other substances were 12.7% of the total number of serious CBD-related ICSRs.Death was detected in 9 of serious cases (9/102; 8.8%) (Table 2).
Regarding the indications for which CBD is suspected to be the cause of SARs, they are listed in Table 3.In ICSRs reporting serious SARs, CBD has been used, in descending order, against epilepsy, for recreational use (as a substance of abuse), and for pain.For a large part (22.3%), adverse reaction was signaled without any specification of intended use.A minor percentage of use was for neurologic, psychiatric, skin, and sleep disorders (Table 3).In Figure 2 SARs related to the use of unlicensed CBD listed by the reaction group are displayed.In descending order, mental disorders, hepatic disorders with raised liver enzymes, aggravation of epilepsy, neurological disorders and hematological disorders are reaction groups more frequently reported in ICSRs related to unlicensed CBD products.Table 4 shows the most frequent SARs to unlicensed CBD products signaled in the years 2017-2022 in EEA and United Kingdom, distributed by sex.
Mental disorders and hepatic disorders and raised liver enzymes occurred more frequently in females, while aggravation of epilepsy, neurological and hematological disorders occurred more frequently in males.Drugs or substances more frequently associated with SARs to CBD were the two antiepileptic agents clobazam and valproic acid followed by cannabis.All concomitant drugs or substances are listed in ascending order in Figure 3. Analysis of serious SARs to CBD occurring more frequently shows that females are more affected by mental and hepatic disorders, while males more suffer SARs characterized by aggravation of epilepsy, neurological and hematological disorders.

| DISCUSSION
Galenic preparations are formulations for medical use prepared in a pharmacy in accordance with a medical prescription.Currently, it is possible to prescribe either galenic preparations containing raw material from cannabis or containing two cannabis-based drugs used in therapy and registered in Europe, United Kingdom, Canada, and Australia.One of these cannabis-based derivatives is nabiximols, which is an oral spray formulation based on two extracts each containing similar doses of THC or CBD and approved for the treatment of pain deriving from spasticity associated with multiple sclerosis.Nabiximols causes acute adverse effects indistinguishable from those produced by THC alone (Bennici et al., 2021).Another drug was approved as an antiepileptic agent and it is based on CBD alone 100 μg/mL contained in THC-free sesame oil.Its registration was also carried out thanks to the numerous preclinical and clinical data that were included in the dossiers prepared for the market authorization (Arzimanoglou et al., 2020).
The effects against inflammation and positive interference with immune system activity together with the absence of psychotomimetic effects, highlighted CBD as one of the most interesting substances to be potentially used in the care of disorders with a prevalence of inflammatory and autoimmune processes (Pellati et al., 2018).Despite the growing popularity of this substance, a complete safety profile of CBD has not been drawn.However, CBD can produce several adverse effects, as it has been observed in children treated for seizures refractory to other drugs (Ammendolia et al., 2023).Some of these adverse effects include raising in temperature, but also convulsions (Devinsky et al., 2019).These symptoms, together with temporary diarrhea and reduction of appetite were confirmed by other studies, but the long-term effects of CBD in epileptic patients are not definitively known (Laux et al., 2019;Wu et al., 2022).This is the first pharmacovigilance report based on real-world data on adverse reactions related to the consumption of unlicensed CBD products and, despite the fact that information is limited to the The detection of mental disorders at the top of reaction groups of serious adverse reactions to CBD could be amazing since this compound has been more times cited as a possible chemical to use to treat psychiatric disorders (Calapai et al., 2019;Hasbi et al., 2023;Telch et al., 2022).A possible explanation for mental disorders could be that CBD is a full agonist toward the serotonergic 5-HT1A receptor (Russo et al., 2005).In this regard, it is noteworthy that serotonin is believed to be involved in several cannabis effects, such as relief of anxiety and pain (De Gregorio et al., 2019) and, is of great importance also for the hedonic tone and reinforcement processes (Müller & Homberg, 2015).
Moreover, it is necessary to consider that use of unlicensed products containing CBD implies their probable consumption in the absence of medical supervision and minor attention toward the concomitant use of other substances.About the presence of serious SARs linked to CBD characterized by hepatic disorders, it is noteworthy that this aspect has also been detected in real-world data describing adverse reactions to CBD licensed products used in the therapy of patients affected by epilepsy (Ammendolia et al., 2023).
CBD hepato-toxicity and associated liver enzyme elevations have been yet noted by clinicians, it may involve disruption of critical metabolic pathways but the mechanisms causing them are not fully understood.For this reason, it is necessary to encourage the monitoring of hepatic function in patients taking CBD at risk for liver diseases (Gingrich et al., 2023).Regarding the occurrence of epilepsy aggravation in people taking CBD, it is noteworthy that while the prevalent response to CBD is a reduction in seizure frequency, a minor number of patients may experience a worsening, in a few cases dramatically so (Rogawski, 2020).Many antiseizure drugs can cause an aggravation of epilepsy.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 (Gayatri & Livingston, 2006).
Following the present analysis, it is emerging that precautions to be adopted when unlicensed CBD is used are: awareness of the use of high doses (due to the lack of clinical evidence), appropriate surveillance of potential adverse effects, with the prevalence of mental disorders, hepatic disorders, aggravation of pre-existing epilepsy, other neurological disorders and hematologic disorders.
Based on data originating from clinical studies conducted with CBD as antiepileptic drug, it is known that patients treated with CBD from 5 to 20 mg/kg twice a day in combination with other antiepileptic drugs show the most frequent adverse events such as somnolence, diarrhea, loss of appetite, fatigue, vomiting, fever, seizures, and susceptibility to upper respiratory tract infections.Of these adverse events, 84% were mild to moderate, while severe adverse reactions comprised fever, convulsions, thrombophlebitis, apnea, and skin rash (Devinsky et al., 2018).These were similar to those reported in short-term studies, the most common being somnolence, convulsions, and diarrhea (Laux et al., 2019).
Data from a clinical study carried out enrolling patients with drugresistant epilepsy associated with tuberous sclerosis complex and treated with oral CBD (25 mg/kg/day) for 16 weeks, showed, as observed for other studies, that the most common adverse effects were transitory diarrhea, appetite reduction, and drowsiness, all resolving during the period of 16-week treatment in most patients (Wu et al., 2022).
Most of serious problems related to treatment with CBD can be caused by interactions with co-administered drugs in polytherapy.In fact, CBD is an inhibitor of CYP450 enzymes such as CYP3A4 and CYP2C19.Regarding this, it has been observed that when high doses of CBD are used to treat childhood epilepsy, a reduction of plasma concentration of co-administered synthetic antiepileptic drugs occurs.When it happens, it could be necessary to enhance the dose of co-administered drugs.As a consequence of this interaction, excessive sedation with CLB, when CBD was investigated as an adjuvant to treat refractory epilepsy in children, has also been observed by other researchers (Anderson et al., 2019;Stout & Cimino, 2014).CBD can be responsible for other clinically significant pharmacokinetic interactions with warfarin, tacrolimus, and methadone with consequent amplification of the adverse effects induced by these drugs (Cortopassi, 2020;Leino et al., 2019).Furthermore, it has also been observed that CBD significantly inhibits P-glycoprotein mediated drug transport and consequently, this could be another added mechanism causing pharmacological interactions (Zhu et al., 2006).In the present analysis drugs or substances taken concomitantly with CBD were considered.In this regard, it can be observed that among the drugs taken by people developing SARs there are antiepileptic agents such as clobazam, indicated by regulatory agencies to be associated with CBD licensed as antiepileptic, but also other anticonvulsants for which the concomitant use of the antiepileptic drugs.This possibility is a further pitfall for those who use CBD without a license without being informed about these unwanted eventualities.Furthermore, to aggravate this aspect there is also the perception that a product, a natural one at that, sold outside the official pharmaceutical market may be less dangerous, or in any case is believed that it is presenting a better safety profile than CBD regularly authorized by regulatory agencies.
ICSRs reporting SARs linked to unlicensed CBD in EU were considered and selected on the basis of Medical Dictionary tor Regulatory Activities (MedDRA) (Guide MedDRA Version 25.0, 2022).SARs linked to CBD licensed as medicinal product (Epidyolex) and not complete ICSRs were excluded.MedDRA is a standardized clinically validated international medical terminology used by regulatory authorities and biopharmaceutical industry.It is published by the International Council for Harmonization, used in particular for coding cases of adverse effects in clinical study reports and pharmacovigilance databases, and to facilitate searches in these databases (Prescrire International, 2016).Characteristics and limits fixed to collect ICSRs related to CBD from EudraVigilance were: type of adverse reaction (they are often more than one for each ICSR), complete for age and sex information, indication, concomitant drugs or substances.Only serious cases signaled by healthcare professionals were taken in account for the analysis.In accordance with the International Council on Harmonization E2D guidelines, ICSRs are classified as serious if they were life-threatening, resulted in death, caused/prolonged hospitalization or disability, determined a congenital anomaly/birth defect or other medically important condition.Appropriate stratification of signals by groups for age and sex was used to reduce bias due to confounding effects due to these variables.Descriptive statistical analysis was carried out in the present study by using the statistical software SPSS version 28.0.0.0 (190).
cannabinoid is not supported by clinical evidence or therapeutic indication.In conclusion, this post-marketing study shows limitations due principally to the lacking of a denominator and the suspected nature of single signals as SARs contained in EudraVigilance, representing any adverse event for which there is a reasonable possibility but not certainty that the substance could have caused it.Starting from the assumption that it is important to remember that the general problem of under-reporting exists and complicates the interpretation of results in the field of pharmacovigilance, results show that unlicensed CBD causes serious SARs in the percentage of 18.9% with respect of the total number of spontaneous signals of adverse effects to this substance available in EudraVigilance.These events are more common in adult people and, at a less extent, in pediatric people aging 3-11 years and show an asymmetrical distribution for sex, because mental and hepatic disorders, the more frequent suspected adverse events, appear more usually in females, while aggravation of epilepsy, neurological and hematological disorders in males.In addition, it is noteworthy that unlicensed CBD was used in the 38.8% of serious cases for epilepsy, much probably as a consequence of empirical treatment of these diseases.More frequent adverse effects are: mental disorders, hepatic disorders, aggravation of pre-existing epilepsy, other neurological disorders, and hematologic disorders.In conclusion, the results of this study suggest the need to broaden the level of information on potential adverse reactions to consumers and physicians about CBD unlicensed products available on the market (often via the web).This is particularly important since it emerges that adverse reactions occur more frequently in subjects suffering from epilepsy, even in pediatric age.Thus indicating that unlicensed CBD products are often used as antiepileptics without any license for this indication.Another concern, confirmed by reports of suspected adverse reactions to unlicensed CBD-based products, is due to the risk of potential drug interactions, particularly with Drugs and substances taken by subjects who have experienced serious adverse reactions with the use of unlicensed products based on cannabidiol (CBD) in European Economic area and United Kingdom in the years 2017-2022.The graph shows only the drugs or substances associated with CBD in at least six cases.Each bar represents the concomitant use of drugs and substances, expressed as the percentage of total cases (N = 102) of serious suspected adverse reactions to unlicensed CBD.
T A B L E 1 Individual Case Safety Reports (ICSRs) with suspected adverse reactions to unlicensed cannabidiol use in European Economic Area (EEA) and United Kingdom in the years 2017-2022, distributed by country of origin and severity.
Note: European countries signaling less than four cases are not reported.
Most frequent suspected adverse reactions to unlicensed cannabidiol products in the years 2017-2022 in European Economic area and United Kingdom distributed by sex.