can cbd cause seizuresDecember 15, 2021
Whether used alone or with other seizure medications, there are some potential side effects of using CBD to treat seizures. It can lead to an increase in suicidal thoughts or behaviors, sleepiness, drowsiness, diarrhea, and loss of appetite. While most of these side effects are inconvenient, interactions can also cause liver damage.
If you have seizures or are the parent of a child who has seizures, then you are probably constantly on the lookout for ways to control seizures with as few side effects as possible. CBD oil is one of the latest things to be touted as a miracle cure for seizures. While its effects are not the miracle cure some people suggest, it is a promising treatment that might be right for you.
The short answer is yes. CBD can help prevent some types of seizures in some people and animals. Clinical trials have demonstrated a significant reduction in seizures for people taking CBD to treat Lennox-Gastaut, Dravet syndrome, or tuberous sclerosis complex. Research in other areas is still in early stages, but there are indications that CBD may help prevent other types of seizure or increase the efficacy of other antiepileptic medications. Early clinical trials suggest that CBD may dramatically reduce seizures in people with CDKL5 deficiency disorder, Aicardi syndrome, Doose syndrome, and Dup15q syndrome. In addition, CBD appeared to retain its efficacy over the length of the clinical trial.
Yes, but not all CBD oils and not all types of seizures. Currently, Epidolex, a prescription form of CBD, is approved to treat seizures caused by Lennox-Gastaut, Dravet syndrome, and tuberous sclerosis complex.
That is a wonderful question, but, unfortunately, the research simply is not sufficient to give a definitive answer. What we do know is that bodies contain natural neurotransmitters and receptors known as the endocannabinoid system. CBD is believed to interact with that system, which is believed to influence a range of bodily functions and systems including immune response, appetite, pain, and sleep.
What are the potential side effects of CBD when used to treat seizures?
Well, people make many claims about what CBD can do. Not all of them have been tested and verified. However, there is support for claims that CBD may help reduce pain and anxiety.
If you have a seizure disorder, you should be seeing a neurologist for treatment. It is very important to discuss whether you should use CBD oil with your neurologist. While it is generally safe to use, there is always a risk of potential drug interactions. In addition, some people actually experience an increase in seizures when they use CBD. Therefore, just like with any antiepileptic drugs, you want to have a professional monitoring your use of CBD.
Yes. We know that CBD interacts with brivaracetam, clobazam, eslicarbazepine, stiripentol, rufinamide, topirimate, valproic acid, and zonisamide. It also possible that it interacts with other antiepileptics, and as research continues, we should have a better idea of other possible interactions.
CBD is short for cannabidiol, which is a chemical found in marijuana. It is not the same as tetrahydrocannabinol (THC), the chemical in cannabis that is responsible for the “high” feeling people get from marijuana.
The starting dose for CBD is 2.5 mg/kg of Epidolex, two times a day. A normal maintenance dosage is 5mg/kg twice daily, and the maximum dosage is 10mg/kg twice daily. As with other antiseizure medications, it should be introduced or stopped gradually, as sudden changes can increase seizure activity.
This is a tricky question to answer. Anecdotally, it seems clear that some percentage of people will have an increase in the number of seizures in response to using CBD. However, why is not so clear. Research seems to suggest that people who use commercial CBD products are likely to see an increase in seizures, while people using prescription CBD are likely to see a reduction in seizures. The speculation is that commercial products are not pure CBD, but are tainted with THC, which is known to be a potential seizure trigger.
The problem with OTC CBD is that it is not regulated by the FDA. This makes it impossible to know what dose you would be getting, if the product is contaminated with impurities, or if it even is CBD. If you want to explore using CBD to treat seizures, talk with your doctor about adding Epidolex, an FDA regulated product that eliminates the specific risks posed by an OTC product, to your treatment plan.
What is CBD?
How does CBD help prevent seizures?
In studies conducted on liver isozymes, CBD has been shown to inhibit the activity of CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4, and CYP2C19 enzymes.71–75 There is also evidence of CBD acting as an inhibitor of transporter systems, such as BCRP and the ABC transporter multidrug resistance-related protein 1.67 Some of these in vitro effects occur at concentrations above those found within the clinically used dose range. However, at least one clinically important interaction mediated by inhibition of drug metabolism has been reported. In a group of 13 patients with epilepsy aged 4 to 19 years, addition of CBD (initial dose 5 mg/kg/day, titrated up to a target dose of 25 mg/kg/day) resulted in an increase in the plasma levels of concomitantly administered clobazam by 60 ± 80% (mean ± standard deviation). More importantly, the plasma concentration of the active metabolite of clobazam, N-desmethylclobazam, increased by 500 ± 300% (95% confidence interval [CI]: +90 to +610%) at 4 weeks after starting CBD.76 Ten of the 13 patients experienced side effects, most commonly drowsiness, which resolved after lowering the clobazam dose. This interaction, which was considered to be mediated by inhibition of CYP2C19, is particularly relevant because clobazam is frequently used in epileptic encephalopathies for which CBD appears to be a promising new treatment. In a safety and pharmacokinetic study in children with Dravet syndrome, there were minimal changes in clobazam levels, but concentrations of N-desmethyl clobazam increased independently of CBD dose, except for patients on stiripentol in whom N-desmethyl-clobazam levels appeared to be unaffected by CBD.69 There were no demonstrable effects on other AEDs (valproic acid, topiramate, stiripentol, levetiracetam).69 Serum levels of concomitant AEDs were also measured in another study which assessed 39 adults and 42 children started on CBD at a dose of 5 mg/kg/day, increased according to clinical response up to a maximum of 50 mg/kg/day.77 In the latter study, increases in the levels of N-desmethyl-clobazam, topiramate, and rufinamide were reported with increasing CBD doses. In adults, there were also increases in serum levels of zonisamide and eslicarbazepine. The results of this study are difficult to interpret, because of the confounding effects of changes in the dose of comedications. Serum clobazam levels, for example, decreased during CBD coadministration, primarily due to a reduction in clobazam dose. In any case, assessment of the data suggested that changes in serum levels of concomitant AEDs during CBD administration were generally minor, with the exception of clobazam and N-desmethylclobazam levels.77 In fact, occurrence of sedation as a result of the interaction with clobazam often led to a decrease in clobazam dose.
Overall, this trial provides for the first time robust evidence that CBD added-on to pre-existing AED treatment reduces the frequency of convulsive seizures in children and young adults with Dravet syndrome. The data also emphasize the need for caution in interpreting results from previous uncontrolled trials–although median convulsive seizure frequency (primary endpoint) decreased by a statistically significantly greater extent in the CBD group compared with the placebo group, the proportion of patients with ≥ 50% reduction in convulsive seizure frequency did not differ significantly between groups, and more than one quarter of patients allocated to placebo had their seizure frequency reduced by one-half or more during the trial. Interestingly, no significant differences between groups were found in sleep scores, behavioral adaptation (Vineland-II) scores, and Quality of Life in Childhood Epilepsy scores, even though duration of treatment was relatively short and possibly insufficient to determine changes in these parameters. A major weakness in the presentation of the trial results is the failure to report changes in plasma concentrations of concomitant AEDs and, most notably, clobazam and N-desmethylclobazam. In view of the fact that 66% of patients in the CBD group were on clobazam comedication, and evidence from a previous study indicating that N-desmethylclobazam levels increase by 500% on average after adding CBD,76 the reported data do not allow to determine whether the reported improvement in seizure frequency can be ascribed to a direct action of CBD, or is simply a consequence of increased plasma levels of comedication.
Number of articles retrieved in PubMed by using the search terms ‘cannabis and epilepsy’, grouped by year of publication.
Clinical evidence of efficacy and safety: exploratory studies.
CBD may also be involved in pharmacodynamic interactions, i.e. interactions which occur at the site of action. In particular, acutely administered CBD may antagonize some of the effects of THC at CB1 receptor sites,78–80 an observation which may explain why patients taking marijuana with higher CBD content are less likely to develop adverse THC-related psychotropic symptoms, and may tolerate high-ecr THC doses.37,81 Studies in animal models, however, suggest that after prolonged exposure molecular interactions between CBD and THC may be more complex than previously thought, and may involve superadditive effects on some measures.82 Terpenoids contained in cannabis extracts may also interact with the action of CBD and other cannabinoids.83.
Overall, review of the available studies suggests that CBD-enriched cannabis may have anti-seizure effects, but the quality of the evidence does not allow to draw firm conclusions. Studies were generally retrospective, and based on patient or parenteral reports without adequately structured data collection. Many of the patients surveyed used unspecified products whose composition and dosage was unknown. Moreover, estimates of apparent efficacy could be affected by patients’ selection bias, reporting bias, and other confounders such as the natural course of the disease, regression to the mean phenomena, and placebo effects.110 In particular, placebo effects are known to be strongly influenced by expectations,111 and the broad media exposure associated with cannabis products is a strong generator of positive expectations. An indication that patient or parental expectations may have a strong impact on the outcome of cannabis treatment is provided by a comparison of perceived improvement among patients included in the Colorado surveys.107,108 Specifically, outcomes of cannabis therapy were significantly better when families moved their residence to Colorado in order to access the medication compared with families already residing in Colorado ( Fig. 3 ). Although there could be alternative explanations for this finding, it is plausible that patients with high expectations/motivations, leading them to relocate to another state, were those who responded best.
As discussed above, the molecular actions involved in CBD anti-seizure activity do not appear to be mediated by a direct effect on cannabinoid receptors, but the precise mechanisms of action have not been ascertained. In various studies, CBD has been reported to exhibit a range of other activities which suggest potential utility in many other conditions, including anxiety, mood disorders, psychosis, fear, trauma-related conditions, tobacco and opioid addition, inflammatory diseases, neurodegenerative disorders, and as a tool to counteract the undesired psychotropic effects of THC.32,51–56.
The pharmacokinetics of CBDV have not been reported in detail. In a recently completed Phase I study, healthy subjects were given single oral doses ranging between 25 and 800 mg, as well as multiple doses of 800 mg once daily over 5 days.36 Peak plasma concentrations and areas under the plasma concentration-time curve were found to be dose proportional. The 7-hydroxy- and 6-hydroxy-metabolites could be detected shortly after dosing.
Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of the first high-quality placebo-controlled trials of a purified oil-based liquid CBD preparation in patients with Dravet syndrome and Lennox-Gastaut syndrome.85,86,124 The results of these studies demonstrate that, at a dosage of 20 mg/kg/day, CBD added on to pre-existing AED treatment is superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome. In the latter patients, a dosage of 10 mg/kg/day treatment was also superior to placebo. Therefore there is now for the first time class 1 evidence that CBD improves seizure control when added on to other AEDs in patients with two difficult-to-treat epileptic encephalopathies. Available data, however, do not allow to conclude that CBD per se has anti-seizure activity. At least for the trial published in full,85 a majority of patients were receiving concomitant clobazam therapy, and it is unclear whether the reported seizure benefits, as well as adverse effects, were related to a direct action of CBD, or were mediated by a previously described 5-fold elevation in plasma N-desmethylclobazam levels. For the two studies in Lennox-Gastaut syndrome, the proportion of patients on concomitant clobazam therapy was not reported, but it is likely to have been significant because clobazam is a frequently used comedication in patients with this syndrome. Clarification of the independent effects of CBD would require re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies after excluding such patients or, alternatively, adjusting blindly clobazam dosages to maintain unaltered concentration of N-desmethylclobazam. Additional well controlled studies are also desirable to determine the potential value of CBD in other seizure types and epilepsy syndromes, including refractory focal epilepsies.
The genus Cannabis refers to a flowering plant of which there are three main species, Cannabis sativa , Cannabis indica and Cannabis ruderalis . These plants contain over 100 biologically active chemicals called cannabinoids, with the most abundant and best characterized among those being THC and CBD ( Fig. 2 ).7 Crude preparations of cannabis include dried leaves, stems and flower pods (marijuana), resins (hashish), and oily extracts (hashish oil), all of which have been used through the centuries mostly for their psychoactive properties. In general, cannabis products derived from Cannabis sativa exhibit a higher CBD/THC ratio than products derived from Cannabis indica . Different Cannabis strains have been bred either to maximize THC content or, conversely, to reduce THC content and increase the concentration of CBD and other non-psychoactive ingredients.8.
To date, the largest exploratory study of the tolerability and anti-seizure activity of CBD relates to a recent physician-sponsored expanded-access programme at 11 epilepsy centres in the USA.84 A total of 214 patients aged 1–30 years with severe, childhood-onset, drug resistant epilepsy received an oil-based liquid formulation of 99% pure CBD at an initial dose of 2–5 mg/kg/day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day, depending on study site. Tolerability and safety were analysed for the group of 162 patients who achieved at least 12 weeks of follow-up–this included 33 patients with Dravet syndrome and 31 patients with Lennox-Gastaut syndrome. In this group, adverse events were reported in 128 (79%) patients, the most common being somnolence (25%), decreased appetite (19%), diarrhea (19%), fatigue (13%), and convulsion (11%). Adverse events leading to discontinuation of treatment occurred in 5 patients (3%). An explorative assessment of efficacy was performed in a subgroup of 137 patients, after excluding patients with less than 12-week follow-up (n = 52), patients with no motor seizures (n = 21), and patients who were aged less than one year or had a severe progressive metabolic disease (n = 3). In those 137 patients, there was a median 35% decrease in total seizures, with the greatest seizure reduction being recorded in patients with focal seizures (−55%, n = 42) and atonic seizures (−54%, n = 32). Nine patients (7%) were free from all seizures during the last 4 weeks of follow-up. It is of interest that a reduction in motor seizures by 50% or greater was observed in 51% of patients comedicated with clobazam (n = 70), compared with 27% of those not receiving clobazam (n = 67). Patients on clobazam, however, were also more likely to develop adverse effects, particularly somnolence and fatigue. These differences in outcome in relation to type of comedication may be explained by the increase in plasma clobazam and N-desmethyl-clobazam levels caused by CBD.76 Additional analyses in the efficacy patient set showed that patients with Dravet syndrome (n = 32) had a 43% median reduction in all seizures, whereas for patients with Lennox-Gastaut syndrome (n = 30) median reduction in total seizures was 36%. In a subgroup of children evaluated with a care-giver-filled quality of life questionnaire, CBD therapy was associated with improved scores for energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global quality of life, which did not correlate with changes in seizure frequency.118 Outcome data from a larger cohort of 261 children and young adults from the same program (including 44 with Dravet syndrome and 40 with Lennox-Gastaut syndrome) have also been reported in summary form.36 Convulsive seizure rate for the whole cohort decreased by a median of 48% compared with baseline, whereas atonic seizures in patients with Lennox-Gastaut syndrome decreased by 71.1%. Overall, the main value of these studies is in providing a preliminary characterization of CBD safety profile. Data concerning improvement in seizure control, however, are difficult to assess in view of the uncontrolled nature of the observations.
One of the reasons for the utilization of cannabis products to have become so popular among patients and their caregivers is that these products are generally regarded as causing fewer adverse effects compared with traditional AEDs, partly out of the misperception that remedies derived from natural products are unlikely to be harmful. In a survey carried out by Epilepsia , 96% of respondents among the general public felt that there was sufficient safety evidence about cannabis products, whereas only 34% of physicians considered this to be the case.135 In fact, in the randomized controlled trials conducted to date the tolerability profile of CDB was relatively benign, with somnolence, decreased appetite and gastrointestinal symptoms being the most common treatment-emergent adverse events. Although these results are encouraging, further studies are required to evaluate the safety profile of CBD and other cannabis products in greater detail, particularly after long-term exposure and whenever these products are used in subpopulations potentially at risk. Elevations of liver enzymes have been frequently observed, especially in patients comedicated with valproate, and although they were generally reversible, close observation for signs suggestive of hepatic toxicity is advisable. Nabiximols, an oromucosal spray formulation containing approximately equal amounts of THC and CBD, has been commercially available in several countries for a number of years and has a relatively extensive safety record.68 However, the maximum approved daily CBD dose in nabiximols is considerably lower than the CBD doses used in epilepsy trials, and experience of nabiximols in pediatric age is limited because the product is not recommended for use ‘below 18 years of age due to lack of safety and efficacy data’.68 As discussed above, prolonged exposure of the immature brain to THC has been shown to cause deleterious effects on brain connectivity, and there is some evidence of prolonged recreational use of marijuana in adolescence being associated with neuropsychological decline and lower academic performance scores.136,137 There are also special concerns for risks to the offspring of mothers who use marijuana during pregnancy.138,139 Although these findings may be specific for THC and other psychoactive cannabinoids, adequate safety data for young children exposed to long-term CBD therapy are not yet available.24 Another area where limited data is available relates to the risk of rebound seizures following abrupt or rapid discontinuation of treatment. Unlike THC, CBD is not associated with the development of tolerance after repeated administration in various seizure models, and there is no evidence of a withdrawal syndrome developing after CBD discontinuation.12.
The list is not exhaustive and not all reported actions may be relevant to anti-seizure activity.
Adverse events most commonly reported in the randomized double-bind placebo-controlled trial of CBD in comparison with placebo in patients with Dravet syndrome85.
Only events occurring with a frequency > 10% in either group are listed.
In addition to web-based surveys, there have several reports based on chart reviews. In one such report from the USA, use of artisanal cannabis in 272 children and adults with a variety of seizure types was associated with at least 50% seizure reduction in 55% of cases, with 10% achieving seizure freedom, and there was no indication of improvement being preferentially associated with a specific seizure type or syndrome.61 In a retrospective survey of 75 children and adolescents with refractory epilepsy from Colorado, where use marijuana for medical purposes was legalized in 2,000, one third of patients experienced a > 50% seizure reduction after starting therapy with oral cannabis, with the highest apparent benefit being reported in those with Lennox-Gastaut syndrome.107 Adverse events were reported in almost one half of the cases and included increased seizures (13%) and somnolence/fatigue (12%), but there were also reports of improved alertness or behavior in one third of the cases. Comparable findings were reported in a similar report from Colorado, which included data from 119 patients (it is unclear whether this population partly overlapped with that described in the earlier report by the same group).108 In the latter study, the proportion of patients who showed >50% seizure reduction was 24% and, interestingly, one third of those who did not report any seizure improvement continued to take cannabis therapy, presumably because of other perceived benefits. The average duration of cannabis use in this cohort was 11.7 months (range 0.3 to 57 months) and overall 71% of patients discontinued cannabis therapy during the study period. Another report from Israel included 74 patients with highly drug resistant epilepsies secondary to various etiologies (mostly epileptic encephalopathies), treated with a CBD dose of 1 to 20 mg/kg/day using an oil product containing CBD and THC in a 20:1 ratio.109 Almost 90% of the patients were cognitively impaired and one half were less than 10 years of age. Unlike other studies, therapy in the Israeli setting was generally prescribed by a physician, and the fact that 81% of the patients received relatively low doses (less than 10 mg/kg/day) was attributed to the fact that most patients kept the oil drops sublingually for several minutes, which would be expected to result in higher bioavailability.102 About one half of the patients reported at least a 50% reduction of their seizures, but five reported seizure aggravation leading to treatment withdrawal. As in previous reports, many patients reported improvements in behavior, alertness, language, communication, motor skills and sleep. Thirty-four (45%) patients reported adverse events, including somnolence/fatigue (22%), seizure aggravation (18%), gastrointestinal symptoms and irritability (7%).
Chemistry and mechanisms of action.
In preclinical studies, CBD has been found to be active in a variety of seizures models, including seizures induced by maximal electro-shock39–41 and by pentylentetrazole in rats and mice,42–44 audiogenic seizures in rats45 and seizures induced by 3-mercaptopropionic acid, bicuculline, picrotoxin, cocaine and isoniazid (but not strychnine) in mice.39,45,46 In addition, CBD shows protective activity in pilocarpine models of temporal lobe seizures and in the penicillin and cobalt models of focal seizures in rats,47–49 and increases the afterdischarge threshold while reducing afterdischarge amplitude and duration in electrically evoked kindled seizures in rats.50 CBD also inhibits epileptiform potentials induced by a Mg 2+ -free medium and 4-amino-pyridine in hippocampal brain slices.42.
Two well controlled double-blind trials in patients with Lennox-Gastaut syndrome have been completed, but results to date have only been reported in summary form.86,124.
The first detailed modern description of the utility of cannabis-based products as an anti-seizure medication was published in 1843 by W.B. O’Shaughnessy, physician in the Bengal Army and Late Professor of Chemistry and Materia Medica at the Medical College of Calcutta. After testing the behavioral effects of various preparations of Cannabis indica in healthy fish, dogs, swines, vultures, crows, horses, deers, monkeys, goats, sheep, cows, and military assistants, he investigated the potential value of extracts of the plant in patients with different disorders, and reported remarkable anti-seizure effects in a 40-days-old baby girl with recurrent convulsive seizures.5 These observations were taken up by other physicians, including Sir William Gowers, who described the effectiveness of Cannabis indica against seizures resistant to bromides.6.
In the cannabis plant, most cannabinoids are synthesized in their acidic form. These acidic cannabinoids undergo decarboxylation to their neutral counterparts (e.g., CBD and THC) under the influence of auto-oxidation, light and heat. In most common extraction and delivery methods, plant materials are exposed to heat, resulting in the conversion of the acidic forms to the neutral constituents.60 However, some cannabis products may retain some content in acidic cannabinoids, particularly cannabidiolic acid (CBDA) and 9-Δ-tetrahydrocannabinolinic acid (THCA). THCA has been found to possess anticonvulsant activity in preliminary preclinical investigations, and be devoid of adverse psychoactive effects.61 Interest in THCA been rekindled recently by the fact that it is sometimes used for anti-seizure purposes in the USA, where it can be more readily available and/or affordable than CBD. One specific concern is that accidental exposure to heat of artisanal THCA preparations may result in partial conversion to THC.61.
Among the many active principles found in the cannabis plant, THC is the most widely investigated for its many actions, including its psychoactive effects and risks associated with overdose and abuse. THC shows some anticonvulsant effects in certain seizure models, but there have also been studies suggesting a proconvulsant effect.14,37 Although it is plausible that THC may contribute to the anti-seizure activity reported for medical marijuana and other cannabis preparations, its adverse psychotropic properties37 and inconsistent activity in seizure models render it undesirable for development for the treatment of epilepsy.38 Therefore, most cannabinoid research efforts in epilepsy have focused on the characterization of non-psycho-active agents, particularly CBD and cannabidivarin (CBDV), and the present review will focus especially on these compounds.
Evidence about the efficacy and safety of oral cannabis preparations is mostly based on surveys and case reports, including the widely publicized story of Charlotte, a little girl with SCN1A-confirmed Dravet syndrome, who experienced a remarkable improvement in her seizures after being switched to a CBD-enriched extract.102 One of the first surveys targeted a Facebook group of approximately 150 parents in the USA supporting the use of CBD-enriched cannabis in their children with drug refractory seizures.103 There were only 19 respondents, with most of the children having a diagnosis of Dravet syndrome and Doose syndrome. Over 80% of parents in this small and possibly biased sample considered their child to have fewer seizures while on CBD-enriched cannabis, at estimated doses up to 25 mg/kg/day for CBD and up to 0.8 mg/kg/day for THC. Two children were free from seizures. Parents also reported other beneficial effects, including improved alertness, and improved mood and sleep. Side effects included drowsiness and fatigue. Another online survey was directed to parents who used CBD-enriched cannabis products for the treatment of their children’s epilepsy.104 There were 117 respondents (including parents of 53 children with infantile spasms and Lennox-Gastaut syndrome), with 85% reporting a reduction in seizure frequency in their children, and 14% reporting complete seizure freedom. The median duration of therapy was 6.8 months, and the median estimated CBD dosage was 4.3 mg/kg/day. Many responders reported that their children showed improved sleep, alertness and mood. In a very recent web-based survey from Australia targeting people with epilepsy nationwide, 137 of the 976 respondents reported to be using, or having previously used, cannabis products for the treatment of their seizures.105 Use of these products increased with increasing number of AEDs used in the past, suggesting that patients with the most drug resistant seizures were more likely to access cannabis therapy. Products were perceived as helpful in managing seizures in 71% of children and 89.5% of adults, and almost one half of respondents reported to have been able to reduce their concomitant AEDs. Interestingly, only 6.5% of responders stated that they used cannabis because it was recommended by their physician, and the majority of the products used were obtained from illegal suppliers, without knowledge of their precise composition. Positive results with cannabis use were also reported in another recent online survey directed to parents of children with refractory epilepsy in Mexico.106.