Jump to Section 1. Introduction 2. Methods 2.1. Survey 2.2. Data analysis 3. Results 3.1. Demographic information 3.2. Prevalence of medicinal cannabis use 3.3. Predictors associated with cannabis product use in people with epilepsy based on medical history 3.3.1. Children with epilepsy 3.3.2. Adults with epilepsy 3.4. Reasons for and against using cannabis products for epilepsy 3.5. Reasons for and against participating in research trials 3.6. Preference of cannabis product type and accessibility 4. Discussion Disclosures of conflicts of interest References

Overall, this Australian nationwide survey indicated that 13% of children and 15% of adults with epilepsy are currently using or have previously used cannabis products to treat epilepsy. The survey findings indicate that both parents/guardians of children and adults who have used cannabis extracts for epilepsy report a high level of perceived efficacy with cannabis products and that people with epilepsy in the Australian community are eager to engage in and assist with future research into cannabinoid medicine. Just under half of the respondents with a history of cannabis product use also reported reducing the number of AEDs after commencing use of cannabis products. The number of past AEDs tried was a significant predictor of cannabis product use in both adults and children with epilepsy. Consistent with this, treatment-resistant epilepsy and dissatisfaction with the side effects of conventional AEDs were the two main reasons for using cannabis products across all survey respondents. Adults with a neurological or pain condition in addition to epilepsy were significantly more likely to have tried cannabis products. Major barriers to using cannabinoids included difficulties with accessing cannabis products and concerns over its safety. The willingness to participate in clinical trials for cannabinoid treatment of epilepsy related to the aims of identifying a safer and more effective alternative to AEDs and to assisting with scientific research. The main reason for not participating involved concerns over safety of use.

Given that the likelihood of “sustained” seizure-freedom decreases and side effects tend to increase with each new combination of AEDs, it is reasonable that people with epilepsy, particularly those whose seizures are treatment-resistant, are pursuing alternative treatments to manage seizures. Adverse side effects of antiepileptic polypharmacy impose restrictions on the quality of life in people with active epilepsy [33x[33]Gilliam, F. Optimizing health outcomes in active epilepsy. Neurology. ; 58: S9–S20

Crossref | PubMed | Google ScholarSee all References, 34x[34]de Kinderen, R.J., Evers, S.M., Rinkens, R., Postulart, D., Vader, C.I., Majoie, M.H. et al. Side-effects of antiepileptic drugs: the economic burden. Seizure. ; 23: 184–190

Abstract | Full Text | Full Text PDF | PubMed | Scopus (25) | Google ScholarSee all References]. A patient survey at a tertiary epilepsy center indicated that the psychiatric side effects of AEDs (depressed mood, irritability, aggression) were the least well-tolerated by patients with epilepsy, followed by cognitive and physiological side effects [35x[35]Witt, J.-A., Elger, C.E., and Helmstaedter, C. Which drug-induced side effects would be tolerated in the prospect of seizure control?. Epilepsy Behav. ; 29: 141–143

Abstract | Full Text | Full Text PDF | PubMed | Scopus (20) | Google ScholarSee all References][35]. Physical side effects, such as weight gain and tiredness, were better tolerated but still imposed a considerable burden. In this survey, just under 50% of all users reported to have decreased some of their AEDs after commencing cannabis products.

Adults with epilepsy, but not parents of children with epilepsy, indicated that recreational use of cannabis had fortuitously assisted in managing seizures. No parent or guardian reported using cannabis products to manage their child’s other medical conditions. In contrast, adults with epilepsy indicated that cannabis assisted in managing other cognitive, neurological, physical, and/or mental health conditions. Interestingly, adults who had reported having pain (e.g. chronic pain, migraines) or other neurological condition in addition to epilepsy were more likely to have tried cannabis products. Sexton and colleagues' survey indicated that pain was the most frequently reported condition for which medicinal cannabis was being used, and that cannabis users reported to experience substantial symptom relief [28x[28]Sexton, M., Cuttler, C., Finnell, J.S., and Mischley, L.K. A cross-sectional survey of medical cannabis users: patterns of use and perceived efficacy. Cannabis Cannabinoid Res. ; 1: 131–138

Crossref | PubMed | Scopus (25) | Google ScholarSee all References][28].

The survey indicated that the majority of respondents wanted to participate in a clinical trial for cannabis-based treatment for epilepsy, with the main reasons similar to those underlying it use; i.e., better management of drug-resistant epilepsy and reduced side effects relative to AEDs. Respondents also expressed interest in wanting to assist with the scientific research, and to find an alternative treatment that is “natural” and therefore safer and more effective. The latter may reflect the naturalistic fallacy, that is, the belief that nature's produce is intrinsically safe [2x[2]Friedman, D. and Devinsky, O. Cannabinoids in the treatment of epilepsy. N Engl J Med. ; 373: 1048–1058

Crossref | PubMed | Scopus (92) | Google ScholarSee all References][2]. Indeed, both adults and parents of children with epilepsy most preferred a botanical whole plant compound, with preference for synthetic compounds forming the minority (2.3%).

The uncertainty over the possibility of short- and long-term side effects of cannabinoid use emerged as one of the main reasons against trying cannabis products or participating in cannabinoid research trials. Preliminary findings from an open-label clinical trial of plant-derived CBD (Epidiolex™) in children with severe epilepsy indicated an adequate safety profile, with only 3% (5/162) of patients discontinuing treatment due to an adverse event despite 12% (14/162) experiencing a serious adverse event [22x[22]Devinsky, O., Marsh, E., Friedman, D., Thiele, E., Laux, L., Sullivan, J. et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. ; 15: 270–278

Abstract | Full Text | Full Text PDF | PubMed | Scopus (206) | Google ScholarSee all References][22]. Future studies with a control group of severe epilepsy types are necessary to determine the rate of CBD-related adverse events following short-term and long-term administration. In the current survey, only a small proportion of people with epilepsy (6.5%) reported using cannabis products following recommendation by their medical doctor (neurologist or epileptologist). This reflects findings from a recent online survey, which indicated that fewer medical specialists support its use as compared to general medical personnel, patients, and the public [36x[36]Mathern, G.W., Beninsig, L., and Nehlig, A. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia's survey. Epilepsia. ; 56: 1–6

Crossref | PubMed | Scopus (24) | Google ScholarSee all References][36]. It is important to note that many locally sourced artisanal cannabis products may contain other cannabinoids, of which the safety profile is currently unknown, along with possible contaminants such as heavy metals, pesticides, bacteria, and molds.

Another concern that both adults and parents/guardians of children with epilepsy identified was the risk of worsening seizure activity by transitioning onto a new medication. Al-Kattan and colleagues identified that missed doses of AEDs was the most frequent precipitating factor for a breakthrough seizure (56.4%), followed by sleep deprivation (36.4%) and psychological stress (34.5%) [37x[37]Al-Kattan, M., Afifi, L., Shamloul, R., and Mostafa, E.E.D. Assessment of precipitating factors of breakthrough seizures in epileptic patients. Egypt J Neurol Psychiatry Neurosurg. ; 52: 165

Crossref | Scopus (3) | Google ScholarSee all References][37]. Other factors include drug-drug interactions whereby the blood concentrations of the affected drug is decreased, resulting in a breakthrough seizure [38x[38]Besag, F. and Patsalos, P.N. Clinically important antiepileptic drug interactions and their influence on adverse effects in epilepsy. in: EK St Louis, DM Ficker (Eds.) Epilepsy and the interictal state: comorbidities and quality of life. Wiley-Blackwell, ; : 110–119

Crossref | Scopus (1) | Google ScholarSee all References][38]. Cannabinoids such as CBD can have complex pharmacokinetic interactions with other drugs, including AEDs, but more in the direction of augmenting of AEDs (e.g. clobazam) via inhibition of specific CYP450 enzymes [39x[39]Geffrey, A.L., Pollack, S.F., Bruno, P.L., and Thiele, E.A. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. ; 56: 1246–1251

Crossref | PubMed | Scopus (111) | Google ScholarSee all References][39]. This may act to improve seizure control, albeit with the potential cost of increasing AED side effects [40x[40]Devinsky, O., Cilio, M.R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C. et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. ; 55: 791–802

Crossref | PubMed | Scopus (259) | Google ScholarSee all References][40]. It would appear important that such information on AED interactions is provided to the community, given the likely increased interest in, and adoption of, cannabis-based therapies.

Naturally, there are intrinsic limitations to an anonymous open-access online survey such as the current one, and this prevents any assertions regarding the overall efficacy of cannabis-based products being used in the community. This includes potential for multiple responses for a single individual (e.g. two parents responding for the same child), lack of clinician confirmation of epilepsy, and participation bias. It is possible that individuals who benefitted from cannabis products were more likely to complete the survey versus those who did not experience any benefits, resulting in a potentially unrepresentative sample. The retrospective nature of parent self-report, which is prone to poor recollection and expectation bias, is also problematic. In a recent survey, families who relocated to Colorado to access legal medicinal cannabis were three times as likely to report a >50% seizure reduction than families with established healthcare in the state [24x[24]Press, C.A., Knupp, K.G., and Chapman, K.E. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav. ; 45: 49–52

Abstract | Full Text | Full Text PDF | PubMed | Scopus (92) | Google ScholarSee all References][24]. This suggests a strong placebo effect, which can amplify parent perceptions of the cannabis product's therapeutic effect.

Moreover, artisanal cannabis products are of uncertain quality and may contain different cannabinoids of varying concentration, and with any number of possible contaminants [41x[41]2016 warning letters and test results for cannabidiol-related products [online article]. U.S. Food & Drug Administration, ; ( )

Google ScholarSee all References][41]. A recent study showed that a large proportion of edible cannabis products (baked food, beverages, and confectionary), sold in three major cities within the United States, failed to meet basic label accuracy standards for pharmaceuticals [42x[42]Vandrey, R., Raber, J.C., Raber, M.E., Douglass, B., Miller, C., and Bonn-Miller, M.O. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA. ; 313: 2491–2493

Crossref | PubMed | Scopus (92) | Google ScholarSee all References][42]. With regards to tetrahydrocannabinol (THC) content, 60% of products had significantly less cannabinoid content than stated on the label, which calls into question whether such products would result in any therapeutic benefit. The present survey did not specifically probe the type of cannabis products being used (e.g. raw form or an extracted preparation), how they were obtained or how they were being administered (e.g. smoked or ingested in oil form), precluding more detailed insight into the range of products being used within the community. Given the lack of regulation and quality assurance of artisanal cannabis products in the community, objective evaluation of standardized cannabis-based extracts is clearly warranted to relate efficacy, safety, and tolerability of these products to cannabinoid dose and concentration.

Despite these issues, what is clear is that we cannot ignore that a significant proportion of children and adults with epilepsy are using cannabis-based products in Australia, and that a high proportion of these people are reporting considerable benefit to their condition. Furthermore, a substantial proportion of respondents also reported reducing their use of AEDs after commencing cannabis products. While this may be due to a reduced requirement for AEDs to manage their condition due to positive effects of the cannabis product, it is concerning if this medication change is undertaken without close medical supervision. Given their prevalence of use identified in the present study, this possibility highlights the growing need to educate key patient groups on cannabis-based products and, in particular, to encourage patients to ensure they seek medical advice before making any major changes to their treatment regimen. Fortunately, preliminary findings from clinical trials examining the safety and efficacy of CBD are promising [21x[21]Hess, E.J., Moody, K.A., Geffrey, A.L., Pollack, S.F., Skirvin, L.A., Bruno, P.L. et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. ; 57: 1617–1624

Crossref | PubMed | Scopus (41) | Google ScholarSee all References, 22x[22]Devinsky, O., Marsh, E., Friedman, D., Thiele, E., Laux, L., Sullivan, J. et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. ; 15: 270–278

Abstract | Full Text | Full Text PDF | PubMed | Scopus (206) | Google ScholarSee all References], particularly for those with treatment-resistant epilepsies, but also for those with treatment-responsive epilepsy seeking a better side effect profile relative to conventional AEDs. However, further studies are necessary to increase our knowledge of the efficacy, interaction effects, and safety of CBD, and to explore the potential role of other cannabinoids, either alone or in combination, in the treatment of epilepsy.

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