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crease five fold when CBD is added). It is notable that 66% of patients in the CBD group were on clobazam; it was uncertain if improvement in seizure frequency was due to a direct action of CBD or increased plasma level of the active me- tabolite of clobazam. A multicenter, randomized, double-blind, placebo-controlled trial (GWP- CARE4) investigated the efficacy of CBD as add- on therapy for drop seizures in patients (aged 2-55 years) with treatment-resistant Lennox- Gastaut syndrome. 7 The median percentage re- duction in monthly drop seizure frequency from baseline was 43.9% (IQR −69.6 to −1.9) in the CBD group and 21.8% (IQR −45.7 to 1.7) in the placebo group. Adverse events were common in patients treated with CBD occurring in 86% (74/86), and 14% withdrew from the study due to adverse effects with the most common being diarrhea, somnolence, pyrexia, decreased ap- petite, and vomiting. Twenty (16 with concurrent use of valproate) patients experienced serum transaminase elevation without concomitant bilirubin elevation. Potential drug-drug interac- tion, long-term safety, and efficacy were not ex- amined in this study. Smaller, uncontrolled studies and case re- ports have suggested that CBD may be effective in the treatment of other forms of drug-resistant epilepsy and seizures such as tuberous sclero- sis, febrile infection-related epilepsy syndrome (FIRES), and Sturge-Weber syndrome. In summary, a class 1 evidence of CBD as an add-on therapy is now available in Dravet syndrome and Lennox-Gastaut syndrome. How- ever, clarification of the independent effects of CBD and clobazam comedication effect needs to be addressed. Controlled studies are required to determine the effectiveness of CBD in new- onset seizures, other epilepsy syndromes, and refractory focal seizures. Controlled, randomized trials have revealed that the actual reduction in seizure frequency in response to CBD is com- parable to that achieved in response to other antiepileptic drugs, and have failed to achieve the 80-85% responder rates in unblended, web- based surveys based on parental reports. CBD is far from a miracle cure, and it is of paramount importance to have a reasonable expectation of its usefulness as an antiepileptic medication. It is also a misconception that CBD is free of adverse effects, a claim attributed to its derivation from a natural source. Rather than spontaneous treat- ment without medical supervision, adequate medical oversight is indicated to monitor and manage adequate dose, side effects, the validity of the product, and drug-drug interaction. Many parents continue to purchase CBD products from local growers or online. Many of these products are without quality validation and may have contents significantly different from that stated on the label. Furthermore, many parents do not pay attention to the CBD concen- tration of the purchased product or comprehend that a very dilute solution is unlikely to provide a therapeutic effect. One report described two children with symptoms concerning for THC in- toxication and seizure exacerbation with a reso- lution of symptoms after switching from a “CBD- enriched cannabis extract” to a purified CBD for- mulation. 8 Well-standardized formulations with fixed high-CBD and low-THC concentrations should be preferred for treatment of epilepsy. It is essential that formulations have a very low THC content, as the antiseizure activity of THC is equivocal and can potentially aggravate sei- zures; moreover, it can be associated with addic- tion liability, psychiatric disorders, cognitive and motor impairments, and cardiovascular toxicity. The adverse effects of THC can be more prob- lematic in the immature brain with impairment of structural and functional connectivity. Ad- equate safety data for young children exposed to CBD, and safety of use during pregnancy, are needed in the future. Evolving legislation and the increased use of cannabinoid products with little or no regulation and medical oversight may in- crease the risk of accidental ingestion, increased emergency room visits, and increased call vol- umes at Poison Control Centers. Strict regulation in manufacturing, packaging, and labeling should be absolutely warranted in order to ensure safe administration. Yet, in many cases, unregulated products may be marketed and sold in a number of venues, including online orders via the inter- net. The American Academy of Pediatrics has recommended robust health surveillance; strict enforcement of rules and regulations that limit access, marketing, and advertising to youth; and use of child-proof packaging to prevent acciden- 280 • THE JOURNAL OF THE ARKANSAS MEDICAL SOCIETY tal ingestion and discourage adults from using marijuana in the presence of children. 9 References: 1. Friedman D, Sirven JI. Historical perspective on the medical use of cannabis for epilepsy: Ancient times to the 1980s. Epilepsy & Be- havior. 2017 May 1;70:298-301. 2. Campbell CT, Phillips MS, Manasco K. Can- nabinoids in Pediatrics. The Journal of Pedi- atric Pharmacology and Therapeutics. 2017 May;22(3):176-85. 3. Gloss D, Vickrey B. Cannabinoids for epilepsy. The Cochrane Library. 2014 Mar 5. 4. Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D. Systematic review: Efficacy and safety of medical mari- juana in selected neurologic disorders Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neu- rology. 2014 Apr 29;82(17):1556-63. 5. Gupta S. Why I changed my mind on weed. CNN. com. 2013 Aug 9;9. 6. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. New England Journal of Medicine. 2017 May 25;376(21):2011-20. 7. Thiele EA, Marsh ED, French JA, Mazurkie- wicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K, GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Len- nox-Gastaut syndrome (GWPCARE4): a ran- domised, double-blind, placebo-controlled phase 3 trial. The Lancet. 2018 Jan 26. 8. Crippa JA, Crippa A, Hallak JE, Martín-Santos R, Zuardi AW. Δ9-THC intoxication by canna- bidiol-enriched cannabis extract in two chil- dren with refractory epilepsy: full remission after switching to purified cannabidiol. Fron- tiers in Pharmacology. 2016 Sep 30;7:359. 9. Ammerman S, Ryan S, Adelman WP, Com- mittee on Substance Abuse. The impact of marijuana policies on youth: clinical, re- search, and legal update. Pediatrics. 2015 Mar 1;135(3):e769-85. VOLUME 115