Topical Review Article

Medical Marijuana in Pediatric Neurological Disorders

Journal of Child Neurology 1-4 ª The Author(s) 2015 Reprints and permission: DOI: 10.1177/0883073815589761

Anup D. Patel, MD1

Abstract Marijuana and marijuana-based products have been used to treat medical disease. Recently, derivatives of the plant have been separated or synthesized to treat various neurological disorders, many of them affecting children. Unfortunately, data are sparse in regard to treating children with neurologic illness. Therefore, formal conclusions about the potential efficacy, benefit, and adverse effects for these products cannot be made at this time. Further robust research using strong scientific methodology is desperately needed to formally evaluate the role of these products in children. Keywords marijuana, epilepsy, children, movement disorders, headache Received March 23, 2015. Received revised May 07, 2015. Accepted for publication May 11, 2015.

Marijuana and marijuana-based products have been utilized for medical purposes in an attempt to treat neurologic disorders since before the 1800s.1 Marijuana is from the plant Cannabis sativa and contains more than 60 distinct phytocannabinoids. These compounds are referred to as cannabinoids.2 The euphoric effect often leading to recreational use comes from a specific cannabinoid, delta-9-tetrahydrocannabinol (THC). Other cannabinoids such as cannabidiol do not possess psychoactive or euphoric properties. Other synthetic cannabinoids and phytocannabnoids may produce euphoria but have not been systematically tested. A common cannabinoid that has been used in treating neurologic disorders such as epilepsy is cannabidiol.2-7 It is important to understand the different components of the plant to fully grasp the potential therapeutic uses and possible adverse effects of these components. Differences exist depending on which specific cannabinoid is being utilized in medical treatment. Medical literature evaluating treatment is available in clinical trials, case reports, and reviews for various neurologic diseases. However, further robust scientific research is necessary to fully understand the potential benefits and risks of products derived from C sativa.8-10 Specifically for children, currently there is poor literature and support for using marijuana-based products to treat neurologic disorders. This topical review highlights the present data and information available. It is important to note that most of the reviewed literature contains information pertaining to adult patients, with some exception. Only case reports and limited information are available on children for treating seizures and on adolescents for treatment of tics in Tourette syndrome.

History and Background The first reports of using C sativa for medical purposes were for the treatment of complications from gastrointestinal disorders, rheumatologic symptoms, pain, and epilepsy.3 In the 1800s, the well-known English neurologist W. R. Gowers reported the use of a marijuana-based product to treat seizures.2 Use of marijuana to treat medical illness dates back to several thousands of years, with reports presented in the medical literature and books.3 Many of the studies performed in various neurologic disorders thus far have been using products with a relatively high content of delta-9-tetrahydrocannabinol. Until recently, products with little delta-9-tetrahydrocannabinol and a high percentage of cannabidiol have been produced for use in human subjects. Further, it is important to note that using delta-9tetrahydrocannabinol or the entire plant may have long-term effects on the pediatric brain and on brain volume.11-14 In addition, stroke as a complication related to recreational and synthetic marijuana products high in delta-9-tetrahydrocannabinol has been reported in young adults and adolescents.15-18 However,


Nationwide Children’s Hospital and the Ohio State University College of Medicine, Columbus, OH, USA

Corresponding Author: Anup D. Patel, MD, Nationwide Children’s Hospital and the Ohio State University College of Medicine, ED 533, 700 Children’s Drive, Columbus, OH 43205, USA. Email: [email protected]

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Journal of Child Neurology

further studies are likely needed to fully understand its short- and long-term effects. To date, no long-term adverse effects have been reported from products with a high content of cannabidiol and a low content of delta-9-tetrahydrocannabinol. Studies are ongoing to fully determine these issues.3 The psychoactive properties of C sativa have been attributed to delta-9-tetrahydrocannabinol resulting from its binding within the brain to 2G-protein–coupled receptors named CB1 and CB2, with CB1 serving as the main site accounting or the psychoactive properties. Many other components of the plant such as cannabidiol do not bind to these receptors, which may explain the lack of euphoric properties within this compound.19,20 Potential mechanisms of action for cannabidiol have been proposed.3,21 However, the exact potential therapeutic target site within the central nervous system has not been fully elucidated.

Use in Neurologic Disorders Epilepsy. In a Cochrane Review, Gloss and Vickery detailed 4 controlled studies performed in the 1970s examining the use of various marijuana-based products when used to treat seizures. The result of the review concluded that significant flaws were present within these studies, thus making any conclusions on potential therapeutic effect difficult. However, it appeared that doses of 200 to 300 mg of cannabidiol were well tolerated in the limited human subjects given the product.2 Safety studies in humans suggest that doses of cannabidiol up to 300 mg used as long as 4.5 months have been shown to be safe in adults.2 Studies evaluating illicit use of marijuana in patients with new-onset seizures found a potential benefit in men, with no clinical significant findings for women; however, a trend toward significance was noted.22,23 Various case reports and series have shown potential benefits of marijuana-based products for the treatment of seizures.7,24 Potential benefits in specific epilepsy syndromes within children such as Dravet syndrome have been documented as specific examples within the media and various other formats.7 Ongoing rigorous clinical phase I-III trials by GW Pharmaceuticals25 will evaluate the potential efficacy, safety, and tolerability of cannabidiol oil, Epidiolex, in children with Dravet and Lennox Gastaut syndromes. A survey of parents giving a cannabidiol-based product suggested seizure reduction from parental report, with many among those surveyed having children with Dravet syndrome.26 Headache and pain. To date, no randomized controlled trials have been performed in the use of any marijuana-based product in the treatment of specific headache syndromes. However, reports exist dating back to the late 1800s with J. R. Reynolds describing use of marijuana to treat migraine and various other forms of neurologic pain and headache.27 Other reports are documented in the medical literature suggesting benefit.28 A case report exists of successful treatment of cluster headaches in a 19-year-old patient using both recreational marijuana and a synthetic high delta-9-tetrahydrocannabinol–based product.29

Proposed mechanisms of actions of cannabidiol acting on serotonin receptors3,21 may yield benefit for patients with migraine-related pain.28 Further evidence of potential impact for headache-related disease has been proposed within the medical literature by various authors through targeting of the endocannabinoid signaling system within the brain.30-33 It is within this system that potential benefit from pain in general has been found.34 A meta-analysis evaluating all randomized controlled trials reported in the literature was performed and found that pain relief was achieved. However, the authors stated that further evaluation is necessary to determine the full risk-tobenefit ratio as significant central nervous system adverse effects were commonly reported within the specific studies.34 The studies selected for inclusion in the review were from patients given oral or a nasal mucosal spray and included a placebo group. They included adult patients with pain from various diseases.34 Movement disorders. A case report exists reporting a decrease in tic burden for a 15-year-old patient with Tourette syndrome who received up to 15 mg of delta-9-tetrahydrocannabinol. However, the patient was also on other atypical antipsychotic medications.35 Other trials containing a small number of patients suggested improvement in tics and obsessive compulsive symptoms, with the youngest patient being 18 years old.36-39 However, guidelines provided by the American Academy Neurology states that data are insufficient to support or refute efficacy of delta-9-tetrahydrocannabinol for reducing tic severity.1 The proposed benefit lies in the mechanisms of action described above. In addition, limited, poorly powered data exist that suggest that marijuana-based products are not effective in reducing chorea related to Huntington disease40 and levodopa-induced dyskinesia seen in Parkinson disease.1,41 Recently, a study suggested potential benefit from cannabidiol in quality of life for patients with Parkinson disease without dementia symptoms.42 Again, no children were included and subject numbers were small. Multiple sclerosis. Studies exist evaluating various marijuanabased preparations in treating complications related to multiple sclerosis in adult patients. Guidelines provided by the American Academy of Neurology evaluated these studies to provide recommendations on its use in multiple sclerosis.1,43 For patients with spasticity from multiple sclerosis, oral extract and synthetic preparations are probably effective when evaluating subjective measures, with unclear benefit with the evaluation of objective measures; however, smoked preparations are of no benefit.1 These oral extracts contain a similar proportion of delta-9-tetrahydrocannabinol and cannabidiol. When evaluating pain and spasms related to multiple sclerosis, the oral extracts are effective, with strong evidence supporting its use.1 Delta-9-tetrahydrocannabinol and other synthetic derivatives may be effective for treating pain and spasms related to multiple sclerosis. For patients with bladder dysfunction related to multiple sclerosis, it was determined that a synthetic preparation, nabiximol, is probably effective for void reduction. In patients with tremor, all marijuana-based preparations are

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probably not effective in addressing tremor-related complications from multiple sclerosis.1 Children were not included in these studies.

Conclusions The current literature for the use of marijuana-based products in children with neurologic illness is sparse. In addition, potential methodologic issues exist for many publications that make interpretation difficult. Therefore, formal conclusions about the potential efficacy, benefit, and adverse effects for these products cannot be made at this time. Further robust research using strong scientific methodology is desperately needed to formally evaluate the role of these products in children. Concern exists from previous reports on use of cannabis and its potential effect on neuropsychological decline44 and psychological and social problems.45,46 Current political, social, and emotional views on the use of marijuana and marijuana-based products as a medical treatment exist, which can complicate rigorous study. Many states in the United States of America have passed legislation allowing use of marijuana-based products for medical purposes. However, there might be untoward consequences that can lead to harm; for example, unregulated and inconsistent preparations could be used and introduced to children.12,47-50 The current scheduling of these products delays potential clinical study because of the additional requirements necessary to prescribe these products for research. The Drug Enforcement Agency currently labels products derived from C sativa as schedule I, which means there is no therapeutic benefit but significant harm and abuse potential. This is likely not true for all preparations, and reclassification may need to occur. Social and emotional passion exists when discussing these products. These feelings can limit the ability to evaluate potential effects of these products in an objective manner. Placebo rates of improvement have been an issue in previous studies51 and will likely continue to be a factor in the data analysis of ongoing and future studies. Further, parental report of perceived benefit will likely be an issue when evaluating use of cannabidiol products in treating children with epilepsy.3,21 Therefore, the need for rigorous and robust clinical research evaluating safety, efficacy, and tolerability of marijuana-based products in children remains high as desperate parents and patients continue to search for potential beneficial and safe treatments. Declaration of Conflicting Interests The author declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ADP receives research support from the Pediatric Epilepsy Research Foundation (PERF) and GW Pharmaceuticals. In addition, he serves as a consultant for Health Logix and Cyberonics. He participates in webinar development for the American Academy of Neurology..

Funding The author received no financial support for the research, authorship, and/or publication of this article.

References 1. Koppel BS, Brust JC, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82:1556-1563. 2. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;3:CD009270. 3. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791-802. 4. Sirven JI. Medical marijuana for epilepsy: winds of change. Epilepsy Behav. 2013;29:435-436. 5. Sirven JI. Cannabis, cannabidiol, and epilepsies: the truth is somewhere in the middle. Epilepsy Behav. 2014;41:270-271. 6. Szaflarski JP, Martina Bebin E. Cannabis, cannabidiol, and epilepsy—from receptors to clinical response. Epilepsy Behav. 2014. 7. Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55:783-786. 8. Patel A, Dominic F, Brust J, Song S, Miller T, Narayanaswami P. Position statement: use of medical marijuana for neurologic disorders. American Academy of Neurology, 2014. https://www.aan. com/uploadedFiles/Website_Library_Assets/Documents/6.Public_ Policy/1.Stay_Informed/2.Position_Statements/3.PDFs_of_all_ Position_Statements/Final%20Medical%20Marijuana%20Posi tion%20Statement.pdf. Accessed 2014, 2014. 9. Gattone PM, Lammert W, Devinsky O. Epilepsy Foundation of America position statement: medical marijuana in epilepsy. Epilepsy Foundation of America, 2014. article/2014/2/epilepsy-foundation-calls-increased-medical-marijuana-access-and-research. 10. AES position on medical marijuana, 2014. https://www.aesnet. org/sites/default/files/file_attach/AboutAES/PositionStatements/ AES%20Position%20on%20Medical%20Marijuana.pdf. 11. Rivkin MJ, Davis PE, Lemaster JL, et al. Volumetric MRI study of brain in children with intrauterine exposure to cocaine, alcohol, tobacco, and marijuana. Pediatrics. 2008;121:741-750. 12. Joffe A. Legalization of marijuana: potential impact on youth. Pediatrics. 2004;113:1825-1826. 13. Battistella G, Fornari E, Annoni JM, et al. Long-term effects of cannabis on brain structure. Neuropsychopharmacology. 2014; 39:2041-2048. 14. Geller T, Loftis L, Brink DS. Cerebellar infarction in adolescent males associated with acute marijuana use. Pediatrics. 2004;113: e365-e370. 15. Tsivgoulis G, Lachanis S, Papathanasiou MA, Chondrogianni M, Brountzos EN, Voumvourakis K. Cannabis-associated angiopathy: an uncommon cause of crescendo transient ischemic attacks. Circulation. 2014;130:2069-2070. 16. Barber PA, Anderson NE, Brust JC. Spice, pot, and stroke. Neurology. 2014;83:772. 17. Barber PA, Pridmore HM, Krishnamurthy V, et al. Cannabis, ischemic stroke, and transient ischemic attack: a case-control study. Stroke. 2013;44:2327-2329. 18. Bernson-Leung ME, Leung LY, Kumar S. Synthetic cannabis and acute ischemic stroke. J Stroke Cerebrovasc Dis. 2014;23:1239-1241.

Downloaded from at NORTH DAKOTA STATE UNIV LIB on June 15, 2015


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19. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. 20. Pertwee RG. Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addict Biol. 2008;13:147-159. 21. Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia. 2014;55:787-790. 22. Brust JC, Ng SK, Hauser AW, Susser M. Marijuana use and the risk of new onset seizures. Trans Am Clin Climatol Assoc. 1992;103:176-181. 23. Ng SK, Brust JC, Hauser WA, Susser M. Illicit drug use and the risk of new-onset seizures. Am J Epidemiol. 1990;132:47-57. 24. Ladino LD, Hernandez-Ronquillo L, Tellez-Zenteno JF. Medicinal marijuana for epilepsy: a case series study. Can J Neurol Sci. 2014;41:753-758. 25. Cannabis-based medicines—GW pharmaceuticals: high CBD, high THC, medicinal cannabis—GW pharmaceuticals, THC: CBD. Drugs R D. 2003;4:306-309. 26. Porter BE, Jacobson C. Report of a parent survey of cannabidiolenriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29:574-577. 27. McGeeney BE. Cannabinoids and hallucinogens for headache. Headache. 2013;53:447-458. 28. Russo E. Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain. 1998;76:3-8. 29. Robbins MS, Tarshish S, Solomon S, Grosberg BM. Cluster attacks responsive to recreational cannabis and dronabinol. Headache. 2009;49:914-916. 30. Greco R, Gasperi V, Maccarrone M, Tassorelli C. The endocannabinoid system and migraine. Exp Neurol. 2010;224:85-91. 31. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90:844-851. 32. Gardner EL. Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav. 2005;81:263-284. 33. Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21-47. 34. Martin-Sanchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med. 2009;10:1353-1368. 35. Hasan A, Rothenberger A, Munchau A, Wobrock T, Falkai P, Roessner V. Oral delta 9-tetrahydrocannabinol improved refractory Gilles de la Tourette syndrome in an adolescent by increasing intracortical inhibition: a case report. J Clin Psychopharmacol. 2010;30:190-192. 36. Muller-Vahl KR. Treatment of Tourette syndrome with cannabinoids. Behav Neurol. 2013;27:119-124.

37. Muller-Vahl KR. Cannabinoids reduce symptoms of Tourette’s syndrome. Exp Opin Pharmacother. 2003;4:1717-1725. 38. Muller-Vahl KR, Schneider U, Koblenz A, et al. Treatment of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry. 2002;35: 57-61. 39. Muller-Vahl KR, Schneider U, Prevedel H, et al. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J Clin Psychiatry. 2003;64:459-465. 40. Armstrong MJ, Miyasaki JM. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2012;79:597-603. 41. Carroll CB, Bain PG, Teare L, et al. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology. 2004;63:1245-1250. 42. Chagas MH, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28:1088-1098. 43. Yadav V, Bever C Jr, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82: 1083-1092. 44. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012;109:E2657-2664. 45. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002;325:1212-1213. 46. Konings M, Stefanis N, Kuepper R, et al. Replication in two independent population-based samples that childhood maltreatment and cannabis use synergistically impact on psychosis risk. Psychol Med. 2012;42:149-159. 47. Wang GS, Narang SK, Wells K, Chuang R. A case series of marijuana exposures in pediatric patients less than 5 years of age. Child Abuse Negl. 2011;35:563-565. 48. Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr. 2013;167: 630-633. 49. Wang GS, Roosevelt G, Le Lait MC, et al. Association of unintentional pediatric exposures with decriminalization of marijuana in the United States. Ann Emerg Med. 2014;63:684-689. 50. Hurley W, Mazor S. Anticipated medical effects on children from legalization of marijuana in Colorado and Washington State: a poison center perspective. JAMA Pediatr. 2013;167:602-603. 51. Consroe P, Laguna J, Allender J, et al. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav. 1991;40:701-708.

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Medical Marijuana in Pediatric Neurological Disorders.

Marijuana and marijuana-based products have been used to treat medical disease. Recently, derivatives of the plant have been separated or synthesized ...
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