17º CONGRESSO BRASILEIRO DE NEUROLOGIA INFANTIL

Dados do Trabalho


Título

CBD-RICH CANNABIS SATIVA ON CORE AND COMORBID SYMPTOMS OF AUTISM SPECTRUM DISORDER: A PROSPECTIVE OBSERVATIONAL STUDY

Introdução

Autism Spectrum Disorder (ASD) is a heterogeneous condition of early neurodevelopment defined by deficits in social interaction and social communication, along with repetitive patterns of behavior, interests or activities.
The pathogenesis of ASD is incompletely understood, although there is general agreement that it is caused by genetic factors that modify brain development, specifically neural connectivity. This process is likely related to the role that microglia can play in controlling synaptic pruning and neuroinflammation.
The Endocannabinoid System exerts control over microglial activity and therefore offers a possibility of intervention in ASD. Preclinical studies indicate that anandamide administration induces an increase in IL-10 (anti-inflammatory cytokine) production by microglia cells. Furthermore, stimulation of CB2R leads to a protective phenotype in microglia, responsible for decreased secretion of IL-1.

Objetivo

There is no established pharmacological treatment for the core symptoms of ASD and the psychotropic drugs used in adjuvant symptoms have limited effectiveness and expressive adverse effects. In this context, new medications are needed to control ASD-related symptoms and to promote quality of life for patients and their families.

Métodos

This observational study was designed to evaluate the effects of CBD-rich Cannabis s. oil on core and comorbid symptoms of ASD over 24 weeks, simultaneously with the withdrawal of commonly used psychotropic drugs. The primary outcomes assessed the core symptoms of ASD. The secondary endpoints assessed neuropsychiatric manifestations and adverse effects. For all participants, a fixed dose of 5 drops of the cannabis oil distributed 3 times daily was started (CBD: 18.8 mg/d; THC: 1.3 mg/d).

Resultados

27 participants completed the follow-up (mean±SD age, 7.2±2.9 years). There was significant (p<0.001) improvement in all core ASD symptoms: communication, sociability, and stereotyped behavior. Of the neuropsychiatric comorbidities, Avoidant Restrictive Food Intake Disorder had the greatest significant improvement at 40%. Attention Deficit Hyperactivity Disorder and Insomnia Disorder also improved significantly (p<0.05). The three most common side effects were restlessness, increased appetite and nervousness and/or aggression.

Conclusões

The present study strengthens the evidence that CBD-rich Cannabis s. oil is an effective and safe therapeutic possibility for the treatment of core and comorbid symptoms of ASD.

Palavras chave

Autism; Cannabis; CBD; Endocannabinoid System; Neuropsychiatric Comorbidities

Referências (se houver)

1. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed., American Psychiatric Association, 2013.
2. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383(9920):896-910. doi:10.1016/S0140-6736(13)61539-1
3. Kleinhans NM, Müller RA, Cohen DN, Courchesne E. Atypical functional lateralization of language in autism spectrum disorders. Brain Res. 2008;1221:115-125. doi:10.1016/j.brainres.2008.04.080
4. Zeidan J, Fombonne E, Scorah J, et al. Global prevalence of autism: A systematic review update. Autism Res. 2022;15(5):778-790. doi:10.1002/aur.2696
5. Montiel-Nava C, Peña JA. Epidemiological findings of pervasive developmental disorders in a Venezuelan study. Autism. 2008;12(2):191-202. doi:10.1177/1362361307086663
6. Fombonne E, Marcin C, Manero AC, et al. Prevalence of Autism Spectrum Disorders in Guanajuato, Mexico: The Leon survey. J Autism Dev Disord. 2016;46(5):1669-1685. doi:10.1007/s10803-016-2696-6
7. Paula CS, Ribeiro SH, Fombonne E, Mercadante MT. Brief report: prevalence of pervasive developmental disorder in Brazil: a pilot study. J Autism Dev Disord. 2011;41(12):1738-1742. doi:10.1007/s10803-011-1200-6
8. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383(9920):896-910. doi:10.1016/S0140-6736(13)61539-1
9. Wang C, Geng H, Liu W, Zhang G. Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis. Medicine (Baltimore). 2017;96(18):e6696. doi:10.1097/MD.0000000000006696
10. von Ehrenstein OS, Ling C, Cui X, et al. Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study [published correction appears in BMJ. 2019 Jun 25;365:l4032]. BMJ. 2019;364:l962. Published 2019 Mar 20. doi:10.1136/bmj.l962
11. Ongono JS, Béranger R, Baghdadli A, Mortamais M. Pesticides used in Europe and autism spectrum disorder risk: can novel exposure hypotheses be formulated beyond organophosphates, organochlorines, pyrethroids and carbamates? - A systematic review. Environ Res. 2020;187:109646. doi:10.1016/j.envres.2020.109646
12. Ecker C, Bookheimer SY, Murphy DG. Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan. Lancet Neurol. 2015;14(11):1121-1134. doi:10.1016/S1474-4422(15)00050-2
13. Muhle RA, Reed HE, Stratigos KA, Veenstra-VanderWeele J. The Emerging Clinical Neuroscience of Autism Spectrum Disorder: A Review. JAMA Psychiatry. 2018;75(5):514-523. doi:10.1001/jamapsychiatry.2017.4685
14. Geschwind DH. Genetics of autism spectrum disorders. Trends Cogn Sci. 2011;15(9):409-416. doi:10.1016/j.tics.2011.07.003
15. Araujo DJ, Tjoa K, Saijo K. The Endocannabinoid System as a Window Into Microglial Biology and Its Relationship to Autism. Front Cell Neurosci. 2019;13:424. Published 2019 Sep 18. doi:10.3389/fncel.2019.00424
16. Di Marco B, Bonaccorso CM, Aloisi E, D'Antoni S, Catania MV. Neuro-Inflammatory Mechanisms in Developmental Disorders Associated with Intellectual Disability and Autism Spectrum Disorder: A Neuro- Immune Perspective. CNS Neurol Disord Drug Targets. 2016;15(4):448-463. doi:10.2174/1871527315666160321105039
17. Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016;79(7):516-525. doi:10.1016/j.biopsych.2015.07.028
18. Almogi-Hazan O, Or R. Cannabis, the Endocannabinoid System and Immunity-the Journey from the Bedside to the Bench and Back. Int J Mol Sci. 2020;21(12):4448. Published 2020 Jun 23. doi:10.3390/ijms21124448
19. Russo EB, Jiang HE, Li X, et al. Phytochemical and genetic analyses of ancient cannabis from Central Asia. J Exp Bot. 2008;59(15):4171-4182. doi:10.1093/jxb/ern260
20. Andre CM, Hausman JF, Guerriero G. Cannabis sativa: The Plant of the Thousand and One Molecules. Front Plant Sci. 2016;7:19. Published 2016 Feb 4. doi:10.3389/fpls.2016.00019
21. Pretzsch CM, Voinescu B, Lythgoe D, et al. Effects of cannabidivarin (CBDV) on brain excitation and inhibition systems in adults with and without Autism Spectrum Disorder (ASD): a single dose trial during magnetic resonance spectroscopy. Transl Psychiatry. 2019;9(1):313. Published 2019 Nov 20. doi:10.1038/s41398-019-0654-8
22. Fusar-Poli L, Cavone V, Tinacci S, et al. Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies. Brain Sci. 2020;10(9):572. Published 2020 Aug 20. doi:10.3390/brainsci10090572
23. Pretzsch CM, Freyberg J, Voinescu B, et al. Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology. 2019;44(8):1398-1405. doi:10.1038/s41386-019-0333-8
24. Horder J, Lavender T, Mendez MA, et al. Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [¹H]MRS study [published correction appears in Transl Psychiatry. 2014 Feb 18;4:e364]. Transl Psychiatry. 2013;3(7):e279. Published 2013 Jul 9. doi:10.1038/tp.2013.53
25. Ivanović I. Psychiatric Comorbidities in Children With ASD: Autism Centre Experience. Front Psychiatry. 2021;12:673169. Published 2021 Jun 9. doi:10.3389/fpsyt.2021.673169
26. Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J. Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review. BMC Psychiatry. 2020;20(1):24. Published 2020 Jan 16. doi:10.1186/s12888-019-2409-8
27. Valicenti-McDermott M, Lawson K, Hottinger K, et al. Parental Stress in Families of Children With Autism and Other Developmental Disabilities. J Child Neurol. 2015;30(13):1728-1735. doi:10.1177/0883073815579705
28. Goel R, Hong JS, Findling RL, Ji NY. An update on pharmacotherapy of autism spectrum disorder in children and adolescents. Int Rev Psychiatry. 2018;30(1):78-95
29. Politte LC, Henry CA, McDougle CJ. Psychopharmacological interventions in autism spectrum disorder. Harv Rev Psychiatry. 2014;22(2):76-92. doi:10.1097/HRP.0000000000000030
30. Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985;89(5):485-491.
31. Losapio MF, Silva LG, Pondé MP, et al. Partial cross-cultural adaptation of the Aberrant Behavior Checklist (ABC) scale for analysis of patients with mental retardation. Cad Saude Publica. 2011;27(5):909-923. doi:10.1590/s0102-311x2011000500009
32. Silva LM, Schalock M. Autism Parenting Stress Index: initial psychometric evidence. J Autism Dev Disord. 2012;42(4):566-574. doi:10.1007/s10803-011-1274-1
33. Mahapatra S, Vyshedsky D, Martinez S, et al. Autism Treatment Evaluation Checklist (ATEC) Norms: A "Growth Chart" for ATEC Score Changes as a Function of Age. Children (Basel). 2018;5(2):25. Published 2018 Feb 16. doi:10.3390/children5020025
34. Schopler E, Reichler RJ, DeVellis RF, Daly K. Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord. 1980;10(1):91-103. doi:10.1007/BF02408436
35. Pereira A, Riesgo RS, Wagner MB. Childhood autism: translation and validation of the Childhood Autism Rating Scale for use in Brazil. J Pediatr (Rio J). 2008;84(6):487-494. doi:10.2223/JPED.1828
36. Panelli RJ, Kilpatrick C, Moore SM, Matkovic Z, D'Souza WJ, O'Brien TJ. The Liverpool Adverse Events Profile: relation to AED use and mood. Epilepsia. 2007;48(3):456-463. doi:10.1111/j.1528-1167.2006.00956.x
37. Martins HH. Psychometric validation of the Portuguese-Brazilian version of the Liverpool Adverse Events Profile in patients with symptomatic partial and idiopathic generalized epilepsies. Repositorio Institucional UNIFESP. 2011. Available from: https://repositorio.unifesp.br/handle/11600/10166
38. Silva EAD Junior, Medeiros WMB, Santos JPMD, et al. Evaluation of the efficacy and safety of cannabidiol-rich cannabis extract in children with autism spectrum disorder: randomized, double-blind and controlled placebo clinical trial [published online ahead of print, 2022 May 26]. Trends Psychiatry Psychother. 2022;44:10.47626/2237-6089-2021-0396. doi:10.47626/2237-6089-2021-0396
39. Ponton JA, Smyth K, Soumbasis E, et al. A pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report. J Med Case Rep. 2020;14(1):162. Published 2020 Sep 22. doi:10.1186/s13256-020-02478-7
40. Fleury-Teixeira P, Caixeta FV, Ramires da Silva LC, Brasil-Neto JP, Malcher-Lopes R. Effects of CBD-Enriched Cannabis sativa Extract on Autism Spectrum Disorder Symptoms: An Observational Study of 18 Participants Undergoing Compassionate Use. Front Neurol. 2019;10:1145. Published 2019 Oct 31. doi:10.3389/fneur.2019.01145
41. Aran A, Cassuto H, Lubotzky A, Wattad N, Hazan E. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. 2019;49(3):1284-1288. doi:10.1007/s10803-018-3808-2
42. McVige J, Headd V, Alwahaidy M, Lis D, Kaur D, Albert B, et al. Medical cannabis in the treatment of patients with autism spectrum disorder. 2020;94:1648
43. Kuester G, Vergara K, Ahumada A, Gazmuri AM. Oral cannabis extracts as a promising treatment for the core symptoms of autism spectrum disorder: preliminary experience in Chilean patients. J Neurol Sci. 2017;381:932–3. doi:10.1016/j.jns.2017.08.2623
44. Aran A, Harel M, Cassuto H, et al. Cannabinoid treatment for autism: a proof-of-concept randomized trial. Mol Autism. 2021;12(1):6. Published 2021 Feb 3. doi:10.1186/s13229-021-00420-2
45. Campbell DB, Datta D, Jones ST, et al. Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder. J Neurodev Disord. 2011;3(2):101-112. doi:10.1007/s11689-010-9071-2
46. Le J, Zhang L, Zhao W, et al. Infrequent Intranasal Oxytocin Followed by Positive Social Interaction Improves Symptoms in Autistic Children: A Pilot Randomized Clinical Trial [published online ahead of print, 2022 May 11]. Psychother Psychosom. 2022;1-13. doi:10.1159/000524543
47. Wei D, Lee D, Cox CD, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci U S A. 2015;112(45):14084-14089. doi:10.1073/pnas.1509795112
48. Zamberletti E, Gabaglio M, Parolaro D. The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models. Int J Mol Sci. 2017;18(9):1916. Published 2017 Sep 7. doi:10.3390/ijms18091916
49. Karhson DS, Krasinska KM, Dallaire JA, et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism. 2018;9:18. Published 2018 Mar 12. doi:10.1186/s13229-018-0203-y
50. Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-852. doi:10.1038/sj.bjp.0704327
51. Klein TW, Cabral GA. Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J Neuroimmune Pharmacol. 2006;1(1):50-64. doi:10.1007/s11481-005-9007-x
52. Jean-Gilles L, Gran B, Constantinescu CS. Interaction between cytokines, cannabinoids and the nervous system. Immunobiology. 2010;215(8):606-610. doi:10.1016/j.imbio.2009.12.006
53. Nezgovorova V, Ferretti CJ, Taylor BP, et al. Potential of cannabinoids as treatments for autism spectrum disorders. J Psychiatr Res. 2021;137:194-201. doi:10.1016/j.jpsychires.2021.02.048
54. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry. 2008;47(8):921-929. doi:10.1097/CHI.0b013e318179964f
55. Leitner Y. The co-occurrence of autism and attention deficit hyperactivity disorder in children - what do we know?. Front Hum Neurosci. 2014;8:268. Published 2014 Apr 29. doi:10.3389/fnhum.2014.00268
56. Cooper RE, Williams E, Seegobin S, Tye C, Kuntsi J, Asherson P. Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. Eur Neuropsychopharmacol. 2017;27(8):795-808. doi:10.1016/j.euroneuro.2017.05.005
57. Leo D, Sorrentino E, Volpicelli F, et al. Altered midbrain dopaminergic neurotransmission during development in an animal model of ADHD. Neurosci Biobehav Rev. 2003;27(7):661-669. doi:10.1016/j.neubiorev.2003.08.009
58. Gold MS, Blum K, Oscar-Berman M, Braverman ER. Low dopamine function in attention deficit/hyperactivity disorder: should genotyping signify early diagnosis in children?. Postgrad Med. 2014;126(1):153-177. doi:10.3810/pgm.2014.01.2735
59. Bloomfield MA, Ashok AH, Volkow ND, Howes OD. The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature. 2016;539(7629):369-377. doi:10.1038/nature20153
60. Swed-Tobia R, Haj A, Militianu D, et al. Highly Selective Eating in Autism Spectrum Disorder Leading to Scurvy: A Series of Three Patients. Pediatr Neurol. 2019;94:61-63. doi:10.1016/j.pediatrneurol.2018.12.011
61. Xia W, Zhou Y, Sun C, Wang J, Wu L. A preliminary study on nutritional status and intake in Chinese children with autism. Eur J Pediatr. 2010;169(10):1201-1206. doi:10.1007/s00431-010-1203-x
62. Pramyothin P, Khaodhiar L. Metabolic syndrome with the atypical antipsychotics. Curr Opin Endocrinol Diabetes Obes. 2010;17(5):460-466. doi:10.1097/MED.0b013e32833de61c
63. Crippa JAS, Zuardi AW, Guimarães FS, et al. Efficacy and Safety of Cannabidiol Plus Standard Care vs Standard Care Alone for the Treatment of Emotional Exhaustion and Burnout Among Frontline Health Care Workers During the COVID-19 Pandemic: A Randomized Clinical Trial. JAMA Netw Open. 2021;4(8):e2120603. Published 2021 Aug 2. doi:10.1001/jamanetworkopen.2021.20603
64. Silva EAD Junior, Medeiros WMB, Torro N, et al. Cannabis and cannabinoid use in autism spectrum disorder: a systematic review. Trends Psychiatry Psychother. 2022;44:e20200149. Published 2022 Jun 13. doi:10.47626/2237-6089-2020-0149
65. Agarwal R, Burke SL, Maddux M. Current state of evidence of cannabis utilization for treatment of autism spectrum disorders. BMC Psychiatry. 2019;19(1):328. Published 2019 Oct 29. doi:10.1186/s12888-019-2259-4
66. Barchel D, Stolar O, De-Haan T, et al. Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities. Front Pharmacol. 2019;9:1521. Published 2019 Jan 9. doi:10.3389/fphar.2018.01521
67. Martin EL, Strickland JC, Schlienz NJ, et al. Antidepressant and Anxiolytic Effects of Medicinal Cannabis Use in an Observational Trial. Front Psychiatry. 2021;12:729800. Published 2021 Sep 9. doi:10.3389/fpsyt.2021.729800
68. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159(1):122-128. doi:10.1111/j.1476-5381.2009.00521.x
69. Valicenti-McDermott M, Lawson K, Hottinger K, et al. Sleep Problems in Children With Autism and Other Developmental Disabilities: A Brief Report. J Child Neurol. 2019;34(7):387-393. doi:10.1177/0883073819836541
70. Reynolds AM, Soke GN, Sabourin KR, et al. Sleep Problems in 2- to 5-Year-Olds With Autism Spectrum Disorder and Other Developmental Delays. Pediatrics. 2019;143(3):e20180492. doi:10.1542/peds.2018-0492
71. Walsh JH, Maddison KJ, Rankin T, et al. Treating insomnia symptoms with medicinal cannabis: a randomized, crossover trial of the efficacy of a cannabinoid medicine compared with placebo. Sleep. 2021;44(11):zsab149. doi:10.1093/sleep/zsab149
72. Kuhathasan N, Minuzzi L, MacKillop J, Frey BN. The Use of Cannabinoids for Insomnia in Daily Life: Naturalistic Study. J Med Internet Res. 2021;23(10):e25730. Published 2021 Oct 27. doi:10.2196/25730
73. Vaughn LK, Denning G, Stuhr KL, de Wit H, Hill MN, Hillard CJ. Endocannabinoid signalling: has it got rhythm?. Br J Pharmacol. 2010;160(3):530-543. doi:10.1111/j.1476-5381.2010.00790.x
74. Kesner AJ, Lovinger DM. Cannabinoids, Endocannabinoids and Sleep. Front Mol Neurosci. 2020;13:125. Published 2020 Jul 22. doi:10.3389/fnmol.2020.00125Dykens EM, Fisher MH, Taylor JL, Lambert W, Miodrag N. Reducing distress in mothers of children with autism and other disabilities: a randomized trial. Pediatrics. 2014;134(2):e454-e463. doi:10.1542/peds.2013-3164
75. Alonso-Pedrero L, Bes-Rastrollo M, Marti A. Effects of antidepressant and antipsychotic use on weight gain: A systematic review. Obes Rev. 2019;20(12):1680-1690. doi:10.1111/obr.12934
76. Bostwick JR, Guthrie SK, Ellingrod VL. Antipsychotic-induced hyperprolactinemia. Pharmacotherapy. 2009;29(1):64-73. doi:10.1592/phco.29.1.64
77. Boon-Yasidhi V, Jearnarongrit P, Tulayapichitchock P, Tarugsa J. Adverse effects of risperidone in children with autism spectrum disorders in a naturalistic clinical setting at siriraj hospital, Thailand. Psychiatry J. 2014;2014:136158. doi:10.1155/2014/136158
78. Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clin Biochem. 2013;46(15):1323-1338. doi:10.1016/j.clinbiochem.2013.06.012
79. Pamplona FA, da Silva LR, Coan AC. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis [published correction appears in Front Neurol. 2019 Jan 10;9:1050]. Front Neurol. 2018;9:759. Published 2018 Sep 12. doi:10.3389/fneur.2018.00759
80. Zamberletti E, Rubino T, Parolaro D. Therapeutic potential of cannabidivarin for epilepsy and autism spectrum disorder. Pharmacol Ther. 2021;226:107878. doi:10.1016/j.pharmthera.2021.107878
81. Ferber SG, Namdar D, Hen-Shoval D, et al. The "Entourage Effect": Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders. Curr Neuropharmacol. 2020;18(2):87-96
82. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35(3):764-774. doi:10.1038/npp.2009.184
83. Lattanzi S, Brigo F, Trinka E, et al. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis. Drugs. 2018;78(17):1791-1804. doi:10.1007/s40265-018-0992-5
84. Jones RM, Carberry C, Hamo A, Lord C. Placebo-like response in absence of treatment in children with Autism. Autism Res. 2017;10(9):1567-1572. doi:10.1002/aur.1798

Fonte de Fomento (se houver)

The CBD-rich Cannabis s. oil used in the research was funded by the Brazilian Association for Access to Therapeutic Cannabis (Abraflor).

Declaração de conflito de interesses de TODOS os autores

All authors have no financial conflict of interest to declare.

Área

Transtornos neuropsiquiátricos e distúrbios de aprendizagem

Instituições

UNIVERSIDADE FEDERAL DE SANTA CATARINA - Santa Catarina - Brasil

Autores

Alysson Madruga Liz, Rafael Mariano Bitencourt, Paulo César Trevisol Bittencourt, Raquel Alberti, Kelser de Souza Kock