Although far from human application, data from rodents suggest that the endocannabinoid system may also be a potential target in developmental and behavioral conditions, although results remain conflicting.70 Findings from rat models of Fragile X syndrome suggest that blockade of cannabinoid receptors may normalize aberrant hippocampal development, and simultaneously correct cognitive deficits, improve seizures, and reduce pain sensitivity.71 Somewhat conflicting are additional findings from the same rat model showing that enhancing endocannabinoid signaling may correct abnormal synaptic plasticity occurring in the prefrontal cortex and ventral striatum, with simultaneous improvement in hyperlocomotion and anxiety-related behaviors.72
Nonetheless, these data have prompted patient and family groups to advocate for the use of cannabis in children,87 occasionally even partnering with private, for-profit organizations who may stand to gain financially from such arrangements.88 This movement is coupled by a possibly increasing willingness of physicians to prescribe cannabis for medicinal purposes.89 Given the significant adverse health effects of cannabis, these 2 forces may result in issuing of medical marijuana permits for developmental and behavioral diagnoses for which no data on efficacy, safety, or tolerability exist. Even if and when studies on cannabis for developmental and behavioral conditions are conducted, they will likely use formulations of oral dronabinol or cannabidiol, both of which can be administered with a known dose and predictable schedule; at this time, the bulk of medical marijuana is sold in plant form, which results in a highly variable dose of active compound and with less predictable onset of effect based on whether it is inhaled or ingested.
REFERENCES
3. Richter KP, Levy S. Big marijuana–lessons from big tobacco. N Engl J Med. 2014;371:399–401.
4. Reinarman C, Cohen PD, Kaal HL. The limited relevance of drug policy:
cannabis in Amsterdam and in San Francisco. Am J Public Health. 2004;94:836–842.
5. Lynne-Landsman SD, Livingston MD, Wagenaar AC. Effects of state medical marijuana laws on
adolescent marijuana use. Am J Public Health. 2013;103:1500–1506.
6. Arie S. Uruguay legalises sale and production of marijuana. BMJ. 2013;347:f7499.
7. Levy S. Effects of marijuana policy on children and adolescents. JAMA Pediatr. 2013;167:600–602.
12. 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.
13. Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched
cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29:574–577.
14. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;3:CD009270.
15. Eaton DK, Kann L, Kinchen S, et al.. Youth risk behavior surveillance–United States, 2011. MMWR Surveill Summ. 2012;61:1–162.
18. Hall W, Degenhardt L. Adverse health effects of non-medical
cannabis use. Lancet. 2009;374:1383–1391.
19. Joffe A. Legalization of marijuana: potential impact on youth. Pediatrics. 2004;113:1825–1826.
24. Abrams DI, Vizoso HP, Shade SB, et al.. Vaporization as a smokeless
cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007;82:572–578.
25. Mehmedic Z, Chandra S, Slade D, et al.. Potency trends of delta9-THC and other cannabinoids in confiscated
cannabis preparations from 1993 to 2008. J Forensic Sci. 2010;55:1209–1217.
26. Winstock AR, Ford C, Witton J. Assessment and management of
cannabis use disorders in primary care. BMJ. 2010;340:c1571.
27. Bramness JG, Khiabani HZ, Morland J. Impairment due to
cannabis and ethanol: clinical signs and additive effects. Addiction. 2010;105:1080–1087.
28. Harkany T, Guzmán M, Hurd YL. Endocannabinoid functions in neurogenesis, neuronal migration, and specification. In: Köfalvi A, ed. Cannabinoids and the Brain. New York, NY: Springer Science + Business Media, LLC; 2008:237–256.
29. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42:327–360.
30. Moir D, Rickert WS, Levasseur G, et al.. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chem Res Toxicol. 2008;21:494–502.
31. Goldschmidt L, Day NL, Richardson GA. Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol. 2000;22:325–336.
32. Wu CS, Jew CP, Lu HC. Lasting impacts of prenatal
cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol. 2011;6:459–480.
35. Substance Abuse and Mental Health Services Administration, Center for Behavioral Statistics and Quality. The DAWN Report: Highlights of the 2011 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Available at:
http://www.samhsa.gov/data/2k13/DAWN127/sr127-DAWN-highlights.htm. Accessed September 3, 2014.
36. Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr. 2013;167:630–633.
37. 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.
38. Creemers HE, van Lier PA, Vollebergh WA, et al.. Predicting onset of
cannabis use in early adolescence: the interrelation between high-intensity pleasure and disruptive behavior. The TRAILS study. J Stud Alcohol Drugs. 2009;70:850–858.
39. Milberger S, Biederman J, Faraone SV, et al.. Further evidence of an association between attention-deficit/hyperactivity disorder and cigarette smoking. Findings from a high-risk sample of siblings. Am J Addict. 1997;6:205–217.
40. Molina BS, Pelham WE Jr. Childhood predictors of
adolescent substance use in a longitudinal study of children with ADHD. J Abnorm Psychol. 2003;112:497–507.
41. Charach A, Yeung E, Climans T, et al.. Childhood attention-deficit/hyperactivity disorder and future substance use disorders: comparative meta-analyses. J Am Acad Child Adolesc Psychiatry. 2011;50:9–21.
42. Groenman AP, Oosterlaan J, Rommelse N, et al.. Substance use disorders in adolescents with attention deficit hyperactivity disorder: a 4-year follow-up study. Addiction. 2013;108:1503–1511.
43. Elkins IJ, McGue M, Iacono WG. Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on
adolescent substance use and abuse. Arch Gen Psychiatry. 2007;64:1145–1152.
44. Wilens TE, Faraone SV, Biederman J, et al.. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics. 2003;111:179–185.
45. Humphreys KL, Eng T, Lee SS. Stimulant medication and substance use outcomes: a meta-analysis. JAMA Psychiatry. 2013;70:740–749.
46. De Alwis D, Agrawal A, Reiersen AM, et al.. ADHD symptoms, autistic traits, and substance use and misuse in adult Australian twins. J Stud Alcohol Drugs. 2014;75:211–221.
47. Carroll Chapman SL, Wu LT. Substance abuse among individuals with intellectual disabilities. Res Dev Disabil. 2012;33:1147–1156.
48. Chaplin E, Gilvarry C, Tsakanikos E. Recreational substance use patterns and co-morbid psychopathology in adults with intellectual disability. Res Dev Disabil. 2011;32:2981–2986.
49. Hall W, Degenhardt L. The adverse health effects of chronic
cannabis use. Drug Test Anal. 2014;6:39–45.
50. Hadland SE, Kerr T, Li K, et al.. Access to drug and alcohol treatment among a cohort of street-involved youth. Drug Alcohol Depend. 2009;101:1–7.
51. Volkow ND, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;371:879.
52. Lisdahl KM, Gilbart ER, Wright NE, et al.. Dare to delay? The impacts of
adolescent alcohol and marijuana use onset on cognition, brain structure, and function. Front Psychiatry. 2013;4:53.
53. Wilens TE, Adamson J, Sgambati S, et al.. Do individuals with ADHD self-medicate with cigarettes and substances of abuse? Results from a controlled family study of ADHD. Am J Addict. 2007;16(suppl 1):14–21; quiz 22–13.
54. Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term effects of
cannabis use on executive cognitive functions. J Addict Med. 2011;5:1–8.
55. Medina KL, Hanson KL, Schweinsburg AD, et al.. Neuropsychological functioning in
adolescent marijuana users: subtle deficits detectable after a month of abstinence. J Int Neuropsychol Soc. 2007;13:807–820.
56. Asbridge M, Hayden JA, Cartwright JL. Acute
cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ. 2012;344:e536.
57. Barkley RA, Murphy KR, Kwasnik D. Motor vehicle driving competencies and risks in teens and young adults with attention deficit hyperactivity disorder. Pediatrics. 1996;98:1089–1095.
58. Jerome L, Segal A, Habinski L. What we know about ADHD and driving risk: a literature review, meta-analysis and critique. J Can Acad Child Adolesc Psychiatry. 2006;15:105–125.
59. Schubiner H, Tzelepis A, Milberger S, et al.. Prevalence of attention-deficit/hyperactivity disorder and conduct disorder among substance abusers. J Clin Psychiatry. 2000;61:244–251.
61. Whitehill JM, Rivara FP, Moreno MA. Marijuana-using drivers, alcohol-using drivers, and their passengers: prevalence and risk factors among underage college students. JAMA Pediatr. 2014;168:618–624.
62. 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–E2664.
63. Moore TH, Zammit S, Lingford-Hughes A, et al..
Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319–328.
64. Manrique-Garcia E, Zammit S, Dalman C, et al..
Cannabis, schizophrenia and other non-affective psychoses: 35 years of follow-up of a population-based cohort. Psychol Med. 2012;42:1321–1328.
65. Horwood LJ, Fergusson DM, Coffey C, et al..
Cannabis and depression: an integrative data analysis of four Australasian cohorts. Drug Alcohol Depend. 2012;126:369–378.
66. Rasic D, Weerasinghe S, Asbridge M, et al.. Longitudinal associations of
cannabis and illicit drug use with depression, suicidal ideation and suicidal attempts among Nova Scotia high school students. Drug Alcohol Depend. 2013;129:49–53.
67. Degenhardt L, Coffey C, Romaniuk H, et al.. The persistence of the association between
adolescent cannabis use and common mental disorders into young adulthood. Addiction. 2013;108:124–133.
68. Galve-Roperh I, Palazuelos J, Aguado T, et al.. The endocannabinoid system and the regulation of neural development: potential implications in psychiatric disorders. Eur Arch Psychiatry Clin Neurosci. 2009;259:371–382.
69. Schneider M. Puberty as a highly vulnerable developmental period for the consequences of
cannabis exposure. Addict Biol. 2008;13:253–263.
70. Busquets-Garcia A, Maldonado R, Ozaita A. New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model. Int J Biochem Cell Biol. 2014;53:121–126.
71. Busquets-Garcia A, Gomis-Gonzalez M, Guegan T, et al.. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat Med. 2013;19:603–607.
72. Jung KM, Sepers M, Henstridge CM, et al.. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun. 2012;3:1080.
73. Zalesky A, Solowij N, Yucel M, et al.. Effect of long-term
cannabis use on axonal fibre connectivity. Brain. 2012;135:2245–2255.
74. Schacht JP, Hutchison KE, Filbey FM. Associations between cannabinoid receptor-1 (CNR1) variation and hippocampus and amygdala volumes in heavy
cannabis users. Neuropsychopharmacology. 2012;37:2368–2376.
75. Battistella G, Fornari E, Annoni JM, et al.. Long-term effects of
cannabis on brain structure. Neuropsychopharmacology 2014;39:2041–2048.
76. Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol. 2006;105:1–25.
80. Foldy C, Malenka RC, Sudhof TC. Autism-Associated Neuroligin-3 Mutations Commonly Disrupt Tonic Endocannabinoid Signaling. Neuron. 2013;78:498–509.
83. Kurz R, Blaas K. Use of dronabinol (delta-9-THC) in autism: a prospective single-case-study with an early infantile autistic child. Cannabinoids. 2010;5:4–6.
84. Strohbeck-Kuehner P, Skopp G, Mattern R.
Cannabis improves symptoms of ADHD. Cannabinoids. 2008;3:1–3.
85. Budney AJ, Hughes JR, Moore BA, et al.. Review of the validity and significance of
cannabis withdrawal syndrome. Am J Psychiatry. 2004;161:1967–1977.
86. Kruger T, Christophersen E. An open label study of the use of dronabinol (Marinol) in the management of treatment-resistant self-injurious behavior in 10 retarded
adolescent patients. J Dev Behav Pediatr. 2006;27:433.
89. Adler JN, Colbert JA. Clinical decisions. Medicinal use of marijuana–polling results. N Engl J Med. 2013;368:e30.
90. Bostwick JM, Reisfield GM, DuPont RL. Clinical decisions. Medicinal use of marijuana. N Engl J Med. 2013;368:866–868.
91. Turcotte D, Le Dorze JA, Esfahani F, et al.. Examining the roles of cannabinoids in pain and other therapeutic indications: a review. Expert Opin Pharmacother. 2010;11:17–31.