Regular cannabis use during adolescence is also associated with adverse psychiatric outcomes, although these psychiatric outcomes have not been rigorously studied among patients with developmental or behavioral concerns. A recent meta-analysis63 and large prospective cohort study64 both reported increased odds of psychosis among adolescent cannabis users, an effect exacerbated by heavy use. Evidence linking adolescent cannabis use and depression are conflicting, with 2 recent systematic reviews63,65 reporting an association, but acknowledging that adjustment for confounders may reduce or eliminate this association. A more recent prospective cohort study66 of high school students demonstrated that heavy cannabis use was associated with later depression, but not suicidality. Another recent prospective study67 showed that adolescent users have nearly triple the odds of an adult anxiety disorder, although a previous systematic review63 examining adulthood anxiety among adolescent cannabis users reported conflicting data on this association. Figures 2, A and B show the association of heavy cannabis use with psychosis and with depression, respectively, as reported by Moore et al.65 How the risk for subsequent psychiatric conditions differs among cannabis-using adolescents with developmental and behavioral concerns, in particular, is a critical area for further study.
To understand how these neurocognitive and psychiatric effects of cannabis might arise, 2 concepts are critical. First, as noted above, the psychoactive compound in cannabis, Δ-9-tetrahydrocannabinol (THC), is highly lipophilic and readily crosses the blood-brain barrier as well as the placenta, with implications for normal neurodevelopment in the marijuana-using adolescent as well as the developing fetus.29 Second, the endocannabinoid system appears to play a significant role in normal neurodevelopment prenatally and extending throughout childhood and adolescence.28 Cannabinoid receptors, which are normally activated by endogenous compounds such as anandamide, appear to modulate axonal migration and long-range subcortical projections in the brain during early brain development and affect synaptic connectivity throughout childhood and adolescence.68 Some of these developmental processes are known to occur throughout adolescence and into young adulthood, and alterations in these processes during critical windows are believed to result in permanent irreversible deleterious effects.69
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
Alterations in neurodevelopment from chronic cannabis use may underlie several known brain changes present in heavy using adults. Functional imaging studies (using diffusion-weighted magnetic resonance imaging and brain connectivity mapping) show that axonal connectivity is impaired in regular marijuana users, particularly with early age of onset of use in adolescence.73 Additionally, regular adult users who started cannabis use in adolescence exhibit decreased volume in the hippocampus and amygdala,73,74 which are involved in memory processing, as well in other portions of the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex, which have high concentrations of cannabinoid receptors and are responsible for motivational, emotional, and affective processing.75 The full extent of structural and functional neural changes from marijuana use is still not fully understood and should be the focus of future study, particularly among adolescents with developmental and behavioral concerns, for whom study findings may differ from the general adolescent population.
Understanding these long-term adverse consequences of cannabis use is especially important as patients and families question whether cannabis may have a role in managing pediatric conditions. Cannabis has had a broad range of proposed clinical applications (predominantly for adult conditions), including for symptomatic management of nausea, poor appetite, and pain, as well as for treatment of multiple sclerosis, spinal cord injury, Tourette syndrome, epilepsy, and glaucoma.76 At this time, good evidence is almost entirely lacking for its application in pediatric developmental and behavioral conditions. Nonetheless, online advocacy groups that support the use of “medical” marijuana for such conditions are gaining popularity, particularly on social media sites such as Facebook. At the time of press, some examples include “Mothers for Medical Marijuana Treatment for Autism,77” “Mothers Advocating Medical Marijuana for Autism,78” and “Pediatric Cannabis Therapy.79”
Many advocates cite scientific literature regarding benefits of cannabis for the treatment of pediatric behavioral conditions, but often, data cited are from animal model-based research that does not yet have translation to human subjects. For example, a 2013 study80 from Stanford University showed that mice with a specific and rare gene mutation linked to autism showed altered endocannabinoid signaling in the central nervous system. These data were then cited by online and print media supporters of medical marijuana (e.g., the High Times81) as evidence that cannabis could be used as a treatment for autism. As another example, when another recent study72 based on a mouse model of Fragile X syndrome (described earlier in this review) showed alterations in endocannabinoid signaling pathways, these data were referenced (in this case, by more mainstream media outlets, such as the Huffington Post8 and Fox News82) as evidence for a promising role for cannabis as treatment. Although these and other high-impact studies share important insights into the pathogenesis of autism spectrum disorders (ASD) and Fragile X syndrome, based on their results alone, it is erroneous and potentially harmful to conclude that cannabis should be used as treatment for either of these disorders at this time.
Regarding human data on use of cannabis for developmental and behavioral conditions, to the best of our knowledge, the only available data are from small case series or single studies. For example, one 6-year-old boy with autism was treated with daily dronabinol for 6 months and was noted to have improvement in hyperactivity, irritability, lethargy, stereotyped behaviors, and speech, as measured by the Aberrant Behavior Checklist.83 This single case study was uncontrolled and unblinded. In another single case study84 of a cannabis-using adult male with attention-deficit hyperactivity disorder (ADHD) off stimulants, the subject's driving skills in a simulated test during a time of abstinence improved after smoking marijuana (What is unclear is whether this subject may have actually been experiencing cannabis withdrawal from his abstinence, with alleviation of his symptoms through subsequent use of marijuana.85). Another small case series86 showed an improvement in self-injurious behaviors among adolescents after dronabinol therapy, but to date, the study has not been published, leaving protocol details scarce. In sum, none of these studies provide sufficient, high-quality data to suggest that cannabis should be recommended for treatment of ASD or ADHD at this time.
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.
Given the current scarcity of data, cannabis cannot be safely recommended for the treatment of developmental or behavioral disorders at this time. At best, some might consider its use as a last-line therapy when all other conventional therapies have failed.90,91 As marijuana policy evolves and as the drug becomes more readily available, it is important that practicing clinicians recognize the long-term health and neuropsychiatric consequences of regular use. Although a decades-long public health campaign has showcased the harms of cigarette smoking, similar movements to illustrate the hazards of cannabis use have not been as rigorous or successful. As a result, accurate information on regular cannabis use remains poorly disseminated to patients, families, and physicians. Furthermore, there are especially few studies examining neurocognitive and psychiatric outcomes among children and adolescents with developmental or behavioral concerns who are exposed to cannabis, and this remains a critical area for future study. In coming to the decision to use marijuana for medicinal purposes, all parties should be fully aware of the long-term hazards of regular cannabis use, recognize the lack of evidence on its efficacy in developmental and behavioral conditions, and incorporate this information into a careful risk-benefit analysis.
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