Persistent and Long-Term Neuropsychiatric Implications of Cannabis Use in Adolescents

As society grapples with questions regarding the legality and safety of cannabis, it is particularly important to consider epidemiological trends and the implications of cannabis use in younger populations. A remarkable 78% of first-time users are between the ages of 12 and 20 years old (1). The annual U.S. Monitoring the Future Survey demonstrates an ongoing, significant decrease in perceived risk that high school students attribute to cannabis use (2). Further evidence suggests that patterns of substance abuse are highly correlated with perceptions of risk (3). The adverse effects of acute cannabis intoxication vary among users but are well-characterized by responses such as impaired short-term memory, impaired motor coordination, altered judgment, paranoia, and psychosis at higher doses (4). The persistent and long-term neuropsychiatric consequences of cannabis use in humans have proven more challenging to investigate, but there is a growing body of recent scientific literature that addresses these concerns. It is noteworthy that the potency of recreationally available strains has also climbed significantly over time (5). The purpose of the present article was to examine the basis for increased adolescent vulnerability to chronic effects of cannabis use, specifically in the domains of cognition, psychosis, and addiction.

Basis for Heightened Vulnerability

Brain development and maturation processes begin in utero and continue significantly through the early decades of life (see reference 6 for a review). Component processes include neuronal migration and differentiation, synaptogenesis, axon formation, dendritic proliferation, myelination, pruning, apoptosis, and other changes, all potentially at risk of disruption with early-onset cannabis use. The effects of delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of cannabis, are known to be mediated by activity at cannabinoid receptors located in the CNS. Cannabinoid receptors mature in adolescence (7) and are highly distributed in critical brain regions such as the prefrontal cortex, anterior cingulate cortex, basal ganglia, hippocampus, amygdala, and cerebellum (8). Various endogenous cannabinoids have been identified as ligands with innate cannabinoid receptor activity, and numerous animal studies suggest that this endocannabinoid system is involved in the regulation of key neurodevelopmental processes that occur through adolescence and may be disrupted by exogenously administered cannabinoids (9). Moreover, neuroimaging studies comparing the brains of adolescent chronic cannabis users and healthy control subjects point to structural and functional alterations that are apparent soon after initiation of drug use and persist even after months of abstinence (10). These studies do not necessarily indicate causation; however, the negative effects of cannabis on functional connectivity in adults are more notable if use begins at young ages (11). Taken together, this evidence makes a strong case for concern over adolescent cannabis use.

Cognition

Impaired verbal learning and memory have been consistently observed in chronic cannabis users in cross-sectional studies, including adolescent populations (12–14). Evidence for working memory impairment has been mixed, but studies have also differed in the specific tasks employed and in subjects’ history of cannabis use. There is strong and largely consistent evidence for attention deficits associated with chronic cannabis exposure in adolescents (see reference 15 for a review). Prior cannabis use appears to impair executive function in an age-dependent, dose-responsive manner, and adolescent-onset cannabis users demonstrate more severe and persistent cognitive impairment than adult-onset users (9, 16–19). Whether there is recovery of impairment with prolonged abstinence remains a topic of debate (see reference 15 for a review).

Prolonged, heavy cannabis use has been associated with an amotivational state (20–22), which may predict impaired learning and educational underachievement. A well-known study by Meier et al. (19) observed a longitudinal 8-point decline in IQ among heavy, adolescent-onset cannabis users, which was not restored by cessation. However, these findings have been challenged due to the possibility of other confounding variables in repeat analyses (23). An analysis of two longitudinal twin sibling studies also did not find a significant IQ decline between frequently using and non-using twins, where frequent cannabis use was defined as 30 or more times of lifetime use (24).

Psychosis

Psychosis outcomes in relation to cannabis use are at times poorly defined, but Ranganathan et al. (25) argues for characterization based on timing, duration, and resolution. Within this framework, cannabinoids have been associated with acute-onset psychosis through intoxication that resolves without clinical intervention, acute-onset psychosis that persists beyond intoxication and requires clinical intervention, and chronic psychotic disorders that emerge later in life, also requiring intervention. A review by Radhakrishnan et al. (6) concluded that the connection between cannabis and varieties of psychosis meets many but not all of the criteria for causality, passing measures such as the existence of a temporal relationship between cannabis use and psychosis, a dose-responsive effect, biological and experimental plausibility, and consistency in findings. However, a causal relationship has been questioned due to an absence of specificity and strength of association. Other factors may also play an important role; for example, variants of the AKT1 and COMT genes, which are involved in dopamine signaling and metabolism, have been proposed as significant moderators of the risk of psychotic disorder with adolescent cannabis exposure (26, 27). These findings ultimately point to significantly greater risk of psychosis associated with adolescent-onset use. Another epidemiological review by Gage et al. (28) proposes that while it is challenging to establish causality without further evidence, the significant cannabis-psychosis relationship still merits attention and public health action.

Addiction

Around 30% of all cannabis users may develop some degree of problem use, which can lead to dependence, and in severe cases takes the form of addiction (29). There is laboratory evidence of tolerance to the effects of THC (30) and clinical evidence of a withdrawal syndrome—commonly characterized by symptoms such as anger, aggression, irritability, anxiety, decreased appetite or weight loss, and sleep difficulties—that complicates abstinence in users trying to quit (31). Theories of addiction suggest that repeated drug use disrupts prefrontal cortex function and results in behavioral changes that contribute to problem use, specifically in areas of emotional regulation, inhibitory control, salience attribution, maintenance of motivational arousal, and self-awareness (32). Moreover, epidemiological studies report an age-dependent, dose-response relationship between prior cannabis use, impaired executive control (16), and development of cannabis use disorder (33–35). In perspective, individuals who use cannabis before the age of 18 are four to seven times more likely than adults to develop problem use (36). Among cannabis-related admissions to substance abuse treatment facilities in the United States, 81% of use was initiated by age 16 (37).

Conclusions

While we are still in the early stages of understanding the effects of cannabis on the developing brain, there is a growing body of scientific literature that supports various long-term consequences of adolescent-onset cannabis use relating to cognitive impairment, psychosis, and addiction. Rather than thinking of these deficits as unique outcomes, it may be useful to consider such dysfunction as a shared product of disrupted neurodevelopment, and early impairments in cognition may very well underlie manifestations of psychosis and patterns of problematic drug use that characterize addiction. Still, much of the existing evidence is based on observational studies that are ultimately limited in generalizability. Going forward, it will be important to build on converging evidence across disciplines to better characterize the relationship between cannabis and chronic neuropsychiatric outcomes. Furthermore, a greater understanding of moderating variables and risk factors will be paramount to guiding effective public health efforts. Finally, it is unclear to what extent the public is aware of the implications of adolescent cannabis use. An accurate and informed opinion of cannabis must be a part of the emerging conversation on recreational consumption and effective drug policy.

Key Points/Clinical Pearls