ABSTRACT
Cannabis is the most common illicit substance used by adolescents and the third most common psychoactive substance after alcohol and nicotine. Cannabis use during adolescence interrupts a critical period of brain development and leads to inappropriate activation of the reward pathway. Because the prefrontal cortex, which is responsible for impulse control and other executive functions, is not fully mature until the mid-twenties, the adolescent brain is especially vulnerable to damage from substance use. Although cannabis remains illegal at the federal level, recent changes in state policies have been associated with increased availability of a wide variety of cannabis products. As new products, formulations, and delivery devices that can deliver higher and faster peak doses of tetrahydrocannabinol enter the market, there is an even greater potential for cannabis to have negative clinical impacts on adolescent health. This article reviews the current literature on the impact of cannabis on adolescent health, including the neurobiology of the adolescent brain, potential clinical outcomes in adolescents who use cannabis, and the effects of changing state policies regarding cannabis on the increased availability of unregulated products.
Introduction
Cannabis is the most common illicit substance used by adolescents and the third most common psychoactive substance after alcohol and nicotine.1 Although cannabis prevalence among adolescents had previously peaked in the late 1970s, it resurged in the 1990s. Most recently, daily cannabis use rose again in 2019, with cannabis use in adolescents at or near its highest level since 1991. In 2019, 78% of 12th graders said cannabis would be fairly easy or very easy to get if they wanted to acquire it. In 2020, 30% of 8th, 10th, and 12th graders reported ever using cannabis. With such a significant number of adolescents endorsing cannabis use, it is critical to understand the impact cannabis has on adolescent health, including the neurobiology of the adolescent brain, potential clinical outcomes in adolescents who use cannabis, and the effects of changing state policies regarding cannabis on the increased availability of unregulated products.
Discussion
Neurodevelopmental Impact
Brain development was previously thought to be completed by the age of 10 years. Studies found that the average adult brain weighs about 3 pounds; during development, the brain reaches this adult size around 10 to 12 years old.2 In the past, the incorrect assumption was that once the brain reached 3 pounds, development must be completed. However, as more detailed methods for studying neuron growth in brain development were developed, it became apparent that brain development continues into young adulthood and is very active during adolescence. Using three-dimensional reconstructed magnetic resonance imaging of the human brain across different ages, there is evidence that brain maturation in most individuals is not complete until the mid-twenties.3As the adolescent brain is still in the process of developing, it is especially vulnerable to damage from exposure to exogenous substances, including cannabis. Entering adolescence, the prefrontal cortices have an abundance of synapses.4 Pruning allows the brain to remove inefficient connections and strengthen those that remain, setting the stage for mature functioning. Pruning constitutes a critical period of development and is susceptible to disruption from outside influences.The pruning process is followed by myelination, the final stage of development. Myelination is the stage in which neuronal axons are wrapped in fatty tissue for insulation, increasing the speed that impulses travel along the axon.5 As gray matter volume decreases due to synaptic pruning, white matter volume increases due to myelination. It is critical that the appropriate connections in the brain are myelinated, as this process is not easily reversed and alterations can affect developmental outcomes. Disruptions in the myelination process have been associated with numerous neurologic and psychiatric disorders.The processes of pruning and myelination occur in different parts of the brain at different ages and developmental stages.3 The prefrontal cortex, which is the part of the brain associated with the executive functions that support mature decision-making, is one of the last structures to mature.6 The nucleus accumbens functions as part of the reward pathway by receiving input via dopaminergic neurons from the ventral tegmental area and producing gamma-aminobutyric acid as output to the prefrontal cortex. It develops in late childhood/early adolescence and drives behavior toward risk taking and reward seeking while the prefrontal cortex is still maturing, creating a developmental imbalance in adolescence.4 This normal imbalance accounts for the risk-taking behaviors common among teenagers and young adults, and places this group at increased risk for substance misuse.6,7 Almost all substances of misuse, including cannabis, have been shown to increase dopamine levels in the nucleus accumbens by acting on the reward pathway, creating bigger dopamine releases than would be seen otherwise in day-to-day activities.6 Substances that produce a big neurochemical “reward” have a higher addictive potential in the adolescent brain than in the adult brain. This was shown in a study examining the neurobiological development associated with reward-seeking behaviors.8 Further research on cannabis use in adolescents has shown that cannabis use disorder is associated with decreased threat responsiveness9 and reduced expression recognition ability.10The human body has an endocannabinoid system that has a neuromodulatory function: cannabinoid binding depolarizes cells, making them less likely to release either excitatory or inhibitory neurotransmitters into the synapse.11 Anandamide is an endogenous neurotransmitter that binds to cannabinoid receptors in the brain. The endocannabinoid system plays a major role in guiding neuronal connections and pruning during brain development. Tetrahydrocannabinol (THC) is structurally similar to anandamide; however, THC has a significantly larger affinity for the CB1 receptor.12 THC is more likely to bind to the CB1 receptor when both molecules are present, and it stays bound longer than the endogenous ligand. Cannabis use that exposes the brain to THC thus can interfere with normal brain growth and development.
Clinical Outcomes
Substance use exposes the adolescent brain to harmful exogenous substances during active periods of development. During acute intoxication, cannabis negatively affects cognitive performance domains, including memory, attention and concentration, coordination, and reaction time.13 Cannabis use in adolescence is associated with increased odds of poor school performance, including not completing high school, not attending college, and not obtaining a degree.14 Adolescent cannabis use was found to be a better marker of poor educational outcomes than adolescent alcohol use. Several studies have found associations between cannabis use and impaired driving performance.13 Chronic cannabis use is associated with impaired driving performance with increased speed, lateral movements, and accidents, and reduced rule following, even when drivers are not acutely intoxicated.15 Greater driving impairment was particularly seen in those with early-onset use of cannabis before age 16 years. Extensive literature has documented associations between cannabis use in adolescence and diminished life satisfaction and achievement, including poorer educational outcomes, negative impact on work commitment, and financial instability.16, 17, 18 Cannabis use is associated with memory impairment in a dose-dependent fashion,19 suggesting causation. Even after controlling for the extent of exposure to cannabis, initiation of cannabis use at a younger age is associated with a greater degree of memory impairment, including poorer recall of words, rate of learning, and retention and retrieval of information. A longitudinal study in New Zealand that followed up >1000 participants from age 13 to 38 years found a significant relationship between cannabis use disorders and change in IQ scores, with participants reporting the heaviest cannabis use experiencing a 6 point drop in IQ over time.20 Among participants who initiated cannabis use during adolescence, later abstinence from cannabis did not fully restore neuropsychological functioning. Another long-term adverse outcome associated with early substance use initiation includes an elevated risk of developing substance use disorders.6 For example, a retrospective study of >8000 adults with a history of cannabis use found that those who initiated use before age 14 years were 4 times more likely to have a cannabis use disorder compared with those who initiated after age 21 years.21 Similarly, a twin study found that participants who initiated cannabis use before 17 years of age were significantly more likely to use other substances and develop a substance use disorder than their twin who did not use cannabis during adolescence.22 Use of cannabis in adolescence is significantly associated with use of other substances.23The associations between cannabis use during adolescence and mental health disorders, including depression, anxiety,24,25 and psychotic disorders,26 are well established. Cannabis use during young adulthood is associated with an increased risk of psychotic disorders,27 a relationship which is thought to be causal.28 One longitudinal study found a sixfold increased relative risk of schizophrenia for young adults with heavy cannabis use.29 There is a dose-response effect, with those who use cannabis the most frequently having the greatest risk of a psychotic outcome.30,31 In a study of patients with first-episode psychosis, odds of a psychotic disorder increased 3 times for those using daily cannabis compared with those who never used.32 Cannabis use at a younger age increases the risk of psychosis and is associated with onset of psychosis at a younger age.31 A longitudinal study found that cannabis use before the age of 14 years was a predictor of schizotypal personality disorder symptoms in adulthood.33 There is also evidence that cannabis use during adolescence is frequently associated with subclinical psychotic symptoms. A survey of >500 adolescents presenting for routine primary care found that of those who reported past year cannabis use, 43% reported experiencing at least one psychotic symptom during or right after cannabis use, with 27% reporting hallucinations and 33% reporting paranoia or anxiety.34
Policy
Under the United States Drug Enforcement Administration’s Controlled Substances Act, cannabis is a Schedule I drug, meaning that it has “no currently accepted medical use and a high potential for abuse.”35 Despite the federal prohibition, cannabis has been legalized by some states for “medical” or “recreational” purposes since November 1996 when California passed a landmark medical cannabis law via ballot initiative.36 Since that time, state policies regarding medical use and nonmedical use of cannabis have continued to evolve. As of February 2022, a total of 37 states, the District of Columbia, Guam, Puerto Rico, and the US Virgin Islands allow the “medical use” of cannabis products.37 In addition, 19 states, the District of Columbia, Guam, and the Northern Mariana Islands allow for the retail sale of nonmedical cannabis for adult use. As cannabis legalization for adult use expands, there is concern for an association between parental use of cannabis and age of onset in children. One study found that children of mothers who ever used cannabis initiated cannabis use on average 2 years earlier than children of mothers who never used cannabis.38Adolescents’ perception of risk from cannabis use has decreased over the past decade, with disapproval of trying cannabis also declining1 in association with changing societal attitudes and state laws. The impact of the changing legal landscape on rates of adolescent use is an area of active research, with inconsistent results. Legalization of medical cannabis has been associated with increased initiation of cannabis use in adolescents.39 After legalization of nonmedical cannabis, some studies found an increase in adolescent use of cannabis40, 41, 42, 43 and cannabis use disorders.44 However, results across the literature are inconsistent, with other studies failing to find increased use in adolescents postlegalization.45,46 Due to the methodologic challenges of ecological studies, including the potential for confounding factors, analysis of the impact of legalization on cannabis use is complex and difficult to interpret. Data for young adults have clearly shown an increase in cannabis use postlegalization of nonmedical cannabis.41,47,48 In 2021, cannabis use among young adults reached an all-time high, with 43% reporting past-year cannabis use and 11% reporting daily cannabis use.49The recent changes in state policies have been associated with increased availability of a wide variety of cannabis products. As new products, formulations, and devices that can deliver higher and faster peak doses of THC enter the market, there is an even greater potential for cannabis to have negative clinical impacts on adolescent health. Cannabis concentrates and extracts (products with a high THC concentration) have become increasingly popular, with average THC levels as high as 69%.50 In one study of >47,000 adolescents, 33% of 12th graders reported ever having used cannabis concentrates.51 Exposure to these concentrated cannabis products can lead to significant adverse health outcomes, including intubation or admission to an intensive care unit.52The recent popularity in vaping has contributed to the increase in cannabis use among adolescents. Cannabis vaping is rising among adolescents; from 2013 to 2020, lifetime prevalence of cannabis vaping doubled, and 30-day prevalence of cannabis vaping increased sevenfold.53 Using cannabis via a vaping device can lead to increased exposure to cannabis via delivery of higher concentrations (using dab pens or vaporizers to vape cannabis concentrates).54 Because vaping devices are often discrete, adolescents can more easily hide the devices and use them covertly in situations in which other forms of cannabis would be highly visible. Thus, choosing to use cannabis via a vape can allow an adolescent to use more frequently, including throughout the day while at school. More frequent use of cannabis in addition to vaping highly concentrated cannabis products together lead to significantly higher exposures in adolescents, increasing their risk of potential adverse effects.The continuously changing state-level policies regarding cannabis have created a confusing legal landscape and led to increased unregulated cannabis products, obtained from both legal and illicit markets. Without imposed federal regulations, different states have instituted a wide range of methods for regulation of cannabis products, with varying policies on product safety testing, package label requirements, and regulation of dispensaries.55,56 This confusing lack of oversight has great potential to lead to the increased availability of cannabis products. In addition, as cannabis becomes commercialized, advertisements for cannabis products are increasing to allow companies to promote their business, which is a looming concern given that exposure to cannabis marketing on social media is associated with increased odds of recent cannabis use in adolescents.57
Conclusions
Adolescent brain development is vulnerable to damage from exposure to cannabis. The current complicated landscape regarding the legalization of cannabis, with heterogeneous state-level policies and regulation, has allowed the cannabis marketplace to flourish. Simultaneously, the perceived risk associated with cannabis use has plummeted among adolescents and parents in association with legalization. The long-term impact of these trends is unknown. We recommend a research agenda that endeavors to track the impact of legalized cannabis products on individuals who initiate use as adolescents. In the interim, we recommend common sense policies such as limiting THC concentration in legal products and restricting products such as candies and chocolates that are most appealing to youth.
DECLARATION OF INTEREST
Dr Levy serves as an expert witness on the case against JUUL. Dr Ross has nothing to declare.
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Both authors made substantial contributions to the conception of the manuscript, drafting the article or revising it critically for important intellectual content, and final approval of the version to be submitted.
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Article info
Publication history
Accepted: March 20, 2023
Footnotes
Accepted for publication March 20, 2023.
Identification
DOI: https://doi.org/10.1016/j.clinthera.2023.03.009
Copyright
© 2023 Elsevier Inc.