Long-Term Outcomes of Adolescent THC Exposure on Translational Cognitive Measures in Adulthood in an Animal Model and Computational Assessment of Human Data

Abstract

ImportanceAlthough perceived as relatively harmless and nonaddictive, adolescent cannabis use significantly increases the likelihood of developing cannabis use disorder in adulthood, especially for high-potency cannabis. Risky decision-making is associated with chronic cannabis use, but given confounds of human studies, it remains unclear whether adolescent cannabis exposure and Δ9-tetrahydrocannabinol (THC) potency specifically predicts risky decision-making or influences cognitive response to the drug later in life.ObjectiveTo leverage a human data set of cannabis users and a rat model to evaluate the long-term outcomes of adolescent THC exposure on adult decision-making and impulse control.Design, Setting, and ParticipantsThis translational rat study tested the link between adolescent THC exposure and adulthood decision-making. A reanalysis of a previously published dataset of human chronic cannabis users was conducted to evaluate decision-making phenotypes. Computational modeling assessed the human and animal results in a single framework. Data were collected from 2017 to 2020 and analyzed from 2020 to 2022.Main Outcomes and MeasuresDecision-making was measured by the Iowa Gambling Task (IGT) and Rat Gambling Task (rGT). Impulse control was assessed in the rat model. Computational modeling was used to determine reward and punishment learning rates and learning strategy used by cannabis users and THC-exposed rats. Cell-specific molecular measures were conducted in the prefrontal cortex and amygdala.ResultsOf 37 participants, 24 (65%) were male, and the mean (SD) age was 33.0 (8.3) years. Chronic cannabis users (n = 22; mean [SE] IGT score, −5.182 [1.262]) showed disadvantageous decision-making compared with controls (n = 15; mean [SE] IGT score, 7.133 [2.687]; Cohen d = 1.436). Risky choice was associated with increased reward learning (mean [SE] IGT score: cannabis user, 0.170 [0.018]; control, 0.046 [0.008]; Cohen d = 1.895) and a strategy favoring exploration vs long-term gains (mean [SE] IGT score: cannabis user, 0.088 [0.012]; control, 0.020 [0.002]; Cohen d = 2.218). Rats exposed to high-dose THC but not low-dose THC during adolescence also showed increased risky decision-making (mean [SE] rGT score: vehicle, 46.17 [7.02]; low-dose THC, 69.45 [6.01]; high-dose THC, 21.97 [11.98]; Cohen d = 0.433) and elevated reward learning rates (mean [SE] rGT score: vehicle, 0.17 [0.01]; low-dose THC, 0.10 [0.01]; high-dose THC, 0.24 [0.06]; Cohen d = 1.541) during task acquisition. These animals were also uniquely susceptible to increased cognitive impairments after reexposure to THC in adulthood, which was correlated with even greater reward learning (r = −0.525; P < .001) and a shift in strategy (r = 0.502; P < .001), similar to results seen in human cannabis users. Molecular studies revealed that adolescent THC dose differentially affected cannabinoid-1 receptor messenger RNA expression in the prelimbic cortex and basolateral amygdala in a layer- and cell-specific manner. Further, astrocyte glial fibrillary acidic protein messenger RNA expression associated with cognitive deficits apparent with adult THC reexposure.Conclusions and RelevanceIn this translational study, high-dose adolescent THC exposure was associated with cognitive vulnerability in adulthood, especially with THC re-exposure. These data also suggest a link between astrocytes and cognition that altogether provides important insights regarding the neurobiological genesis of risky cannabis use that may help promote prevention and treatment efforts.

Propensity for risky choices despite lower cue reactivity in adolescent rats

“…Meanwhile, human epidemiological studies have shown that age of exposure to gambling is related to the later probability and severity of pathological gambling ( Rahman et al, 2012 ; Dowling et al, 2017 ). Moreover, a substantial body of literature shows that adolescent drug use in rodents – especially exposure to alcohol or THC – is related to later maladaptive risky decision-making ( Nasrallah et al, 2009 ; Clark et al, 2012 ; McMurray et al, 2016 ; Ferland et al, 2023 ). Because problem gambling and substance disorders share overlapping neural substrates ( Hynes et al, 2021 ), it is possible that early exposure to gambling and early exposure to drugs of abuse might result in similar changes in adult risk-taking behavior.…”

Nondisordered Cannabis Use Among US Adolescents

“…Cannabis use is associated with deficits in cognitive and executive functioning, including processing speed, sustained attention, working memory, judgment and planning, problem-solving, decision-making, and self-regulation . Adverse mental health outcomes, including increased rates of depression and suicidal behaviors, have also been associated with youth cannabis use .…”

“…Cannabis use is associated with deficits in cognitive and executive functioning, including processing speed, sustained attention, working memory, judgment and planning, problem-solving, decision-making, and self-regulation. 3 , 4 , 5 , 6 Adverse mental health outcomes, including increased rates of depression and suicidal behaviors, have also been associated with youth cannabis use. 7 , 8 , 9 Well-controlled longitudinal epidemiologic studies have demonstrated that adolescent cannabis exposure is associated with a 4-fold increase in adult psychosis diagnoses.…”

THC exposure during adolescence increases impulsivity-like behavior in adulthood in a WIN 55,212-2 self-administration mouse model

“…However, the consequences of early-life cannabis use are still poorly understood. Recent evidence indicates that early exposure to 9 -tetrahydrocannabinol (THC), the primary psychotropic constituent of cannabis, produces changes in the structure and function of brain circuits implicated in decisionmaking and cognitive processes (3). However, whether such changes might be long-lasting and persistently disrupt healthy behaviors remains unknown.…”