Our search resulted in 1482 studies once duplicates were excluded (see Fig. 1). 1263 studies were excluded after reviewing the abstracts. 198 studies were excluded after reviewing the full text. After this process, 21 rodent (N = 15) and human (N = 6) studies were included in our final qualitative review. The characteristics of the final studies are detailed in Tables 1 and 2. In addition to all standard reporting practices according to PRISMA , we also listed the qualitative description of the effect sizes in the studies and evaluated the quality of evidence for human work based on our own objective criteria. We included this information in Table 1.
All authors independently reviewed and rated the quality of human evidence: (1) strong level of causality: longitudinal studies with a comparison of adolescent and adult values and that included relevant covariates; (2) moderate level of causality: studies that were longitudinal with a comparison of adolescent and adult values without accounting for relevant covariates or cross-sectional human studies with matched adult and adolescent groups that considered relevant covariates; (3) weak level of causality: studies that were cross-sectional but did not have matched adolescent and adult groups and/or did not consider relevant covariates. Notably, we did not rate the quality of rodent work. Given the enhanced experimental control, the quality was very similar (and strong) across rodent studies. In the discussion, we did provide an overview of the limitations that reduce the generalizability of the rodent work overall.
Human studies on cannabis and cognition
Human studies explored the role of age on the relationship between some form of cannabis use history (e.g., dependence/amount past use) and cognition or alternatively, on the relationship between cannabis intoxication and cognition. These two types of studies are discussed separately below.
Age, history of repeated cannabis exposure, and cognition
Four human studies assessing the relationship between history of repeated cannabis exposure and cognition met our inclusion criteria (see Table 1 for study characteristics). Meier et al.  investigated participants over the course of 33 years and were interested in the persistence of cannabis dependence (total number of times a cannabis dependence diagnosis was met across 5 study waves; 1, 2, or 3 +) by age of first diagnosis (before age 18 and after age 18) on change in intelligence quotient (IQ). Past year cannabis dependence was assessed through a diagnostic interview at age 18, 21, 26, 32 and 38, and IQ was assessed before and after the initiation of cannabis use at age 7, 9, 11, 13 and 38 (Wechsler Intelligence Scale for Children-Revised or for Adults-IV). There were no effects of age of first diagnosis on change in IQ (i.e., post-cannabis IQ minus average IQ before cannabis initiation) with only 1 or 2 diagnoses of cannabis dependence. However, individuals that had a dependence diagnosis at 3 or more waves and that met their first diagnosis before age 18 experienced a 0.55 standard deviation reduction in IQ compared to those that had a first diagnosis after age 18. Meier et al.  repeated this analysis using weekly cannabis use (instead of diagnosis of dependence) before or after age 18 on change in IQ and results were similar .
Like Meier et al. , three separate studies found age-related cognitive vulnerabilities in adolescents but only for heavier cannabis users. More specifically, Scott et al.  administered the Penn Computerized Neurocognitive Battery to almost daily and daily cannabis users (~ 3–7 times per week) and discovered that adolescents (i.e., ages 14–17) compared to adults (i.e., ages 18–21) exhibited lower executive control, consisting of sustained attention and working memory subtests, in comparison to the non-user control group. However, this age-related deficit did not extend to weekly cannabis users (1–2 times per week or less) when compared to the non-user group. Additionally, there was no age by cannabis effect on other cognitive domains, including memory (i.e., verbal episodic, face, and spatial episodic memory), complex cognition (i.e., mental flexibility, language reasoning, nonverbal reasoning, and visuospatial ability), or social cognition (i.e., emotion identification, emotion differentiation, and age differentiation). However, weekly cannabis users, but not almost daily or daily users, performed better than non-users in executive control, memory, and social cognition, suggesting a potential positive effect for weekly cannabis users regardless of age .
Lee et al.  discovered that adolescents, compared to adults, in outpatient therapy for CUDs showed a smaller reduction in bias toward immediate, smaller cannabis and monetary rewards from pre to post treatment, as measured by a delay discounting task. Adolescents and adults both showed decreased reductions in bias towards cannabis compared to money from pre to post treatment, suggesting no age-related differences in delay discounting based on the type of reward presented. These results suggest that adolescents with CUDs, compared to adults, exhibit less positive change in impulsive responding to cannabis and money from pre to post-treatment . Lastly, although not one of their central questions, Albertella et al.  cross-sectional study analyzed the effect of continuous age (15–24 years old) by cannabis use frequency, defined as less than once a week or more than once a week over the past 6 months, on the ability to detect relevant targets amongst distracting stimuli in a location-based negative priming task. There was no main effect of age on negative priming. However, there was an interaction between age and cannabis use frequency such that weekly younger users showed lower negative priming scores, or lower accuracy in detecting relevant targets amongst distracting stimuli, compared to weekly older users. This effect did not extend to monthly users, suggesting compromised inhibitory control in younger, weekly users specifically .
We categorized these four studies as only meeting a weak-to-moderate level of causality. Additionally, we assessed the strength of the significant age by cannabis interactions with the reported standardized beta coefficients or z-scores. The effects were small (0.20 or less) for Scott et al. , small to medium (between 0.20 and 0.50) for Albertella et al. , and medium to large (between 0.50 and 0.80) for Meier et al. .
Meier et al.  study was classified as a moderate level of causality. The analyses were between-subject, and thus, it could be that other variables not accounted for are associated with adolescent-onset cannabis dependence and the time-varying effect of IQ . For instance, two commentaries concluded that the effect could be accounted for by a simulation model of the confound, socioeconomic status , and by personality traits . These arguments were later rebutted by a commentary from the original authors, who showed that effects replicated when only looking at subjects in the middle socioeconomic class and after accounting for self-control . However, since the age-related analyses are based on a between subject factor, the study was not classified as having a strong level of causality. Scott et al.  study was classified as a moderate level of causality as well. Their effects were robust beyond numerous confounds, including socioeconomic status. However, given the cross-sectional nature, it is impossible to determine if the observed deficits were pre-existing .
Lee et al.  study was classified as weak level of causality. Adolescents showed a smaller decrease in bias toward immediate cannabis-related and monetary rewards from pre to post treatment. These results could indicate poorer cognitive recovery in adolescents. If true, it is surprising given that adults used twice the amount of cannabis than adolescents in their sample (22.2 days for adults vs. 10.7 days for adolescents; ). Alternatively, though, it may mean that adolescents are resistant and unmotivated to therapy in general. Adolescents are rarely self-referred to treatment for CUDs. Moreover, it has been shown that motivation, pre-treatment expectations of positive change, and therapist–client relationship account for most of the variance in client outcomes, with actual treatment modality only accounting for 1% of the variance in symptom reduction [36, 37]. Additionally, it could also be that adolescents may have reached a developmental ceiling for delay discounting with treatment, and therefore, could not reach the same level of reduction in delay discounting as adults. This is in line with literature suggesting that adolescent controls, compared to adult controls, displayed higher rates of delay discounting to money . Without control groups for adolescents and adults within their investigation, it is impossible to determine how age-matched peers without CUDs would perform in delay discounting tasks. Along with these issues of interpretation, we also classified the quality of the evidence for causality as weak due to several methodological issues. Specifically, the unmatched groups regarding past cannabis use (22.2 days of cannabis use per month for adults, 10.7 for adolescents), motivation or expectancy for therapy, gender (88% male for adolescent, 55% male for adults), and group size (N = 165 for adolescents, N = 104 for adults), as well as the use of different treatment modalities across groups all limited the study’s evidence of causality. Similarly, Albertella et al.  study was classified as weak evidence for causality because (sub)acute effects of cannabis intoxication might have confounded the findings as 37% of the weekly and 3% of the less than weekly users used cannabis within the past 24 h.
Overall, these four studies suggest that adolescent weekly to daily cannabis users experience greater reductions in general executive functions like working-memory and attention, which may in turn affect cognitive tasks that rely on these functions. The effect in one study seems to extend to IQ in individuals with persistent cannabis dependence (diagnosis at 3 or more study waves) with a first diagnosis before age 18. This further supports the hypothesis that age-related deficits in executive functioning and Full-Scale IQ are probably most noticeable in the most heavy and problematic cannabis users. However, it is unclear if these age-related deficits would extend beyond a prolonged abstinence period. Specifically, none of these studies had a standardized abstinence period. Therefore, intoxication levels during the cognitive assessment might vary between participants within studies as well as between studies. For the studies of Scott et al.  and Lee et al. , it is unclear whether (sub)acute effects of intoxication could have affected the results, as no measure of recent cannabis use was included. Meier et al.  and Albertella et al.  did assess past 24-h cannabis use and took this into account in part of their analyses. Meier et al.  showed that their main results did not change significantly after exclusion of past 24-h cannabis users. Albertella et al.  showed that across all participants, past 24-h cannabis use was not a significant predictor of their main outcomes measure, negative priming, but did not take into account the existing group difference in past 24 h use. Given this confound, the limited amount of studies, and the strength and quality of evidence, results should be considered preliminary.
Age, cannabis intoxication, and cognition
Two human studies, that met our inclusion criteria (see Table 1 for study characteristics), conducted studies on the effects of cannabis intoxication in current adolescent and adult cannabis users. Notably, only one of these studies  had a standardized abstinence period, although it was only 24 h and was not biologically verified. Mokrysz et al.  administered both vaporized cannabis (12% THC) and a placebo control, in separate sessions, to a matched sample of 20 male adolescents (16–17 years old; mean of 10.58 days of cannabis use per month) versus 20 male adults (24–28 years old; mean of 7.94 days of cannabis use per month). Interestingly, adolescents showed signs of both risk and resilience. Adolescents showed less memory impairments, both immediate and delayed. That is, adults showed twice as large of a reduction in delayed prose recall following intoxication, compared to placebo, as well as lower immediate prose recall than adolescents. Moreover, adolescents did not show a difference in reaction time to a spatial N-back working memory task during intoxication compared to placebo; whereas, adults were significantly slower during cannabis intoxication compared to placebo. There were no age-related differences for spatial N-Back accuracy. Lastly, adults reported significantly higher cognitive disorganization and significantly lower alertness on a visual analogue scale while intoxicated than adolescents.
In contrast to the working memory findings, adolescents showed heightened risk for craving (measured by a visual analogue scale) and accuracy, but not reaction time, in an inhibitory control task (measured by a stop signal task). Specifically, pre- to post-intoxication craving increased in adolescents but decreased in adults. Moreover, adults’ inhibitory control score was unaffected by cannabis; whereas, adolescents showed reduced inhibitory control accuracy when intoxicated . In a partial replication of Mokrysz et al. , Padovano et al.  conducted an Ecological Momentary Assessment in cannabis users, aged 15–24 years old, who averaged roughly 21 days of cannabis use per month and 0.65 g per use day. The researchers tracked participants across 14 days and administered craving and alertness measures via a wireless device that delivered several prompts each day. Researchers then categorized their assessments as during non-use days, before cannabis use, or after cannabis use . In line with Mokrysz et al.  age was negatively associated with change in alertness post-cannabis use, such that younger individuals were more alert relative to older individuals. This effect did not extend to sedation. Unlike Mokrysz et al. , there was no effect of age on craving from pre- to post-cannabis use.
We rated both studies as moderate evidence of causality, given the sound experimental design and control of confounding variables. The strength of the effects for Padovano et al.  were small (less than 0.20), as determined by the presented standardized beta coefficients. For Mokrysz et al. , the strength of the effects were medium (0.20–0.50) for alertness, immediate/delay prose recall, reaction time to the N-back task, and inhibitory control accuracy and were small (less than 0.20) for craving, as determined by the presented eta-squared values. Given Mokrysz et al.  finding of reduced cognitive impairment post-intoxication in adolescents, one could hypothesize that this would be beneficial to negative outcomes of acute intoxication (e.g., risky driving) as well as long-term cognition. Therefore, this resilience effect of cannabis on adolescents’ cognition when intoxicated contradicts the risk effects observed in non-intoxicated cannabis users. However, Mokrysz et al.  finding for inhibitory control is consistent with the studies reviewed above. This suggests that age effects may vary based on intoxication state and discrepancies may only appear for certain cognitive functions.
In addition, the observed effects of age on craving conflict; however, this could be due to methodological differences across the two studies. Specifically, Mokrysz et al.  treated age dichotomously (adolescents vs. adults), whereas Padovano et al.  treated age continuously. Furthermore, the cannabis users in Padovano et al.  sample exhibited two times higher frequency of cannabis use than Mokrysz et al.  sample. These methodological influences may have had more of an impact in their discrepant findings particularly because the effect for craving was small in Mokrysz et al.  study.
Overall, the results of these two studies of current cannabis users under acute cannabis intoxication appear to contradict each other for craving but not alertness. Additionally, except for the inhibitory control outcome, Mokrysz et al.  findings on cognition differed from included human studies that did not incorporate acute intoxication. It is possible that age intersects with acute intoxication differently, thereby leading to distinct patterns with cognitive outcomes compared to non-acute intoxication investigations.
Animal studies on cannabis and cognition
Across animal work, researchers typically expose rodents to daily cannabinoid injections, including tetrahydrocannabinol (THC), the main compound in natural cannabis, or synthetic cannabis. The reviewed THC administration studies are most relevant to the human studies described above, of which none considered the use of synthetic cannabinoids. Findings for synthetic cannabinoid administration studies do not necessarily directly translate to the effects of natural and synthetic cannabinoids in humans. However, such studies are important because they provide insight into synthetic cannabinoids, which are studied very minimally in human work. Animal studies that tested cognition in repeatedly exposed rodents during THC intoxication are most comparable to human studies that tested cognition post-cannabis intoxication (see [39, 40]). Rodent studies that tested cognition in repeatedly exposed rodents after prolonged abstinence are most comparable to human studies that tested abstinent cannabis users . In terms of the translation of rodents to human development, rats and mice have similar developmental periods  and are considered ~ 10–18-years-old during post-natal day 25–42 (i.e., adolescence) and 18–25-year-old during post-natal day 43–65 (i.e., emerging adulthood; ). Given the fast development, it is common for researchers to only administer THC or synthetic cannabis for 5 days, which is roughly comparable to 6 months of daily exposure in humans .
Researchers studying rodents use a variety of measures designed to match human cognitive functions. In Fig. 2, we present a more in-depth description of the tasks used across the included rodent studies and what domain of cognition they target. Fifteen rodent studies met our inclusion criteria (see Table 2 for study characteristics), of which five administered THC and ten administered a synthetic cannabinoid. Across studies, half of the rodents at each development period were administered the active cannabinoid and half were administered a vehicle control. Synthetic cannabinoid studies used compounds such as CP 55,940 (CP), WIN 55212-2 (WIN), and HU210 (HU). All these compounds interact with both Cannabinoid (CB) 1 and CB2 receptors, like the main active ingredient in natural cannabis (i.e., THC), but are significantly more potent [44, 45]. All included animal studies used rodents and neurocognitive assessments were performed during acute intoxication or after prolonged abstinence. The results of these studies are discussed separately below.
Age, repeated cannabinoid exposure, and cognition after prolonged abstinence
Three experiments explored the effect of repeated THC exposure on learning and/or memory after prolonged abstinence. To investigate the effects on spatial and non-spatial learning through the Morris Water Maze, Cha et al.  administered 2.5 mg/kg THC or 10.0 mg/kg THC to male Sprague Dawley rats for 21 days (1 injection per day)  and then, extended their design to a mixed-gender sample . For both of their experiments, the authors did not provide statistics for their age by cannabis treatment interaction, despite proposing it in their statistical analyses. However, there were no main effects of cannabis treatment (THC vs. control) on spatial and non-spatial learning in adolescents or adults across both studies [46, 47]. Kasten et al.  administered 10 mg/kg THC or control vehicle to male B6 and D2 mice across 24 days (1 injection every 72 h) and found no evidence of age-related differences on object recognition, as measured by the Novel Object Recognition test, following repeated THC administration and a 4-week washout period. No overall main effect of treatment emerged across the age groups .
Four experiments investigated age-related differences of the effect of synthetic cannabinoid exposure after prolonged abstinence. To investigate working memory, O’Shea et al.  administered different dosages of CP to female Wistar rats for 21 days (1 injection per day). After 21 days of abstinence, there was no age by cannabis treatment effect or main effect of treatment on working memory across age groups, as measured by the Novel Object Recognition Task . In a follow-up study, O’Shea et al.  repeated the same protocol in male Wistar rats with a 28-day abstinence period. CP reduced working memory in both adolescents and adult CP-treated rats compared to vehicle, but like their study in females, age did not moderate the effect of CP on working memory .
Gleason et al.  investigated the effect of WIN administration (3- to 5-day exposure and 10-day exposure) on cued and contextual fear conditioning and sensorimotor gating in adult and adolescent C57BL6 mice. After prolonged abstinence, there was an age by cannabis treatment effect in the 10-day exposure group only. Specifically, adolescent mice showed increased reductions in sensorimotor gating (a measure of attentional abnormalities) and cued and contextual fear-conditioning, while no impairments were found in adult mice . Lastly, Bambico et al.  administered WIN to male Sprague–Dawley for 20 days to investigate its effects on the firing rates of serotonergic and noradrenergic activity in dorsal raphe neurons and locus coeruleus neurons (areas involved in appetitive and aversive information processing; see [52, 53]). After a 20-day washout, they observed a moderating effect of age on serotonergic activity in the dorsal raphe but not on noradrenergic activity in the locus coeruleus. Specifically, adolescents experienced a significantly greater reduction in serotonergic activity in the dorsal raphe compared to adults. While there was no significant interaction for noradrenergic activity, main effects suggested that adolescents, not adults, experienced significant enhancement in noradrenergic firing rates in a dose-dependent manner following cannabis exposure .
Following prolonged abstinence, the THC and synthetic studies suggest that age does not moderate the effects of THC on memory. Additionally, for spatial and non-spatial learning, THC, relative to control, does not affect spatial learning or non-spatial learning in adolescent and adults after prolonged abstinence. It is unclear if age changes this relationship, as interaction effects were inconclusive. There appeared to be a different pattern for neural and behavioral outcomes more closely linked with emotional processes (i.e., fear conditioning and appetitive and aversive information processing), with adolescents showing increased neural and behavioral reductions if exposed to synthetic cannabis. It is unclear if this extends to natural THC, after prolonged abstinence, as this was not explored.
Age, repeated cannabinoid exposure, and cognition during intoxication
Seven experiments explored the effect of 5-day THC exposure without a prolonged abstinence (minimal or no wash-out) period on learning and/or memory. Behavioral testing occurred 30 min after each injection, except for Moore et al.  who exposed rats to THC for 5 days, and then, administered behavioral testing on days 6 and day 10, 30 minutes after each THC injection.
For spatial and non-spatial learning (Morris Water Maze), Cha et al.  administered 2.5 mg/kg THC, 10.0 mg/kg THC, or control vehicle to male Sprague Dawley rats in one experiment (experiment 1) and then administered 5.0 mg/kg in another experiment (experiment 2) with a different sample of male Sprague Dawley rats . In experiment 1, adolescents showed a greater reduction in spatial and non-spatial learning than adults at both dosages, despite no significant differences between adult and adolescent rats who received vehicle injection. For experiment 2, results for the interaction were inconclusive as statistical results were not presented. Cha et al.  extended their design in a mixed-gender sample of Sprague Dawley rats across two experiments; in experiment 1, they administered only one dosage of THC and in experiment 3, they administered three dosages of THC . In experiment 1, there was a significant moderation of cannabis treatment by age with adolescent rats showing reduced spatial learning compared to adults. However, there was no age by dosage (2.5 mg/kg, 5.0 mg/kg, and 10 mg/kg) interaction on spatial learning in the third experiment, suggesting that effects of age on spatial learning are insensitive to THC potency.
In male Sprague Dawley rats, Moore et al.  observed that adults pre-treated with THC (5-day THC exposure) showed decreased reductions in spatial learning (Morris Water Maze) on day 6 and 10 after acute intoxication than treatment-matched adolescents. It remains inconclusive if the effects extend to neural mechanisms (e.g., CB1 hippocampal distribution) underlying this behavioral deficit. The interaction was a proposed analysis in their statistical section, but the result was not presented . Nonetheless, this suggests that the age effects of 5-day THC exposure on learning remain evident up to 10 days.
Schramm-Sapyta et al.  were interested in whether there are age-related differences in another type of learning—aversive responses to low and high potency of THC. Notably, THC was not paired with an aversive stimulus, but rather was investigated alone as it is thought to have aversive effects at high dosages (5 mg/kg). The researchers administered 0.5 mg/kg, 5 mg/kg, or control vehicle for 5 days to male Sprague Dawley rats. There was a moderating effect of age on conditioned place aversion (cannabis treatment or vehicle control treatment paired with specific locations). Specifically, adolescent and adults both showed greater place aversion after 5 mg/kg THC administration, relative to control rats, but THC-treated adults spent less time in the drug-associated place than THC-treated adolescents, indicating greater place aversion in adults. There were no age-related differences for the lower dosage. Both age groups showed an increase in taste aversion when treated with THC at both dosages following saccharin, relative to vehicle, but there was a null effect for age by treatment on taste aversion . Additionally, in a separate study of B6 and D2 male mice, there was no main effect of THC treatment on object recognition, measured by the Novel Object Recognition task, across both age groups, and there was a null effect for age by treatment on object recognition .
Overall, adolescents appear to be more vulnerable to learning impairment but not memory decline following THC exposure with minimal to no abstinence period. Additionally, it may be that adolescents experience reduced aversive responses to THC, thereby reducing the conditioning effects to neutral cues (i.e., place; as shown in Schramm-Sapyta et al.  work). This would indicate that repeated exposure to THC without an abstinence period decreases general learning and increases drug-specific learning for cannabis’ positive effects in adolescents at high dosages, compared to adults.
Six studies explored the effect of synthetic cannabinoid exposure without prolonged abstinence, two of which focused on behavior and four of which focused on neuronal changes. Acheson et al.  investigated the effect of WIN exposure on spatial memory in adolescent and adult male Sprague Dawley rats. WIN did not affect spatial memory and there was no age by cannabis interaction effect. Fox et al.  investigated novelty seeking in male Sprague–Dawley rats 30 min after WIN exposure. There was no main effect of treatment or an interaction of treatment by age on novelty-seeking behavior, regardless of exposure length (1 or 7 days; ). The results of these two studies suggest that there is no behaviorally measurable impact of acute WIN intoxication on spatial memory and novelty-seeking regardless of age.
To connect behavioral differences to brain changes, Carvalho et al.  exposed male Sprague Dawley rats to WIN for 14 days with a 24-h abstinence period and then measured conditioned place aversion (a behavioral measurement of aversive learning) and neuronal morphology (the shape and structure of neuronal components). Changes in the shape of dendrites were evaluated in the nucleus accumbens and the prefrontal cortex. Only cannabinoid exposed adult rat brains demonstrated increased dendritic length in the medial prefrontal cortex. However, age did not significantly moderate the treatment effect, indicating changes at the neuronal level did not differ between the adult and the adolescent brain. No conclusions could be drawn for any discrepancies in aversion, as authors did not present the results of the interaction analysis .
Three studies investigated the effects of synthetic cannabinoids on neuronal activity in the brains of rats after acute intoxication with mixed results. Klugman et al.  measured changes in the level of NMDA receptors (subunits NR1 and NR2b) and Homer protein levels in male Wistar rats. Both are involved in synaptic plasticity and are important for processes such as learning and memory at the cellular level. In both the striatum and medial prefrontal cortex of WIN treated rats, they found a differential effect of age on treatment with an increase in the NR1 subunit in adolescents but a decrease in adults. They also observed a slight reduction in levels of the NR2 subunit in the medial prefrontal cortex, but they did not report the result of the age by treatment interaction. Homer protein levels were also significantly more elevated in adolescents compared to adults . Verdurand et al.  investigated the effect of synthetic cannabinoid HU210 on GABAA receptor density—the chief inhibitory compound of the brain—after exposure for 1, 4, or 14 days. They observed higher density of GABAA receptors in the brains of 4-day treated rats than the 14-day treated rats. However, there was no differential impact of age group . Kang-Park et al.  applied WIN to brain slices of Sprague Dawley rats and measured inhibitory and excitatory activity of neurons in the hippocampal CA1 region. Although acute intoxication with WIN significantly decreased the excitatory activity in both adolescent and adult rats, there was not a differential effect on adults and adolescents. However, WIN-treated adolescents experienced a greater reduction in inhibitory activity than adults. Reduced inhibition of inhibitory neurotransmission can be understood as increased sensitivity to exogenous cannabinoid-mediated effects at the neuronal level . Overall, all three studies found some evidence for a differential impact of synthetic cannabinoids on neuronal activity based on age.