Cannabis use in adolescents and anxiety symptoms and disorders: a systematic review and meta-analysis

ABSTRACT

Background: The use of cannabis is highly prevalent during adolescence compared to the general adult population. In addition to the high comorbidity between cannabis use and anxiety disorders, early evidence suggests that cannabis may precede the development of anxiety. Moreover, adolescence represents a major developmental period for both neurobiological and psychological processes, placing these individuals at a heightened vulnerability to the influence of cannabis.

Objectives: This systematic review and meta-analysis examined the prospective associations between adolescent cannabis use and subsequent anxiety outcomes (i.e. anxiety disorders and/or symptoms).

Methods: Following PRISMA guidelines, a systematic review and meta-analysis were conducted encompassing data from articles published between database inception and September 2022.

Results: Six longitudinal studies were identified for quantitative analysis, while twelve non-overlapping longitudinal studies were identified for qualitative review (total N = 18; 33380 subjects). Meta-analytical findings supported an association between adolescent cannabis use and the development of a subsequent anxiety disorder (Odds Ratio = 2.14, 95% CI: 1.37–3.36, p < .01). These findings were consistent with our qualitative synthesis where nine of the twelve longitudinal studies observed a significant relationship between adolescent cannabis use and exacerbation of anxiety symptoms later in life, irrespective of an anxiety disorder diagnosis.

Discussion: In summary, the current evidence suggests a prospective association between adolescent cannabis use and later anxiety symptoms and disorders. These findings underscore the importance of refining research methodologies, considering sex-based differences and controlling for confounding factors, as well as implementing educational initiatives and developing clinical interventions to address the mental health risks associated with cannabis use among adolescents.

KEYWORDS:

• Adolescents
• anxiety disorders
• cannabis
• child development

Introduction

The relationship between cannabis use and anxiety remains complex. Across epidemiological studies, both acute and chronic cannabis use is associated with elevated rates of comorbid anxiety disorders, with studies demonstrating dose-dependent relationships between frequency of use and severity of symptoms (1–5). This finding has been replicated among adolescent populations, where significant cross-sectional associations between cannabis use and presence of an anxiety disorder have been observed (6,7). Nonetheless, discrepancies exist concerning the self-reported effects of cannabis, which range from exacerbation of anxiety symptoms to anxiety-related symptom relief. These varying effects may be dependent on multiple factors, including variability among user profiles, the specific cannabis preparation, and the method of administration (1,4,8).

To better understand the complex relationship between cannabis use and anxiety, it is crucial to understand the pharmacological properties of cannabis and the human endocannabinoid system. The endocannabinoid system consists of cannabinoid type 1 and 2 (CB1 and CB2) receptors, located predominantly in the cerebellum, hippocampus, mesolimbic dopamine systems, and prefrontal cortex, in addition to endocannabinoids, which are endogenous compounds that activate these receptors (9). Endocannabinoids, such as anandamide, primarily influence CB1 receptors pre-synaptically, which modulates other neurotransmitter systems, including GABA, glutamate, serotonin, and the endogenous opioid peptide system (10–12). Accordingly, the endocannabinoid system is essential for the regulation of numerous physiological and psychological processes, including mood, stress reactivity, and emotion regulation (12–14). Delta-9-tetrahydrocannabinol (THC), a partial agonist of CB1 and CB2 receptors, and cannabidiol (CBD), a weak, partial agonist of CB1 and CB2 receptors, are the two primary exogenous cannabinoids found in Cannabis Indica or Sativa. THC is associated with the “high” that users experience and produces anxiogenic effects, whereas CBD is non-psychoactive and has been associated with therapeutic effects, including anxiety relief (4,15–17).

In adolescent populations, the neurobiological effect of cannabis is particularly complex. During adolescence, the endocannabinoid system supports normal neurodevelopmental processes, such as synaptic pruning and white matter development (18). Therefore, these processes may be especially susceptible to the effects of exogenous cannabis administration (18). Adolescent cannabis use has been associated with subsequent adverse outcomes, including the development of a mental health or substance use disorder and reduced socioeconomic outcomes (19). With respect to the relationship between anxiety and adolescent cannabis use, a smaller body of literature has explored these associations. Nonetheless, there is intriguing preliminary evidence that early cannabis use is associated with the development of anxiety, which persists after controlling for relevant confounding factors, including presence of another psychiatric illness, concurrent substance use, and parental relationships (20–24).

Since the onset of cannabis use is particularly high among adolescents in comparison to the adult population, it is important to understand whether the relationship between adolescent cannabis use and subsequent anxiety symptoms and/or disorders are clinically significant. In 2017, for example, past-year rates of cannabis use in Canada were approximately 43% in individuals 16 to 24 years (25), compared to 18% in individuals over 25 years (26). To date, we are aware of two meta-analyses investigating the relationship between cannabis use and the development of anxiety. Following adolescents until young adulthood, Gobbi et al. (27), observed a non-significant association between cannabis use and subsequent anxiety symptoms. However, the conclusions drawn by the authors may be limited by the small sample size of included studies, with only three publications meeting the authors’ inclusion criteria. A more recent systematic review and meta-analysis by Xue et al. (28) detected a significant relationship between cannabis use and risk of developing a subsequent anxiety disorder. However, this review focused on cannabis use within the general population, and, consequently, could not evaluate the window of risk during adolescence.

In tandem with a growing interest among the scientific and healthcare community in elucidating the effects of cannabis use during adolescence, numerous longitudinal studies have been published within the last decade. Investigation of cannabis use in adolescence is imperative due to the vulnerable developmental state of the adolescent brain. Moreover, with increasing recreational cannabis legalization, there is a concern that cannabis use in adolescents and young adults may be rising (29). Accurately unraveling the relationship between cannabis use in adolescence and anxiety is vital for identifying potential public health implications and devising effective intervention strategies to safeguard the mental health and well-being of this vulnerable population. Therefore, we conducted a systematic review and meta-analysis that combines qualitative and quantitative approaches to comprehensively summarize and update the existing literature on adolescent cannabis use and its relationship with anxiety, a term, for the purpose of this investigation, encompassing the presence of anxiety symptoms, regardless of a formal anxiety disorder diagnosis.

Methods

Search strategy

Using Cochrane Library, PsycINFO, PubMed, MEDLINE, EMBASE and CINAHL databases, original, peer-reviewed research articles were searched for based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISM-A) guidelines (see Figure 1 and Figure A1 for the search process) (30). Articles published in the English language from database inception to September 2022 were considered. Search terms were used in three groups and included: cannabis, marijuana, cannabinoids (group 1) AND anxiety, generalized anxiety disorder, social anxiety disorder (group 2) AND adolescents, children, young adults (group 3). All MeSH terms were included within the search.

Figure 1. PRISM-A flowchart.

Inclusion and exclusion criteria

Following the PICOS framework (31), we defined the populations, interventions, comparisons, outcomes, and study designs of interest prior to conducting our literature search. Studies were included in our meta-analytical review if the following criteria were satisfied – population (P): individuals in early (13–16 years old) or late (17–19 years old) adolescence without a physical or mental health disorder at baseline; intervention (I): adolescent cannabis use; comparison (C): studies including a control group of adolescents without cannabis exposure; (O); general or social anxiety symptoms as assessed through a validated measurement tool (e.g., scores from the Beck Anxiety Inventory) or diagnosis of an anxiety disorder; and study design (S): studies employing a prospective design. We selected prospective studies to ensure greater confidence in elucidating the temporal relationship between exposure and our outcome variable (32). Titles and abstracts were reviewed by two independent coders (DJEL and MS) to identify studies meeting inclusion criteria. Discrepancies were resolved through discussion until consensus was attained.

Data extraction

Two authors (DJEL and MS) extracted study characteristics, including country of data source, author information, year of data collection, length and frequency of follow-ups, and baseline sample characteristics. Information on how cannabis use, anxiety symptoms, and anxiety disorders were assessed by the original investigators were extracted (e.g., questionnaire, diagnostic tool, single-item question). For our main outcome of anxiety, corresponding authors were contacted if data could not be extracted in a usable form from the original publication.

Risk of bias

The Newcastle-Ottawa Scale (NOS) (Table A1) was used to assess the quality of studies included in this review (33). The NOS evaluates observational studies on a scale from 0 to 9 based on three main criteria: (1) selection of cases and controls (e.g., adequate definition, representativeness, and selection of cases); (2) comparability of cases and controls (e.g., adequate controlling or adjustment for confounding variables); and (3) ascertainment of exposure (e.g., adequate assurance that the cases were exposed to the variable of interest). Quality assessment thresholds for the Newcastle-Ottawa Scales are based upon the Agency for Healthcare Research and Quality (AHRQ). To maximize data for this review, no studies were excluded due to low methodological quality.

Data analysis

Using RevMan 5.3, a random-effects meta-analysis was conducted to investigate the relationship between adolescent cannabis use and subsequent anxiety disorders. Odds ratios were calculated for dichotomous data and heterogeneity was assessed using the I² statistic. Respective cutoff-values of 25%, 50%, and 75% denoted whether heterogeneity was low, moderate, or high (34). Publication bias for included studies was assessed using funnel plots. Sensitivity analyses were performed excluding studies that did not control for other substance use as a potential confound.

Results

Study characteristics and quality assessment

A total of 746 papers were identified from the initial database search results (Figure 1). After removing duplicates, 626 studies remained. Articles were then independently screened by the first and second authors with 570 exclusions; 56 articles were read in full and assessed for eligibility. A further 38 articles were excluded, leaving 18 studies included for qualitative or quantitative synthesis.

Characteristics of the 18 included studies are presented in Table 1. These studies were epidemiological in their approach, and included sample sizes ranging from 250 to 6,325, with a total of 34,622 participants. Follow-up periods ranged from 1 to 20 years. Cannabis use was predominantly assessed via self-report Likert scale ratings, and the outcome (i.e., anxiety) was primarily measured using diagnostic criteria.

Table 1. Study characteristics.

Authors	Year		Sample	Ages	Design	CU Measure	AX Measure	Main Findings
Meta-Analysis (N = 6; 12549 subjects)
Fergusson et al.	1996		N = 927	Baseline = birth (0 years) Final = 16 years	18-wave follow-up: at birth, 4 months old, 1 year old, and annually from ages 1 to 16	Categorical Self-Report (user versus non-user)	DISC, DIS and DSM-II-R	Cannabis use onset before or at age 15 was associated with elevated odds of development of an anxiety disorder at age 16, but when controlling for confounding factors (e.g., school dropout, police contact, etc.), the odds became nonsignificant.
Windle et al.	2004		N = 1,205	Baseline average = 15.54 years Final average = 23.5 years	5-wave follow-up: every 6 months (waves 1 to 4), and 5 years (wave 5)	Scaled Self-Report (never used to daily use)	WHO-CIDI	Cannabis use at ages 15 or 17 did not increase the odds ratio of developing an anxiety disorder in young adulthood.
Zvolensky et al.	2008		N = 1,709	Baseline average = 16.6 years Final average = 24.2 years	3 timepoints: one year later and ~6 years later	Categorical Self-Report (user versus non-user) K-SADS (<18) LIFE (18+)	K-SADS (<18) LIFE (18+)	Cannabis dependence from ages 14 to 18 was associated with an increased odds of developing panic attacks and disorder one year later.
Hengartner et al.	2020		N = 591	Baseline average = 19 to 20 years Final average = 50 years	8-wave follow-up over 30 years	Self-report (user or non-user, age of first use, number of times used)	DSM-III	Cannabis use during adolescence was not associated with an elevated risk of a subsequent diagnosis of an anxiety disorder at any point in adulthood.
Chan et al.	2021		N = 1,792	Baseline average = 14.9 years Final average = 35.1 years	10-wave follow-up: every 6 months (waves 1 to 6), and every 4 years (waves 7 to 10)	Scaled Self-Report (never used to daily)	CIDI Short Form	Adolescent-onset cannabis users reported higher levels of concurrent anxiety symptoms; however, this was not observed in adulthood.
Mustonen et al.	2021		N = 6,325	Baseline = 15 to 16 years Final = 33 years	Single follow-up from baseline to age 33	Scaled Self-report (never to regularly used cannabis)	ICD-10	Cannabis use in adolescence was associated with an increased risk of symptoms of anxiety in adulthood.
Qualitative Review (N = 12; 20831 subjects)
Brook et al.		1998	N = 975	Baseline average: 1 to 10 years old Final average: 22.05 years	3 timepoints: at average ages of 13.69, 16.30, 22.05	Scaled Self-Report (never used to daily use)	DISC-1 (DSM-III-R); data from mothers and adolescents	Adolescent cannabis use did not have a statistically significant relationship with diagnosis of an anxiety disorder in young adulthood.
McGee et al.		2000	N = 900	Baseline average = 13 and 15 years Final average = 21 years	3 timepoints: at average ages of 15, 18 and 21 (+ an initial assessment at age 13)	Scaled Self-Report (never used to daily use) Illegal Activity Assessment (frequency of use) DIS (dependence)	DISC-C (<18) DIS (18+)	Adolescent cannabis use at ages 15 and 18 was not predictive of later anxiety symptoms at ages 18 or 21.
Patton et al.		2002	N = 1,601	Baseline = 14 and 15 years Final = 20 and 21 years	7-wave follow-up; every 6 months (wave 1–6), with a final follow-up at an average age of 20–21 (7 wave)	Scaled Self-Report (never used to daily use)	CIS-R (computerized version)	Female adolescent cannabis users had 1.9X the risk and male adolescent users had 0.47X the risk for anxiety/depression in adulthood.
Hayatbakhsh et al.		2007	N = 3,329	Baseline = birth (0 years) Final = 21 years	3 timepoints: at ages 5, 14, and 21. (0 –> 21) (+ mothers were interviewed 3–5 days after birth, and again 6 months later)	Scaled Self-Report (never used to daily use)	YSR – DSMIIIR (14) YASR (21)	Adolescents who reported cannabis use were more likely to report symptoms of anxiety at age 21. If age of cannabis use onset was before 15, the risk became greater.
Degenhardt et al.		2013	N = 1,756	Baseline average = 14.9 years Final average = 29 years	9-wave follow-up; Waves 1 to 6 spanned across ages 14.9 to 17.4, and waves 7 to 9 across ages 20.7 to 29	<18 years: Scaled Self-Report (never used to daily use) 18+ years: Scaled Self-Report (never used to daily use) & CIDI	CIS-R (<18) CIDI-Short Form (18+)	Daily cannabis users in adolescence had 2.3X odds of anxiety disorder in adulthood. Weekly cannabis use in adolescence was associated with a 2X greater risk for anxiety disorder in adulthood, especially if cannabis use continued at 29 years.
Gage et al.		2014	N = 4,561	Baseline = 16 years Final = 18 years	2 timepoints: at ages 16 and 18	Scaled Self-Report (times used: 0, 1–20, 21–60 or 60+ times)	Computerized CIS-R	Cannabis use at age 16 did not increase the odds of developing anxiety at 18 after controlling for confounding factors.
Guttmannova et al.		2017	N = 808	Baseline = 10 years Final = 33 years	12-wave follow-up; annual assessments until grade 10, one in grade 12, and every 3 years until the age of 33	Scaled Self-Report (never used to daily use) DIS Short Form (DSM-IV)	DIS Short Form (DSM-IV)	Regular cannabis users in adolescence reported more symptoms of generalized anxiety disorder in adulthood if cannabis use persisted into adulthood.
Otten et al.		2017	N = 1,424	Baseline average = 13 years Final average = 18 years	5-wave follow-up; yearly assessments	Scaled Self-Report (past 12-month use)	YSR	Cannabis use in adolescence was associated with symptoms of anxiety in young adulthood, but only in carriers of the short allele of the 5-HTTLPR genotype.
Duperrouzel et al.		2018	N = 250	Baseline average = 14 to 17 years Final average = 15 to 18 years	2 timepoints: participants followed for one year	Drug Use History Questionnaire	Short version of the DASS 21	Adolescents exhibiting higher initial levels of cannabis use displayed more persisting self-reported anxiety across time.
Meier et al.		2020	N = 506	Baseline average = 13.4 years Final average = 26 years	Longitudinal assessments every 6 months from ages 15 to 16, and yearly from ages 17 to 26.	Self-Report SUQ	YSR	Cumulative years prior of weekly cannabis use were associated with increases in anxiety symptoms in young adulthood. Each additional year of prior weekly cannabis use was associated with a small increase in anxiety symptoms.
London-Nadeau et al.		2021	N = 1,548	Baseline = 13 years Final = 17 years	Individuals were assessed at ages 13, 15 and 17.	Scaled Self-Report (never used to daily use)	Child Behaviour Checklist (13 years) MIA (15 &17 years)	Cannabis use at 13 and 15 predicted anxiety symptoms at 15 and 17, respectively.
Duncan et al.		2021	N = 3,173	Baseline = 13 years Final = 18 years	Rolling cohorts were analyzed yearly from ages 13 to 18.	Scaled Self-Report (never used to daily use)	7-item GAD7	The study found that increasing to at least weekly cannabis use within a 1-year period was associated with increased anxiety symptoms.

CUD, Cannabis use disorder; DISC, Diagnostic Interview Schedule for Children; DIS, Diagnostic Interview Schedule; CIS, Clinical Interview Schedule; CIDI, Composite International Diagnostic Interview; WHO, World Health Organization; YASR, Young Adult Self-Report; YSR, Youth Self-Report for adolescents; K-SADS, Schedule for Affective Disorders and Schizophrenia for School-Age Children; LIFE, Longitudinal Interval Follow-Up Evaluation; DSM, Diagnostic Statistical Manual; SCID, Structured Clinical Interview for DSM; NP, Non-patient version; GHQ, General Health Questionnaire; DUHQ, Drug Use History Questionnaire; DASS, Depression, Anxiety, Stress Scale; SCL-90, Symptoms Checklist 90-R.

The overall quality of the 18 included studies are presented in Appendix Table A1. The majority of studies demonstrated high methodological quality. The most common methodological limitation observed among studies consisted of either inadequacy of assessment or ascertainment of cannabis use or anxiety.

Meta-analytical findings

Six longitudinal studies were combined in a meta-analysis to determine whether adolescent cannabis use predicted subsequent diagnosis of an anxiety disorder (including panic disorder) and/or increased anxiety symptoms (pooled N = 11,636) (35–40). In comparison to adolescents reporting no cannabis use at baseline, adolescents reporting cannabis use were significantly more likely to be diagnosed with a subsequent anxiety disorder at follow-up (OR = 2.14, 95% CI: 1.37–3.36, p < .01, I² = 83% Figure 2). Results from a sensitivity analysis restricted to studies controlling for comorbid substance use led to the exclusion of one publication, and produced similar results (pooled n = 1,016, SMD = 2.38, 95% CI = 1.34–4.20, p < .01, I² = 85%) suggesting the findings were robust. To assess publication bias, we found that the funnel plot was symmetrical, and Egger’s test showed no significant publication bias among the included studies (Figure 3).

Figure 2. Forest plot demonstrating pooled odds ratio of developing any anxiety disorder with adolescent cannabis use.

Figure 3. Funnel plot of the six included studies reporting the odds of developing an anxiety disorder.

Qualitative findings

An additional twelve prospective studies were identified; however, data were unextractable and, therefore, could not be included in the meta-analysis. Of these publications, nine studies observed a significant, longitudinal association between adolescent cannabis use and later symptoms of anxiety (20–22,41–43). Of these, eight studies reported an increased likelihood of anxiety symptoms (21,22,42–47), while one study reported an increased likelihood of an anxiety disorder diagnosis (20). In a recent study examining the relationship between cannabis and depression and anxiety symptoms at ages 13, 15, and 17, London-Nadeau et al. (45) found cannabis use at age 13 predicted subsequent anxiety symptoms at both timepoints. Furthermore, the authors did not detect a reverse relationship, where baseline anxiety symptoms predicted subsequent cannabis use. Similarly, Duperrouzel et al. (47) observed a significant relationship between cannabis use in early adolescence and subsequent levels of anxiety. In a sample of 250 adolescents between the ages of 14–17, individuals who reported cannabis use at a younger age reported greater levels of anxiety at the one-year follow-up than those who reported cannabis use in older adolescence. In a recent publication examining symptoms of generalized anxiety disorder over a 1-year period, Duncan et al. (46) found that at least weekly cannabis use predicted subsequent anxiety symptoms in a sample of Canadian adolescents between 14–18 years of age. Furthermore, increasing cannabis use was associated with increased anxiety at follow-up, while decreasing use improved anxiety symptoms. Following a large sample of adolescents annually for five years, Otten et al. (43) investigated the relationship between cannabis use, anxiety, and the serotonin transporter gene (5-HTTLPR) (48). Polymorphisms in the promotor region of 5-HTTLPR are involved in the regulation of post-synaptic actions of the monoamine neurotransmitter serotonin, which plays a significant role in the pathophysiology of mood and anxiety disorders (49). The authors found that cannabis use was longitudinally associated with increased anxious symptoms, but only in individuals carrying the short allele of the HTTLPR genotype.

Six prospective studies following adolescents until young or middle adulthood observed a significant relationship between adolescent cannabis use and elevated levels of anxiety (20–22,41–47). Meier et al. (44) observed that increases in weekly cannabis use and continuing cannabis use throughout adolescence in a sample of boys dose-dependently predicted symptoms of anxiety and depression 10 years later. Evidence of reverse causation was not observed, and this relationship held even after controlling for relevant confounds, including baseline demographics, baseline mood and anxiety symptoms, and other substance use. Patton et al. (22) found that over a 7-year period, any cannabis use was not predictive of subsequent anxiety in male adolescents, but did elevate the risk of anxiety for females. However, across both sexes, weekly or daily cannabis use at baseline predicted subsequent anxiety in young adulthood.

In contrast, three prospective studies did not observe a significant, longitudinal association between cannabis use and increased levels of anxiety (6,50,51). Of these, two studies found no increased likelihood of anxiety symptoms (6,51), while one study found no increased likelihood of an anxiety disorder diagnosis (50). In one study examining the relationship between alcohol, cigarette, cannabis, and illicit substance use on subsequent depressive and anxiety disorders in 975 adolescents, after controlling for relevant confounders, cannabis use did not increase risk of developing a depressive or anxious disorder at follow-up (50). Similarly, McGee et al. (6) observed that adolescent cannabis use at the ages of 15 or 18 was not significantly associated with development of any internalizing disorder at ages 18 or 21, respectively. Rather, cannabis use was associated with an increased risk of externalizing disorders, while daily cigarette use elevated the risk of an anxiety or depressive disorder. More recently, a longitudinal study following a birth cohort of UK children, found that after adjustment for pre-birth and childhood confounders, adolescent cannabis use was not associated with anxiety in adolescence (52). However, there was a strong association between cannabis and elevated risk of developing depression.

Discussion

Findings from our systematic review and meta-analysis suggest an association between adolescent cannabis use and later anxiety symptoms and disorders. Our qualitative analysis revealed a consistent pattern pointing toward a relationship between cannabis consumption during adolescence and subsequent anxiety, a trend that is corroborated by our meta-analytical synthesis of eligible studies. Our findings provide compelling support for the association between adolescent cannabis use and the heightened risk of anxiety in later years. Quantitatively, adolescents (N = 11,636) who reported cannabis use were more likely to develop a subsequent anxiety disorder in later adolescence or adulthood, which persisted after controlling for comorbid substance use (SMD = 2.38, 95% CI = 1.34–4.20, p < .01). This was a consistent, significant finding which remained robust after controlling for possible early influential factors, such as parental psychiatric disorders, baseline emotional and behavioral problems (40). However, contradictory findings did arise. For example, Hengartner et al. (38) observed a non-significant relationship between adolescent cannabis use and later anxiety disorders. In contrast, the authors observed a significant relationship between adolescent cannabis use and later depression and suicidality in adulthood, with greater effects occurring in early-onset users (i.e., before the age of 17) and frequent users. The obtained qualitative findings parallel the meta-analytical results, where nine out of twelve studies reported a significant, longitudinal association between adolescent cannabis use and later anxiety (20–22,41–43).

Anxiety disorders are a highly prevalent and debilitating psychiatric disorders associated with elevated physical and psychiatric morbidities among those impacted. While the causes of anxiety disorders are complex and multifactorial, this meta-analysis and review suggests that cannabis exposure may be a contributing factor to later anxiety. During adolescence, maturational brain changes, namely myelination and synaptic pruning proceed well into middle adulthood (18). These processes are linked to efficient neural processing and disruptions related to neurotoxic effects of chronic cannabis use may significantly alter typical neurodevelopmental trajectories. Indeed, a recent review of preclinical and clinical neurobiological studies revealed adolescent cannabis users as demonstrating functional and structural neural alterations than matched controls (53). The alterations were more pronounced among adolescents who consumed cannabis at more frequent doses or reported an earlier age of onset. Moreover, the authors’ obtained findings in adolescent cannabis users were paralleled preclinically, in which experimental studies of adolescent animals exposed to CB1 receptor agonists, including THC, demonstrated significant, persisting neurobiological changes than matched controls.

Some general limitations regarding our systematic review and meta-analysis should be noted. First, the measurements of anxiety and cannabis use were highly variable (e.g., self-report, diagnostic interviews, and urine toxicology) with heterogeneity insofar the operational definitions of such constructs. Cannabis use was primarily measured by self-report, with substantial variation in assessments of frequency of use. For example, some studies assessed cannabis use dichotomously (yes/no), while others provided multiple options to evaluate frequency of use. Dichotomous assessments of cannabis use may complicate assessments of the relationships between cannabis use and anxiety, as many of the studies included within our review suggested a dose-dependent relationship between frequency of cannabis use and subsequent symptoms of anxiety (21,44,47). Moreover, there was heterogeneity across studies in defining anxiety, with some studies focusing on anxiety disorders, while others assessing anxiety symptoms more broadly, including social anxiety, panic attacks, and generalized anxiety symptoms. A further limitation concerns the lack of studies assessing THC/CBD ratios in cannabis use, despite a significant body of literature indicating differential effects of THC and CBD on anxiety, including anxiogenic and anxiolytic responses (5,54,55). Given that frequency and quantity of use play a substantial role within the relationship between cannabis and anxiety, future studies may benefit from conducting more rigorous investigations of such variables, including biochemical verification of THC levels through urine or plasma testing. Similarly, with the legal landscape of cannabis availability changing, a growing body of evidence indicates that forms of cannabis use methods are changing, which may impact cannabis use patterns and subsequent behavioral outcomes in youth (56). Thus, assessing cannabis administration methods and its relationship to use patterns in future studies is also of importance. Withdrawal alleviation should also be considered in future studies depending on the characteristics of use, as withdrawal of cannabis may influence the presentation of anxiety symptoms (57). Finally, across the included studies there were no analyses conducted on the variation in impact of cannabis use disorder based on various demographic and socioeconomic variables, such as sexual orientation, gender identity (e.g., LGBTQ+ community), racial/ethnic identity (e.g., minority ethnic groups), or socioeconomic status. This is a critical limitation, as variable consumption patterns and subsequent influence in these specific subgroups has been demonstrated (58–60). These subgroups have been shown to disproportionally experience symptoms of stress and anxiety (61,62), further substantiating the need for this focus. Moreover, the amalgamation of data from countries with diverse cultural backgrounds and varying response rates may introduce a potential for selection bias, as these factors may impact the generalizability of findings.

Conclusions

In summary, this review offers robust epidemiologically evidence to support a prospective connection between adolescent cannabis use and anxiety. Future longitudinal research that clinically assesses participants more rigorously, such as quantitatively assessing THC/CBD ratios and specific categorization of various anxiety disorders and symptoms, is warranted to better characterize the effects of cannabis use during adolescent development. Moreover, studies should investigate sex differences in outcomes, because while only one of the included studies conducted such an analysis, findings were significant, where females demonstrated poorer outcomes than males at follow-up (22). Finally, as psychosocial variables such as socioeconomic status, parental-child relationships, and other substance use are known to influence anxiety-related outcomes, it is imperative that future research controls for such variables at baseline to elucidate the relationship more clearly between cannabis use and subsequent anxiety. Furthermore, it is also important to understand the potential impact of premorbid anxiety on adolescents’ initial cannabis use. With cannabis becoming increasingly available due to shifts within the legal landscape, there is a significant need to implement effective initiatives educating adolescents on the mental health risks associated with cannabis use.

Disclosure statement

MS and DL have no competing interests. Dr. George has received consulting fees from Roche, Frutarom, Aelis and Sanford Burnham Prebys. He also serves as Co-Principal Editor, Neuropsychopharmacology (NPP).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/00952990.2023.2299922

Additional information

Funding

This study was supported in part by NIDA grant R21-DA-043949, CIHR [PJT-190053] and the CAMH Foundation [to Dr. George].