Cannabis and Intentional Self-injury: a Narrative Review

Observational studies assessing the association of cannabis use with subsequent intentional self-injury have reported mixed findings. Longitudinal studies examining the association of cannabis use with subsequent suicide death are notably rare. Our objective was to review longitudinal studies examining cannabis use and subsequent self-harm, suicide attempt, or suicide death. Few population-based studies have focused on self-harm with considerable variability across studies in how this outcome has been operationalized. Studies assessing the association between cannabis use and suicide attempt are equivocal in their conclusions and heterogenous in terms of samples utilized and assessment of confounding bias. The results of one meta-analysis were suggestive of dose dependency. For suicide death, the findings are inconsistent, and there is reason for concern of selection bias. The existing evidence base on these associations is not yet rigorous enough to allow drawing conclusions on causality. However, cannabis might be seen as an adverse prognostic marker for intentional self-injury.


Introduction
Cannabis use has been associated with adverse psychiatric sequelae such as psychosis [1,2], depression, and anxiety disorders [3, 4, 5•]. Particularly, the association of cannabis use and psychotic disorders is supported by multiple lines of converging evidence [6][7][8][9][10][11][12]. However, the nature of the association between cannabis use and different forms of intentional self-injury, such as suicide, suicide attempts, and non-suicidal self-injury is yet far from clear. Moreover, though the association between cannabis use and suicide attempts have been examined in a considerable number of studies with prospective data [5•, 13••], there is a paucity of knowledge regarding the association of cannabis exposure and other intentional self-injury-related outcomes such as self-harm and suicide [14•, 15]. In this review, intentional self-injury is used as an umbrella term for all self-injurious behaviors even encompassing suicide death. Suicide attempt is defined as an event of intentional self-injury with a preceding intent to die. Self-harm is used to denote self-inflicted injury regardless of preceding intent.
Suicide is among the leading causes of death among young people [16], and self-harm phenomena exert a particularly heavy burden on adolescents and young adults [17,18]. Notably, self-harm requiring medical attention is of importance, as it has been estimated that one of the twentyfive people hospitalized due to intentional self-injury will die by suicide in the following 5 years [19,20]. Thus, identifying potential environmental risk factors for intentional self-injury are an important public health priority.

This article belongs to the Topical Collection on Cannabis
Concerns regarding the possible effects of recent changes in legislation on cannabis use and its adverse sequelae are topical [21,22]. Planning harm reduction measures is thus particularly timely, and knowledge of the mechanisms by which cannabis use is possibly associated with serious adverse outcomes such as intentional self-injury must be furthered to guide these efforts. While a mediating role of cannabis use in complex pathways between psychopathology and self-injury has been suggested, these theories are backed by only limited empirical evidence [23]. First cannabis use has been associated with psychiatric disorders such as psychosis and depression [1, 4, 5•, 24], both of which have been associated with self-harm, suicide attempt, and suicide death [25][26][27]. Moreover, cannabis withdrawal syndrome often presents with depressive mood or anxiety [28]. Thus, it is reasonable to believe that these affective symptoms related to cannabis withdrawal could elevate the risk of intentional self-injury. This theory is backed by findings indicating that risk of suicide attempt is elevated during the same day when cannabis is consumed [29], as withdrawal symptoms may emerge within 24 h of last exposure to cannabis [30]. Also, imaging studies with both experimental and observational designs point to the capacity of cannabis or tetrahydrocannabinol (THC) to induce changes in brain regions of relevance to impulse control [31], and poor impulse control has been associated with self-injurious behaviors [32]. Experimental research indicates that oral ingestion of THC, a partial cannabinoid receptor agonist, may cause suicidal ideation [33]. In the same vein, the cannabinoid receptor 1 antagonist rimonabant was associated with serious psychiatric side effects in a randomized controlled trial with more suicide deaths and suicide attempts observed in the group receiving active treatment than in the placebo group. [34]. Lastly, it has been postulated that human endocannabinoids may play a role in the pathophysiology of suicidal behaviors [35,36]. Taken together, these data suggest that there might be a biological mechanism underlying the association between cannabis use and intentional self-injury.
Previous meta-analyses and systematic reviews have focused mutually exclusively on the association of cannabis use with either suicidal behaviors [5•, 13••, 15, 37] or nonsuicidal self-injury [38•]. In this narrative review, we aim to present the existing evidence base on all forms of intentional self-injury, i.e., self-harm, suicide attempt, and suicide. Moreover, findings of the most recent studies are included [14•, 39•, 40•]. As studies with cross-sectional designs do not allow for accounting for reverse causality, we aim to focus primarily on studies with longitudinal data such as prospective cohort studies and high-quality register-linkage studies. Emphasis is placed on studies with population-based data as opposed to those utilizing at-risk cohorts, as the former are more likely void of selection bias and to yield generalizable results. Importantly, we also review the evidence regarding a dose-response relationship between cannabis use and the subsequent intentional self-injury, as this is one of the key criteria when attempting to infer causality [41]. The findings of relevant meta-analyses are also described.

Method
The search strings described in the meta-analyses by Borges et al. and Escelsior et al. were used to conduct a PubMed search to identify longitudinal studies assessing the association of cannabis use and intentional self-injury [13••, 38]. The search string for suicide and suicide attempt was ("cannabis" OR "marijuana" OR "marihuana") AND ("suicide" OR "suicide attempt" OR "suicide ideation" OR "suicidal" OR "suicidality") [13••]. For self-injurious behaviors, the following search string was utilized ("non-suicidal selfinjury" OR NSSI OR "self-injury" OR "self-injuries" OR "self-injurious" OR "self-harm" OR "self-inflicted violence" OR "self-abuse" OR "wrist-cutting" OR "self-mutilation" OR "enucleation" OR "skin cutting" OR "burning" OR "self-hitting" OR "hair pulling" OR "skin picking" OR "nail-biting" OR "skin scratching" OR "head banging" OR "bruising" OR "self-hitting" OR "biting" OR "woundexcoriation" OR "bone-breaking" OR "face slapping") AND ("cannabi*" OR "delta-9-tetrahydrocannabinol" OR "tetrahydrocannabinol" OR "THC" OR "cannabidiol" OR "CBD" OR "marijuana" OR "hashish") [38]. These searches were conducted from the dates until which the respective meta-analyses had concluded their searches and up to the beginning of May 2022. Also, relevant existing meta-analyses [5•, 13••, 38], systematic reviews [15,37], and recently published important longitudinal studies [40•] assessing these associations were hand-searched to identify additional references to relevant studies with longitudinal designs.

Self-harm
"Self-harm," "deliberate-self harm," and "self-injurious behaviors" have been used almost interchangeably to denote self-injurious behaviors irrespective of preceding objective, i.e., whether or not a preceding intent to die was tied to the event [14•, 17, 31, 34]. Hence, outcomes thus defined do not discern between non-suicidal self-injury and suicide attempt.
In the recent meta-analysis by Escelsior et al. with nine studies available for analysis, cannabis use was associated with subsequent self-injurious behaviors (OR = 2.57; 95% CI 2.03-3.26) [38•]. However, the studies pooled in this analysis were markedly heterogenous as it included two crosssectional studies [43,44], one Mendelian randomization study [45], studies focusing on veterans [46], or individuals with psychiatric disorders [47]. Although the focus of this meta-analysis was on self-injurious behaviors regardless of preceding intent, one study pooled in the meta-analyses had an outcome operationalized as suicide attempt [48].
To our knowledge, there are four adolescent studies examining the association of cannabis use and subsequent self-harm [14•, 17, 40•, 49]. A summary of these studies is presented in the online supplement table of Denissoff et al. [14•]. Two of these are population-based studies [14•, 17], whereas one study focused on adolescents receiving treatment for mood disorders [40•] and another study utilized a cohort of socio-economically deprived adolescents [49]. Also, this association has been examined in one populationbased adult cohort [50].
Moran et al. utilized a school-based cohort of 1809 adolescents with both self-harm and cannabis use during the past 6 months assessed at four time points [17]. Self-harm was defined broadly encompassing even risk-taking. Thus, the cumulative incidence of self-harm by end of adolescence was 8%. Cannabis use during the past 6 months was associated with subsequent self-harm independent of sex, depression or anxiety, cigarette use, high risk-alcohol use, antisocial behavior, and parental divorce (aHR = 1.8; 95% CI 1.0-3.1). However, adolescent cannabis use was not associated with incident self-harm in adulthood in this study.
Fontanella et al. published a large register-linkage study (n = 204 780) focusing on the association of cannabis use disorder (CUD) and subsequent severe self-harm requiring medical attention in adolescents receiving treatment for mood disorders (mean age = 17.2) [40•]. The outcome variable was operationalized as ICD-10 diagnostic codes indicating severe intentional self-injury. With a follow-up of only 1 year, the cumulative incidence of the outcome thus defined was 1%. CUD was found to be associated with subsequent severe self-harm independently of comorbid substance use disorders (SUD), psychiatric comorbidities, age, sex, and ethnicity (aHR 3.28; 95% CI 2.55-4.22).
Denissoff et al. conducted the first population-based cohort study assessing the association of adolescent cannabis use and subsequent severe self-harm requiring medical attention [14•]. The adolescents participating in the Northern Finland 1986 Birth Cohort study were asked information about their substance use including cannabis at age 15/16 years after which they were followed for 18 years (i.e., until age 33 years) with nationwide healthcare registries for ICD-10 codes implying severe intentional selfinjury requiring medical attention. Using this data, lifetime cannabis use by age 15/16 years was associated with subsequent severe self-harm independent of other illicit drug use, frequent alcohol intoxications, parental psychiatric disorders, and psychiatric disorders at baseline (HR 2.06; 95% CI 1.07-3.95).
An inclusive self-harm variable encompassing even "denying oneself a necessity" was utilized in a study by Moller et al. in their population-based study focusing on adults [50]. In this study, two cohorts of adults in their third and fifth decades of life were pooled to examine the antecedents of self-harm. Past year cannabis use was associated with self-harm even after extensive confounder control including use of ecstasy and amphetamines, problem alcohol use, smoking, and several sociodemographic variables (aOR 1.77; 95% CI 1.09-2.87).
In sum, five longitudinal studies on cannabis use and subsequent self-harm [14•, 17, 40•, 49, 50] have been published with four of them [14•, 17, 40•, 50] reporting a significant positive finding. The cannabis exposure variables of these studies vary greatly from lifetime use as a binary variable [14•] to cannabis use disorder [40•]. Even more importantly, outcome variables range from very inclusive definitions of self-harm [17,50] to severe self-harm requiring medical attention [14•, 40•]. We are not aware of studies or metaanalyses focusing on heavy use or high-potency cannabis and subsequent self-harm.

Suicide Attempt
The association of cannabis use and subsequent suicide attempt has been assessed in two meta-analyses: The metaanalysis by Borges et al. (2016) included studies on both adolescent and adult populations with both longitudinal and case-control designs. There, pooled estimates were reported for the associations between cannabis use and suicide attempt (OR = 2.23; 95% CI 1.24-4.00) and heavy cannabis use and subsequent suicide attempt (OR = 3.20; 95% CI 1. 72-5.94). In this meta-analysis, "heavy" cannabis use in the studies available for analysis ranged from monthly [51,52] to daily [53] use. This was also assessed by Gobbi et al. (2019) in their meta-analysis pooling three longitudinal adolescent studies in which an association between adolescent cannabis use and subsequent suicide attempt was reported (OR = 3.46; 95% CI; 1.53-7.84) [5•]. A separate meta-analysis was not reported for heavy cannabis use.
To our knowledge, there are 16 prospective longitudinal studies assessing the association between specifically adolescent cannabis use and subsequent suicide attempt [48,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65], of which eight [48, 53, 55-57, 60, 63, 64] reported a statistically significant association. While there is a lack of consistency in the findings, the studies are also very heterogenous in terms of measurement of suicidal behaviors, sample sizes and characteristics, lengths of follow-up, and covariates controlled for (for a summary, please see online supplement table in Denissoff et al.) [14•]. Notably, four studies focused on special populations such as individuals with suicidal ideation [57], individuals with suicidal ideation or a history of non-suicidal self-harm [48], individuals with a substantial genetic disposition to alcohol use disorders [54], and a sample consisting of participants of African American origin [59]. Furthermore, of the eight studies reporting a significant positive finding, four [48,55,56,60] did not adjust for any other substance use in adolescence.
Most of the few longitudinal studies examining this association in adults have utilized selective samples: A Danish register-linkage study examined the association of cannabis use disorder with suicide attempt in individuals diagnosed with psychiatric disorders and found this association only in patients diagnosed with schizophrenia [66]. A study focusing on people who inject drugs reported a negative finding on an association of cannabis use and suicide attempt. [67]. A cohort study with a sample comprising of African Americans found an association between cannabis and suicide attempt in the male subsample only [68]. Population-based studies are scarce. One large population-based prospective study with a 3-year follow-up using data from the National Epidemiological Survey on Alcoholism and Related Conditions (NESARC) examined the association between cannabis use and "suicidality" with ideation and attempt compressed into a single outcome variable [69]. The analyses were stratified by sex, and a significant positive association was reported for men (aOR = 4.28; 95% CI 1.32-13.28) but not for women (aOR = 0.75 (95% CI 0.28-2.05). When suicide attempt was studied as a separate outcome, the analyses yielded statistically nonsignificant findings for both sexes.
To conclude, longitudinal studies examining adolescent cannabis use and subsequent suicide attempt are inconsistent in their findings and markedly heterogenous in accounting for confounding bias introduced by other substance use. The few longitudinal observational studies assessing this association using adult cohorts have mostly utilized samples from high-risk populations limiting the generalizability of the results. There is some meta-analytic evidence implying a dose-response relationship between cannabis use and suicide attempt [13••].

Suicide
In the meta-analysis by Borges  Six studies have focused on special populations such as adolescents receiving treatment for mood disorders or individuals diagnosed with psychiatric disorders [40•, 66], veterans [74], and patients treated for CUD [71] or other substance use disorders [73]. Lastly one study utilized a cohort of individuals reported by authorities of cannabis possession [72]. The findings have been mixed with five studies reporting a significant positive finding [39•, 66, 71, 72, 74]. Only one study with a suicide death outcome assessed frequency of cannabis use with a multiclass exposure variable [70••]. The sample of this study comprised of males only thus limiting the generalizability of the findings.
Crump et al. conducted a register base study on all 6,947,191 adults in Sweden [39•]. Those diagnosed with SUD, including CUD, were identified from national registries on ICD-10 diagnoses made in clinical practice. After adjusting for age, sex, marital status, education, employment, income, psychiatric, and SUD comorbidities, CUD was associated with subsequent suicide death as compared to the general population (aHR = 3.10, 95% CI 2.42-3.97). In an analysis stratified by sex, the effect sizes for men and women did not differ with statistical significance. While statistical significance was retained for all SUDs including CUD in all fully adjusted multivariable models, opioid and sedative/hypnotic use disorders were associated with the greatest risk of suicide death.
Price et al. conducted the largest population-based prospective cohort study assessing this association [70••]. The sample included all Swedish males aged 18-20 who were conscripted during the year 1969-1970 (n = 50,087). IQ tests were conducted by a psychologist and detailed information on alcohol and drug use gathered at the time of conscription. If a psychiatric disorder was reported by the conscript or suspected by the psychologist, the conscript was referred to a psychiatrist for diagnostic evaluation according to the ICD-8. Lifetime cannabis use at baseline was coded as never, 1-10 times, 11-50 times, and more than 50 times. Lifetime use was studied both as binary variable (yes/no) and as a four-class variable with the aforementioned categories. Lifetime cannabis use at baseline was reported by 10.7% of the participants. During 33 years of follow-up, the cumulative incidences of definite suicides and undetermined deaths were 0.9% and 0.3%, respectively. A crude association was reported for lifetime cannabis use (OR 1.63; 95% CI 1.28-2.07). With the multiclass cannabis variable, an association was seen for those reporting lifetime use of at least 50 times even in crude analysis (OR 3.45; 95% CI 2. 21-5.39). The association of both binary and multiclass cannabis use variables and suicide death attenuated to nonsignificant after extensive confounder control including variables such as smoking more than > 20 cigarettes/day, alcohol consumption of more than 250 g/week, other illicit drug use, and psychiatric disorder at baseline. The study by Denissoff et al. is described in detail in the section on self-harm [14•]. In this birth cohort study with a follow-up of 18 years, the cumulative incidence of suicide was 0.3%. Cannabis use was not associated with suicide even in crude analysis. In univariable screening, the prevalence of lifetime cannabis use did not differ significantly among those who died by suicide and other study participants (13.6% vs 5.7%, p = 0.128).
In conclusion, most observational studies with prospective data examining cannabis use and suicide have focused on at-risk populations (for a summary of these studies, please see Table 1). Of the three population-based studies published thus far [14•, 39•, 70••], only one reported a statistically significant positive association [39•]. Lastly, while it would be important to learn more about the association of frequency of cannabis use and suicide death, most studies examining this association have operationalized the exposure as CUD. This methodological choice precludes dose-response analysis.

Discussion
Key considerations when studying causality include plausibility of the association and complementary lines of evidence, consistency of findings, evidence of dose response, temporality of the association, and issues pertaining to confounding bias [41]. As described in the introduction, theories have been presented regarding putative mechanisms by which cannabis use could be linked to subsequent selfinjurious behaviors [23]. There is limited complementary evidence from experimental studies indicating that orally ingested THC has the capacity to induce suicidal ideation [33], and Mendelian randomization studies on these associations have also been published recently [45,75,76]. However, as described in the previous sections, the findings from longitudinal observational studies examining the association of cannabis use and all forms of intentional self-injury are markedly inconsistent. Furthermore, the variation across studies in the way in which self-harm has been operationalized limits the comparability of the results.
There seems to be limited evidence of a dose-response effect for cannabis use and subsequent suicide attempt [13••] and insufficient such evidence for self-harm or suicide. Notably, the majority of studies examining suicide have examined this association with CUD as a predictor limiting the analyses for dose response [39•, 40•, 71]. When assessing dose response, it should be noted that the potency of cannabis has increased steadily during the last three decades [77], and thus the risks of cannabis consumption today may be higher than, e.g., in 1969-1970, when data on cannabis consumption was gathered in the Swedish conscript cohort study [70••]. Importantly, we are not aware of studies in which the persistence of cannabis use and its effects on subsequent risk of intentional self-injury would have been studied by assessing cannabis use at multiple time points.
Neither have complementary sources of information on cannabis exposure, such as urine screens or hair samples, been utilized in the longitudinal observational studies assessing these associations. Lastly, while the association of highpotency cannabis with other adverse outcomes such as psychotic and affective disorders has been examined in previous literature [78], this exposure has not been studied with respect to subsequent intentional self-injury.
Residual confounding is always a concern in observational studies. Particularly, addressing confounding bias introduced by other substance use is of significance, as polysubstance use is common [79], other illicit drug use and heavy drinking have been found to be associated with suicide attempt [80,81], and opioid and sedative use disorders may predict subsequent suicide more strongly than CUD [39•]. As discussed in the respective section on suicide attempt, a significant proportion of adolescent studies reporting a positive outcome regarding this association failed to adjust any concomitant use of substances other than cananbis [48,55,56,60]. Assessing the confounding effect of psychiatric disorders preceding cannabis use is also crucial, as psychiatric disorders are established risk factors for intentional self-injury [82][83][84], and conversely early psychopathology has been also associated with initiation of cannabis use [85]. Most adolescent studies assessing outcomes related to intentional self-injury have taken to account this source of confounding (see online supplement in Denissoff et al.) [14•]. It may also be that the mechanism by which cannabis use confers risk to subsequent intentional self-injury involves contribution to the onset of psychiatric disorders. Thus, as Carvalho et al. point out, psychiatric disorders emerging after onset of cannabis use may be regarded as mediators rather than confounders of these associations [15]. Lastly, though temporality is not an issue when examining incidental behavior such as intentional self-injury with longitudinal data, previous self-injurious behavior is known to be a particularly strong predictor of future intentional self-injury [19,20]. It is imperative that this source of confounding be addressed by some means in longitudinal observational studies, e.g., by excluding those with previous intentional self-injury from the analyses [14•].
The lack of evidence for a positive association between cannabis use and suicide may be due to the fact that suicide is such a rare outcome, and the pathway leading to death by suicide is notoriously complex and involves a confluence developmental and acquired risk factors as well as acute stressors [86]. A positive finding regarding an association between CUD and subsequent suicide has been reported in only one population-based register-linkage study [39•]. Most importantly the large Swedish conscript cohort study with detailed information on heavy lifetime cannabis exposure and a long follow-up of 33 years reported a negative finding [70••]. Notably, using the same data and a similar multivariable model, a positive association was found between cannabis use and schizophrenia, another rare outcome [87]. Thus, Price et al. concluded that the lack of an association between cannabis use and suicide death was not explained by power issues only and that cannabis use might not in fact be associated with suicide death.

Conclusions
The association of cannabis use and intentional self-injury has frequently been reported in existing literature. However, the existing evidence base is not rigorous enough to draw definite conclusions. Even if cannabis use might not prove to be independently associated with intentional self-injury, it may yet have clinical importance as an adverse prognostic marker for such outcomes. Adequately powered longitudinal population-based studies, with preferably multiple time points of cannabis use assessment are needed to shed further light on these associations. To elucidate a possible dose-response relationship between cannabis use and different forms of subsequent self-harm, studies focusing on high potency cannabis and subsequent self-injury would be an important increment to the existing evidence base. In the same vein, knowledge of THC content of cannabis consumed and even utilization of standard unit doses for THC would serve this purpose as well [88,89]. There is also a need to gain consensus on the definition of self-harm to improve the comparability of the results of future studies. Lastly, studies with within-person analyses may be needed to account for unmeasured confounding and mitigate concerns for type II error [90].
Funding Open Access funding provided by University of Turku (UTU) including Turku University Central Hospital. For this publication, AD has received funding from Juho Vainio Foundation and Yrjö Jahnsson Foundation. For this publication, AM has received funding from Hospital District of South Ostrobothnia, Emil Aaltonen Foundation, Juho Vainio Foundation, and Finnish Foundation for Alcohol Studies.
The funders had no role in the design of the publication; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Thus, the authors do not have existing conflicts of interest.
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