User-individuals, however, showed greater regional volumes in the left putamen, lingual cortex, and rostral middle frontal cortex. There were no differences in cognitive performance indicators, suggesting minimal impact on brain structure and function . Adverse impacts of cannabis use in older-age PWUC may be influenced by or arise from interactions with independently existing age-related deficits. For example, cannabis-related impairment of cognitive and executive functions and reaction/memory may amplify age-related declines in these abilities . Furthermore, slowed metabolism/liver function and interactions with commonly used psychotropic medications may increase cannabis-related intoxication and impairment, and thereby magnify the risks of falls and injuries, including as related to driving and crash involvement . A recent, large-scale US-based case-control relative risk study found no overall association between cannabis use and risk of MVC involvement; however, significant interaction effects between age and THC emerged at age 64, resulting in significantly increasing risk of crash involvement for older THC-exposed drivers . There is some evidence of declines in lung function associated with cannabis smoking and potentially elevated risk of cardiovascular problems in older-age PWUC . Some of these older age-specific risks may be attenuated by the use of low-potency cannabis, titration of doses, and other intake precautions.

Individuals with combinations of the risk factors identified above are likely to be at markedly elevated risk of experiencing cannabis related adverse health outcomes. The combination of greatest concern is the high-frequency use of high-potency cannabis products, especially when initiated at and sustained from a young age. This pattern predicts increased risks of multiple adverse mental and physical outcomes, including neuro-cognitive, greenhouse benches psychosis and cardiovascular problems . An analysis of a sample of patients with first-episode-psychosis found that those who continued daily use of high-potency cannabis had an increased risk of relapse , shorter time-to-relapse , and required more psychiatric care after the initial episode . Similarly, adolescent-aged individuals with high-potency cannabis use were more likely to engage in daily use and report cannabis-related problems and anxiety disorders than lower-risk controls . In a systematic review, adolescent cannabis use increased the risk for psychosis ; this association was significantly moderated by age of onset and frequent cannabis use, concurrent use of other substances, and genetic risks, among other factors . As noted above, the evidence is mixed on whether an early age of-onset independently increases the risks of major adverse outcomes. It may be that individuals who report early age of onset of use more often engage in intensive cannabis use, commonly involving higher potency cannabis, that adversely affects their developmental and physiological vulnerabilities and increases their risks of neuro-cognitive impairment, poor mental health, and cannabis dependence.

A systematic review, however, found stronger evidence for the role of cannabis use intensity and potency than age-of-onset in predicting psychosis outcomes . Studies of brain structure and functioning and neurocognitive impairments in young individuals with cannabis use found deficits associated with frequency of use and possibly the potency of cannabis used.Elsewhere it has been emphasized that the earlier the onset of use and the more intensive the use, the greater the risk of adverse health and psychosocial outcomes later in life . Notably, while cannabis use was generally associated with MDD among US adolescents, individuals reporting frequent use had a significantly lower prevalence of lifetime and past year MDD than those with less frequent use . Other risk-combinations that may be relevant are understudied. For example, sex, age-of-onset and mode of use have shown associations with cannabis-related problem severity among different populations of PWUC, and their combination may differentially contribute to risk for adverse health outcomes . Combined use of cannabis with alcohol and/or tobacco increases the risk of acute and chronic adverse outcomes, such as dependence, cardiovascular problems , and potential neonatal deficits related to use during pregnancy . Similarly, frequent cannabis use among adolescents/young adults predicts an increased risk of alcohol use disorder, nicotine dependence, and CUD in mid-adulthood .While cannabis control regimes are liberalizing in many settings, evidence on the adverse health outcomes of cannabis use and related risk factors has substantially grown, but findings are mixed for some outcomes. Systematic reviews and seminal studies have expanded and enhanced the knowledge bases related to some of the earlier findings, and so allow for the strengthening of confidence in the LRCUG recommendations on risk factors and ways to reduce adverse outcomes from use.

The evidence has suggested some important additions and refinements. Notably, the role of ‘early-age-onset’ as an independent determinant of adverse outcomes has become less clear, particularly with regards to neuro-cognitive effects. Current evidence suggests increased importance of frequency of use and the potency of cannabis used, the adverse impacts of which may increase if cannabis use is also initiated at a young age . There are other major areas where evidence gaps or limitations remain. For example, comprehensive evidence is lacking on the comparative health risks of the increasingly diversified routes of cannabis administration. There is also no robust evidence to quantify thresholds for cannabis potency or THC/CBD ratios that may allow consumers to reliably reduce risks of adverse outcomes. The same is true of recommendations for driving-related risks. These require qualifications in light of the multiple factors that influence impairment. There is a need to define and quantify cannabis use in multi-factorial ways that ideally take account of the frequency, amount, and potency of cannabis used for measuring the ‘magnitude’ of use. Overall evidence on direct and causal associations between cannabis use and – much-debated – adverse outcomes, for example, mental health or reproductive harms, are limited or mixed. There is minimal evidence on the risk of cannabis use among older-aged PWUC, a growing group of user-individuals especially in settings that have liberalized cannabis use. All of these limitations add to the complexity of defining and guiding individuals to adopt ‘lower-risk’ patterns of cannabis use as clearly as possible while not being overly precise or pretending to universality . While a basic start has been made on defining cannabis consumption units , we are currently unable to quantify ‘risk-thresholds’ for harms in the way that has been done for ‘low-risk drinking’. This reflects the complexity of cannabis as a pharmacological product and of the factors influencing risks, the legal status of cannabis, the marked heterogeneity and limitations of operational definitions of use, and the limited quality of data on adverse outcomes from cannabis use . For these reasons, the present LRCUG explicitly focus on ‘lower risk’ cannabis use, and the recommendations are mostly qualitative rather than quantitative.

It should be a principal future aim of cannabis health research to generate the evidence needed to define threshold levels for at least the major adverse outcomes associated with cannabis use . While most cannabis use involvement occurs without major consequential problems, substantive sub-groups – an estimated 25 to 30% of PWUC – experience adverse outcomes that substantially burden cannabis-related public health outcomes . In summary, current evidence suggests that a substantial extent of the principal long-term adverse health effects of cannabis use can be reduced, considering the main individual risk factors, if: the initiation of use is delayed until after puberty; the frequency of use is ‘occasional’ rather than frequent ; THC-potency of cannabis used is kept low; and use occurs in ways other than smoking. These recommendations need to be qualified for persons with increased pre-existing risks for select adverse outcomes. It deserves note that possible acute harms of cannabis use, such as injury or even death occur infrequently but may arise from singluse episodes .The LRCUG require some important qualifications. First, they have been developed chiefly for non-medical cannabis use . This differs from the use of or exposure to cannabinoids that is mainly for medicinal reasons, for which there is good evidence of therapeutic benefit for selected conditions . Survey data suggest that as many as two in five PWUC report their consumption to be for medical purposes, although this includes extensive self-medication practices , whereas rates of prescribed medical cannabis use are much lower . In the case of PWUC for medical purposes, some of the LRCUG recommendations may conflict with therapeutic use needs or practices, while some risks for harm identified may still apply and so should be considered. Second, PWUC can only act on some of the LRCUG recommendations if there are legal markets and complementary regulatory provisions that aim and aid to reduce risks, such as labelling of THC-strength and other product composition and availability restrictions . Other recommendations are based solely on scientific evidence and geared towards improving health outcomes regardless of applicable laws or regulations for use, such as those concerning age-of-onset and driving under the influence of cannabis use . Third, a considerable number of PWUC, and especially those with frequent use over long periods of time may meet at least some criteria of CUD, characterized by craving, withdrawal symptoms, compulsive use,growers equipment and neglect of obligations . Recent estimates suggest that 60-80% of cannabis is consumed by 10-20% of individuals with high-frequency use, many of whom likely meet criteria for CUD . It is unrealistic to expect these user-individuals to be helped principally by information-based behavior change advice such as the LRCUG.

Neither are the LRCUG intended as a diagnostic tool for CUD, but they may allow some PWUC to recognize the presence of problems related to their cannabis use. It is crucial for PWUC experiencing persistent severe problems associated with their use, including potential CUD symptoms to seek professional assessment and assistance, which may need to include treatment . Fourth, the principal objective of the LRCUG is to reduce adverse effects on the health of users rather than the social or legal outcomes for users or their adverse effects on the health and welfare of others. Nonetheless, cannabis use is an activity common in ‘social’ contexts or interaction settings that, hence, may cause harm to others. The LRCUG recommendations as framed by public health principles, therefore, acknowledge in basic terms that individuals who choose to engage in cannabis use have a social responsibility to protect others from any adverse consequences of their use .There is limited and mixed evidence on the impact of educational/behavioral interventions like the LRCUG on population-level harms in other areas of health or substance use . In recent assessments of population-level data in North America, sizable subgroups of PWUC did not adhere to key LRCUG recommendations, including the mode of cannabis use, use frequency, and driving under the influence . Recent data from jurisdictions where cannabis has been legalized suggest that selected higher-risk use behaviours persist or may even be increasing. The prevalence of these risk behaviors may be increasing in these contexts as a result of expanding availability and marketing of cannabis at the population level and the socio-cultural ‘normalization’ of use . Altogether, this suggests considerable room and potential for the LRCUG to provide and serve as an intervention tool that contributes to protecting and improving cannabis use-related public health especially in contexts of liberalized control. The LRCUG may serve at least two didactic functions. One is to create general awareness among PWUC that there are gradations of risk for adverse outcomes from cannabis use that are within the individual-user’s control. They underscore the fact that PWUC can substantively reduce some of these risks by actively modifying use-related behaviors and choices, and adopting safer and responsible use practices. This may also help to shape emerging norms around cannabis use, especially in new contexts of legality . The second is to provide specific advice and guidance to PWUC on how to reduce cannabis-related risk of health problems. These efforts should ideally be linked with and reinforced by other targeted intervention efforts and programs, such as targeted prevention campaigns on specific risk factors of relevance. Knowledge translation strategies are a key to the effective implementation, dissemination and uptake of the LRCUG. These may include endorsements by leading organizations and stakeholders and buy-in from science, health, and prevention experts that amplify their profile and credibility.