A placebo-controlled crossover study involving individuals with infrequent use given cannabis ‘edibles’ at different doses found dose-dependent acute impairments in attention, memory and psychomotor performance. Perceptible drug effect onset occurred 30-60 minutes after intake, peaked at 2-5 hours, and lasted eight hours or more . While the cognitive impairments observed were comparable to similar doses of inhaled cannabis the THC-blood concentrations observed were lower than peak concentrations reported in other studies on cannabis inhalation . On this basis, individuals with ‘edibles’ use could have been under existing limits for THC blood level for cannabis-impaired driving, despite their marked impairment being comparable to that from smoking or vaping THC. Furthermore, extending the evidence on the role of different use modes for cannabinoids, the pharmaco-dynamic effect patterns of CBD itself have been observed to be similar to those for THC products, yet generally also vary depending on the use mode/route employed . Moreover, a recent study reported students using cannabis products in multi-modal ways were at greater risk of cannabis-related problems, dependence, and alcohol co-use than those individuals with single-mode use .Systematic reviews suggest that individuals reporting frequent use of cannabis may develop tolerance to the acute effects of THC, especially its effects on memory, executive functioning, and psychomotor impairments, which are less pronounced in individuals with frequent than those with non-frequent use .
Tolerance is generally evident in a blunting effect on impairment, rather than its avoidance; it appears to be a result of neuroadaptation, a down regulation of cannabinoid receptors in response to frequent THC exposure . A recent meta-analysis confirmed a moderating effect of frequent cannabis use on the subjective impairment and psychosislike effects of THC . A double‐blind,pot drying randomized, placebo‐controlled study of the acute effects of cannabis use on neuro-behavioral functioning found that in subjects with occasional use, cannabis-induced alterations in brain functioning were associated with increased subjective intoxication and decreased behavioral performance; conversely, neuroadaptive processes were observed as facilitating reduced responses in individuals with chronic use . Other studies suggest that acute tolerance may be limited to persons with extremely high-intensity patterns of cannabis use . Individuals engaging in frequent cannabis use may also develop tolerance to the protective effects of CBD . Tolerance may lead to increased cannabis intake in order to achieve the desired level of intoxication, thereby increasing the risk of adverse effects. Some adverse neuro-cognitive effects of cannabis on memory, learning and mental state may reverse after a period of abstinence or substantial reductions in use . Reversible down regulation of brain functioning has been reported in animal and human studies, with structural levels returning to those of healthy controls within a few weeks, or even days, of non-exposure . A recent systematic review concluded that abstinence from cannabis use for periods of >72 hours diminished the neurocognitive deficits found in adolescent and young adult PWUC . Other studies have found reversals in key cognitive deficits but observed residual effects on higher-order cognitive functions and related brain networks .
Overall, conditions and measures of related studies vary considerably . In a sample of young cannabis using women, reductions in cannabis use frequency at 3- and 6-months post-baseline were associated with significant reductions in depressive symptoms, with the largest changes for more severe depressive symptoms at baseline . Furthermore, abstaining or reducing the amount of cannabis smoked can reduce respiratory problem symptoms .Key reviews have documented moderately but significantly increased associations between driving under the influence of cannabis and user-drivers’ involvement in MVCs that cause injury or death . Risk ratios may be higher if evidence is limited to drivers with acute impairments in relevant cognitive and psychomotor control functions . Similar risk associations have been confirmed for motorcycle crashes and occupational injuries . Using cannabis together with alcohol increases multi-fold the impairment of driving-relevant performance skills and MVC involvement risk Driving simulator and on-road performance studies confirm that acute cannabis use impairs driving-related reaction, tracking, and psychomotor control, including among youth drivers as a particular high risk group for driving-related adverse events . THC increases self-administration of nicotine in animals, suggesting increases in its rewarding effects . CBD reduces increased attentional bias towards cigarettes in humans who use both drugs, suggesting it may have anti-nicotine addictive properties . Adolescents who co-use tobacco and cannabis report more problems with and dependence on both drugs, consume more alcohol, and experience stronger withdrawal symptoms than those individuals with singular drug use . In large samples of young adults, co-users of cannabis and tobacco reported more intensive use and poorer physical and behavioral functioning than those without co-use ; similarly, among adults, cannabis use has been significantly associated with the initiation of cigarette smoking, smoking persistence, and relapse after cessation.Maternal tobacco co-use has been identified as a confounder for the possible effects of cannabis use on adverse neonatal outcomes, for example birthweight or gestational age , and predicts future use of cannabis and tobacco by offspring .
The concurrent use of cannabis and alcohol can have complex effects . Individuals reporting daily cannabis use who also used alcohol did not differ in brain structure from matched individuals with alcohol-only use; however alcohol co-use is a potential confounder in studies of long-term cannabis-related cognitive function . Concurrent adolescent cannabis and alcohol use may be associated with better neurophysiological and structural brain outcomes than alcohol-only use, but data are limited and effect dynamics uncertain . It is possible that THC exposure may acutely increase the rewarding effects of alcohol and produce quicker and more marked intoxication, and thus lower alcohol use. Co-using individuals may use both drugs more frequently, increasing the risks of co-morbid substance use and mental health problems, and poorer treatment outcomes than those not using both drugs . Comprehensive reviews suggest that frequent cannabis and alcohol co-use by adolescents is associated with greater neuropsychological impairments, adverse health and psycho-social outcomes, such as poorer academic performance and impaired driving. Concurrent use of cannabis and alcohol increases acute impairment, and increases the risk of MVC involvement and other injuries . Concomitant use of alcohol and/or tobacco with cannabis increases the risks of adverse cardiovascular events, including stroke . Interactions between cannabis and other psychotropic drugs, for example, psychostimulants, may negatively influence physical and mental health outcomes . As specifically relevant for prescription drugs, cannabinoids can inhibit the liver and other enzymatic systems, increasing the plasma levels and hence the toxicity of other psychotropic drugs via adverse drug-drug interactions .
Conversely, there may be some health-protective effects for individuals with high-risk use , but research in this area is underdeveloped. Both THC and CBD can produce drug-drug interactions and related adverse events, such as impaired neurological and cardiovascular functioning and infections . They both can interact with tricyclic antidepressants, central nervous system depressants, protease inhibitors, and warfarin therapy .Some reviews have found cannabis smoking to be associated with adverse cardiovascular outcomes such as acute myocardial infarction , arrhythmias, and ischemic attack , while other reviews have questioned the strength of the evidence . A systematic review found that the association with using large doses of THC was stronger for ischemic stroke than for other cardiovascular outcomes . Case studies have reported temporal relationships between cannabis drying smoking and adverse cardiovascular events, but the confounding role of tobacco and alcohol is unclear . While the evidence for cannabis-related cardiovascular outcomes is limited, it appears that THC exposure can exert substantial stress on the cardiovascular system, especially in individuals with novice or occasional use and consequentially limited tolerance to its effects . Systematic reviews have documented acute dose-response effects of cannabis use on tachycardia in young subjects without cardiovascular deficits . Similarly, cannabis smoking has been suggested as a trigger for AMI in young individuals immediately after use . Furthermore, risks for adverse acute cardiovascular events appear to be dose-dependent, and higher in individuals with frequent use of high THC-potency cannabis as well as in older PWUC and in individuals with pre-existing cardiovascular conditions .It is estimated that approximately half or more of the risks of developing substance use disorders is related to genetic susceptibility/heritability . These effects are partly explained by the additive effects of common variants on neurotransmission pathways and other physiological processes that are partially shared between substances . Comprehensive studies suggest a possible role of specific genetic predispositions for cannabis use problems, adverse psychiatric outcomes, and other substance use disorders .
Large genome-wide studies of cannabis dependence have identified independent regions with genome-significant polymorphisms . In a large genome-wide association study, eight independently associated polymorphisms explained a substantial amount of the variance in associations between cannabis use and risks of other SUDs and schizophrenia. Small but significant associations were found between polygenic risk scores for multiple SUDs and select mental health disorders, some indicating that those with a genetic risk for schizophrenia were more vulnerable to CUD than persons pre-disposed for other psychiatric conditions Overall, data suggest that individuals with an immediate or familial history of SUD or schizophrenia and depression are at elevated risk of developing chronic cannabis-related problems. Given the limitations of genetic risk diagnosis, such histories may serve as the best general indicators of increased risk. In those affected by mental health problems the prevalence of cannabis use is commonly elevated and associated with increased disease severity, progression or outcome severity . The causeand-effect dynamics involved between cannabis use, SUD, and mental health problems are complex, including possibly bi-directional relationships. The effects of cannabis may vary in response to other causes, and its use among those with mental health problems may also be a form of self-medication.Cannabis use has traditionally been twice as common in men as women, but the sex ratio of PWUC has substantially narrowed in more recent birth cohorts in many contexts . Fewer women than men, however, engage in intensive cannabis use, and some sex-based and suggestive gender differences in outcomes have been found, although the data may primarily reflect differential exposure levels . There are sex-related biological differences in the ECS and its role in the metabolic and endocrine systems, which may produce sex-based differences in the effects of cannabis on brain structures and functions and on mental health outcomes . Male PWUC develop CUD more often and typically express more problem symptoms than females. A series of double‐blind, placebo‐controlled pharmacodynamic studies comparing the effects of vaporized and oral cannabis use at different doses by sex found overall dose‐related increases in subjective drug effects and cognitive/psychomotor performance, heart rate, and blood-cannabinoid concentrations in female PWUC. Females exhibited greater peak-THC concentrations in blood and subjective effects as well as ratings of “anxious/nervous,” “heart racing,” and “restless” than males, suggesting differential effect profiles .
Women seem to experience greater and more prolonged sedation and psychomotor impairment from cannabis that also may increase their risks of MVC involvement . Female PWUC may have a higher prevalence of anxiety symptoms or disorder and an earlier onset of schizophrenia, although studies of depression outcomes are mixed . Women engaging in cannabis use, overall, may show a ‘telescoping effect’ in which they may more quickly transition from use initiation to CUD or other problems, although these dynamics may also include gendered differentials in social responses; furthermore, some studies suggest that women may experience more severe dependence and withdrawal symptoms . Male PWUC have been found to have twice the prevalence of cannabis-impaired driving as females .Cannabis use is increasing among older adults in North America but there are only very limited data on health outcomes in this specific age group . Human and animal data on ECS upregulation suggest that some age-related decrements may be balanced by neuro-protective effects or improved cognitive function in older PWUC. Reviews have found limited evidence for adverse effects on neuro-cognitive functioning . Systematic reviews of mental and cognitive health among older adult PWUC found only modest reductions in cognitive performance, and were concentrated in individuals with intensive and higher-dose use . A structural MRI study of frequent older-adult PWUC and non-using controls did not find any inter-group differences in in the brain’s total volumes of gray or white matter.