In the United States, 18% of persons 12 or more years of age reported previous month use, and 1.5% in this age category Cannabis and Brain met diagnostic criteria for Cannabis Use Disorder (4). The Drug Enforcement Agency has placed cannabis in Schedule I of the Controlled Substances Act, but 10 states have legalized its recreational use, and 32 have legalized its use for medicinal purposes. The goal of this review is to update and consolidate relevant findings in order to inform attitudes and public policy regarding the recreational and medical use of cannabis and cannabinoid compounds. The finding may help explain why people who use both cannabis and tobacco often report increased depression and anxiety, and why quitting cannabis is harder for them than for people only using cannabis. Fatty acid amide hydrolase (FAAH) degrades anandamide, and greater FAAH levels may underlie poorer clinical outcomes in people who co-use relative to those who use only cannabis. The researchers are now recruiting people who smoke cigarettes and people who vape nicotine in a new study to test whether the same brain changes occur without cannabis.
Clinical implications
Changes in this structure might have widespread, yet varied effects on brain function, affecting different networks and regions differently. Differences in structural and functional alterations might also stem from the diverse functional roles of various brain regions. Overall, our results illuminate the intricate interplay between structural and functional brain alterations, emphasising the need for comprehensive investigations to uncover their underlying mechanisms. The researchers found that cannabis had a statistically significant effect on brain function during working memory tasks, meaning the observed impact is very unlikely to be due to random chance.
Cannabis effects on brain function
- Cheng et al. (94) used a two-level multi-voxel pattern analysis of resting state fMRI data to classify cannabis users from control participants with an accuracy rate of 84–88% in predicting whether a single participant was a cannabis user.
- The disparity between observational and Mendelian randomisation findings could result from several mechanisms.
- Several individual aspects of memory appear to be affected (46,134,145,146), with the most robust effects on verbal learning, including decrements in measures of encoding, recall, and recognition (see (134) for review).
- Despite a higher prevalence of use during the late 1970s, public opinion toward legalization of cannabis has become more favorable.
Multiple linear regression was performed to determine the relationship between cannabis use and brain measures, accounting for confounds. Aside from studies evaluating effects of THC on brain activity and various functions, such as memory retrieval and emotional processing, potential effects are being evaluated in chronic pain, bipolar disorder, and improvement of sleep. Dronabinol is FDA-approved to treat patients with Acquired Immune Deficiency Syndrome, who are experiencing anorexia and cachexia, as well as cancer patients who are undergoing chemotherapy and suffer from nausea and vomiting that is resistant to conventional antiemetic treatments. Marinol® has been assigned to Schedule III of the Controlled Substances Act, but the DEA maintains FDA-approved products of oral solutions containing dronabinol in Schedule II.
Can Annual Eye Checkups Reduce Risk of Alzheimer’s and Other Dementias?
- The researchers are now recruiting people who smoke cigarettes and people who vape nicotine in a new study to test whether the same brain changes occur without cannabis.
- Among these, Δ9-tetrahydrocannabinol (THC), the primary psychoactive ingredient, has promoted widespread recreational use and misuse of the plant.
- Additionally, the raw MRI data that had the wrong dimensions, were corrupted, missing, or otherwise unusable were not processed any further.
- “What surprised us was how strong the effect was, and how different it was from those who only used cannabis, compared to those who used both tobacco and cannabis,” said co-author Romina Mizrahi, Professor of Psychiatry and director of the McGill Research Centre for Cannabis.
- Additionally, considerations for preclinical models of cannabis inhalation (instead of injection) may facilitate translation of results in the human population.
Contrary to these findings, recent studies have shown that THC can promote neurogenesis, restore memory and prevent neurodegenerative processes and cognitive decline in animal models of Alzheimer’s disease (151–153). To reconcile these seemingly contradictory results, it has been suggested that THC modulates memory and cognition in an age- and dose-dependent manner (155). The localizations of cannabinoid receptors also are consistent with important roles in reward, reinforcement, and addiction. CB2 receptors are expressed in dopamine neurons of the midbrain ventral tegmental area (19), where effects on THC receptors may modulate addiction-related behaviors, such as drug reinforcement (19). CB1 and mu receptors are co-localized in striatal output projection neurons of the nucleus accumbens and dorsal striatum, which modulate reward and habit formation, respectively (20). Because of the increased and widespread availability and use of cannabis, and FDA-approved medical uses of cannabinoid compounds, information regarding potential untoward effects and safety limits is needed to guide public policy.
Review of Longitudinal Studies on Cannabis Use and Neuropsychological Functioning
First, the observational associations might be confounded by an unmeasured variable, such as family history, dietary intake or use of certain medications. Second, our Mendelian randomisation analyses had less statistical power than our observational analyses to detect small effects. However, despite potential concerns about weak instrument bias in Mendelian randomisation studies, our SNPs demonstrated robust instrument strength, evident from the F-statistics.
In long-term users, lasting impairments in memory and attention worsened with increasing years of regular cannabis use (135,140,149,150). There is substantial evidence that acute administration of cannabis or THC adversely affects executive function. On tasks of planning, reasoning, interference control, and problem solving, impaired performance was observed in some (115–120), but not all studies (121–123) of occasional, moderate and heavy users. In test of inhibitory control, such as go/no-go or stop-signal tasks, THC administration increased reaction time in occasional and heavier cannabis users (116,118,122,124), but other findings in chronic users were mixed (125–129). These side effects, as well as the recreational and medical effects of cannabis on the central nervous system, occur primarily through activity at cannabinoid receptor type 1 (CB1) (Pertwee, 2006; Pertwee, 2008).
Finally, numerous individual differences may influence who most is at risk for experiencing cannabis-related declines in neuropsychological functioning, which were not explored in the reviewed studies. Nonetheless, these studies represent the vanguard of ongoing research in the area, with arguably the strongest research designs to detect such effects. Continued progress will likely be made with the recently launched Adolescent Brain Cognitive Development (ABCD) project. Supported through several NIH institutes, ABCD employs a prospective longitudinal design with a representative sample of 10,000, 9- to 10-year-old youth, prior to initiation of any drug use, who will be followed for 10 years. Across multiple time points, data will be collected on genetics, stress hormones, physical activity, mental health, environment (family, school, cultural), substance use, neuropsychological functioning, and brain structure and function. Through studies such as these, we will continue to come closer to understanding who, and under what conditions, is most vulnerable to neuropsychological declines from cannabis use.
Links to NCBI Databases
One study examined whether patients receiving medical marijuana would exhibit improvement in cognitive functioning, perhaps related to primary symptom alleviation (179). The results suggested that these patients experienced improvement in measures of executive functioning, in addition to positive changes in some aspects of quality of life. Few studies beyond this have directly examined the potential impact of medical marijuana on cognitive performance, and further research is needed to clarify the specific neural and cognitive impact of medical marijuana use and how it compares to recreational use. Memory has been the cognitive domain most consistently impaired, with verbal learning and memory tasks particularly sensitive to the acute (142–144) and chronic (134) effects of cannabis. Several individual aspects of memory appear to be affected (46,134,145,146), with the most robust effects on verbal learning, including decrements in measures of encoding, recall, and recognition (see (134) for review). Associations between poorer performance in regular cannabis users and frequency, quantity, duration, and age of onset of cannabis use have also been reported (97,98,114,147,148).
Task functional MRI employed the Hariri faces/shapes ‘emotion’ task, which represented summary measures of activation in regions chosen from the group-level activation map. Resting‐state functional MRI conducted at two distinct dimensionalities (25 and 100), resulting in 21 and 55 signal networks, provided information on measures of both within-network and between-network functional connectivity. Additional details on the acquisition parameters, image processing, and specific measurements derived from each imaging modality is in online supplemental methods. A total of 3921 brain measures of structural and functional connectivity were used in the analysis (online supplemental table 1).
Substantial gaps remain in examining neurocognitive and psychiatric outcomes in later life after treatment with cannabis among children and adolescents with ADHD. Mendelian randomisation provided no support for a causal effect of cannabis use or dependence on brain structure or function, nor a causal effect of brain structure or function on cannabis use. The disparity between observational and Mendelian randomisation findings could result from several mechanisms.
Past use of cannabis has been linked with multiple aspects of brain structure and function in adult and adolescent populations.2 The most consistent brain regions linked to cannabis use are the subcortical regions. In summary, based on our review of the current longitudinal literature examining relationships between cannabis use and changes in neuropsychological functioning, our answer to the question, “Does cannabis use cause declines in neuropsychological functioning? ” is a qualified “yes.” The available evidence suggests that declines in neuropsychological functioning are most likely to manifest among daily (or almost daily) cannabis users and the magnitude of these declines are relatively modest (though not necessarily insignificant). Our conclusions may not generalize to neurologically (or otherwise) vulnerable populations that may be at greater risk for neuropsychological decline nor do they suggest an absence of more subtle effects on brain structure and function. Furthermore, it is well documented that the potency of cannabis has continued to rise in recent years, with use of more potent products growing (e.g., extracts, “wax” and “shatter”), which may have over 60% THC (e.g., Smart et al., 2017; Mehmedic et al., 2010). Whether the current findings generalize to individuals using such formulations, which were not likely represented in the reported cohort studies, will need to be determined with future research.
Consistency in experimental design remains a challenging aspect of studying the long-term effects of chronic cannabis use on cognition (141). Most information on the impact of cannabis use in humans that has come from studies of individuals with chronic, heavy recreational use, and relevant reviews from 1976 to 2002 have presented some inconsistencies regarding effects on brain structure (34–37). Structural neuroimaging studies provide evidence of morphological abnormalities in chronic adolescent as well as adult users (38,39); these effects may be related to the amount of cannabis exposure.
Recent evidence indicates that CBD is a negative allosteric modulator at CB1 receptors and a partial agonist at CB2 receptors (32). Cannabis is the most widely used illicit substance worldwide, and legalization for recreational and medical purposes has substantially increased its availability and use in the United States. We use the term Effect Size (ES) to refer to various different measures of standardized mean differences (e.g., Cohen’s d, Hedge’s g).
Another FDA-approved THC formulation for chemotherapy-induced nausea and vomiting is nabilone (Cesamet®). There are indications that frequent cannabis use may be particularly harmful to the adolescent brain (56). It is plausible that those who begin cannabis use early in adolescence would be more likely to become heavily dependent.
