Ask a Doctor: How does marijuana affect the adolescent brain?

New research suggests cannabis use can alter development of the cerebral cortex, and in a fraction of patients, increase risk for psychosis

Advice by Richard A. Friedman, MD

January 30, 2023 at 6:00 a.m. EST

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Q. What are the effects of marijuana use on teenage brain development? Are there some people who should not use marijuana even if it’s legal?

A. Marijuana, also called cannabis, is a widely popular recreational drug. Nearly half of all Americans have smoked, vaped or eaten a form of marijuana. Marijuana for recreational use is now legal in 21 states, as well as D.C. and Guam.

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Still, despite its general safety, there is recent evidence that suggests that cannabis may pose a risk to adolescents whose brains have not yet matured. And for certain teens and adults at risk for psychiatric disorders, cannabis use also has the potential to trigger a first episode of psychosis or depression.

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A brain-imaging study looked at cannabis exposure over time

New research suggests cannabis use can alter development of the cerebral cortex, the brain’s center of reasoning and executive function. A 2021 study published in Jama Psychiatry examined the effect of cannabis on brain development in a group of 799 adolescents, aged 13 to 17, who had a brain MRI scan at baseline and after 5 years of follow-up.

This is the largest longitudinal brain-imaging study to address this question to date. All the subjects were cannabis-naive to start, so the study could assess the impact of cannabis exposure over time.

The study found that cannabis use was associated with thinning of the prefrontal cortex and that this effect was dose-dependent — the greater the cannabis exposure, the greater the cortical thinning.

The researchers reported that accelerated cortical thinning was associated with attentional impulsivity, but there was no link with any other cognitive function. (There have been several other studies of the effect of cannabis on brain structure in teens, which reported similar findings.)

What does this mean? The cerebral cortex is the center of reasoning and critical thinking; it undergoes significant structural change during adolescence and doesn’t fully mature until around age 25.

We know that cannabinoid receptors are widely distributed throughout the brain and play an important role in mammalian brain development, so it is not surprising that cannabis exposure might affect brain development, especially during adolescence when the brain is uniquely sensitive to environmental influence.

Putting the risk in perspective

We don’t yet know if these effects are enduring and whether there are any long-term psychological or cognitive effects of cannabis on young people. It’s not clear from this study exactly how much cannabis use is problematic. It seems reasonable that the risk of occasional marijuana smoking or edible use is less worrisome than daily or frequent use.

And it’s important to put this hypothetical risk of cannabis in perspective. We have come a long way since the misguided moralism of “Reefer Madness,” an over-the-top propaganda film made in 1938 to discourage marijuana use. Alcohol, when used at a certain level, is highly toxic to many organs, including the brain. And opiates are responsible for a staggering epidemic of addiction and mortality, killing millions of Americans. In contrast, there is not a single case of death from cannabis overdose.

Still, I think these studies should give us pause, particularly in young people, given the explosive popularity of cannabis. Developmentally, teens are notorious risk takers and have heightened sensitivity to all kinds of rewards, like drugs, money and sex, which makes it harder for them to check their impulses. This new data suggests that cannabis could make it even more difficult for teens to exert self-control, leading to a self-sustaining cycle of cannabis use.

The risk of psychosis after cannabis use

Although recreational cannabis is generally safe for most people, for a small fraction of both teens and adults, use of the drug also can raise the risk of psychosis.

The notion that cannabis use might be associated with psychosis has been controversial and typically has been based on clinical anecdotes or small cross-sectional studies, which demonstrate a correlation but can’t prove a causal link.

If cannabis can cause psychosis, then increasing rates of cannabis use should be paired with a rise in the rates of psychotic illness over time. This is just what researchers found in a nationally representative study of nearly 80,000 adults.

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In the study, published in 2021 in the American Journal of Psychiatry, subjects were asked about their cannabis use and whether they had been diagnosed with schizophrenia or another psychotic disorder by their physician or other health professional.

The researchers reported an approximate 2.5-fold increase in the prevalence of self-reported psychotic illness between 2001 and 2013, which is surprising since the rates of psychotic disorder in the general population have been steady for decades. They also found that psychotic illness was significantly more prevalent in those with any cannabis use than those without.

To be clear, the risk to any one individual was low. At the end of the study, 1.89 percent of those who had ever used cannabis reported psychotic illness compared to 0.68 percent in the never-used group.

This large observational study doesn’t prove a causal link between cannabis and psychosis, but it is consistent with other studies showing a similar trend.

The growing potency of cannabis

While it is always possible that the researchers did not account for other factors, aside from alcohol and stimulants, that might explain the rising rates of psychotic illness, it’s worth noting that this trend has occurred alongside growing recreational use — and potency — of cannabis.

For example, the concentrations of THC, the active cannabinoid in marijuana, which ranged from 1.5 percent to 4 percent in the 1980s and 1990s, have soared in recent years with some strains having as much as 29 percent THC. And concentrated cannabis products like “dabs” can contain upward of 76 percent THC.

How to identify those at risk

If we accept that there is a small but real risk that cannabis can cause psychosis in some individuals, the critical question is how to identify those people.

As of yet, there is no test or biomarker for individual vulnerability for psychosis. But we do know that family psychiatric history is an important risk factor. For example, those with a first-degree relative with a psychotic disorder like schizophrenia have an elevated genetic risk of this illness and should avoid using cannabis.

In addition to family history, low-level symptoms of a psychotic illness — such as odd behavior, perceptual disturbances and blunted affect — could indicate a higher risk of psychosis and a need to avoid cannabis exposure.

If a teen has such risk factors, parents should have a frank talk with them about the fact that they are at a higher risk of a bad psychological and emotional reaction to cannabis.

The conversation is especially important if a teen has had an episode of psychosis or depression in response to other recreational drugs in the past. That is a tip-off that such a teen has significant psychiatric genetic risk and should avoid all recreational drugs.

I and my colleagues have seen many instances where young people with siblings or parents with a psychiatric disorder develop the first episode of psychosis or depression after cannabis exposure. Would the disorder, for which they are at risk, never have been unleashed in the first place or perhaps developed later in life if they had not used cannabis? It’s a counterfactual question that we can’t answer. But why take the chance?

Richard A. Friedman is professor of clinical psychiatry and director of the Psychopharmacology Clinic at Weill Medical College of Cornell University.

Research Report

Cannabis (Marijuana) Research Report

What are marijuana's long-term effects on the brain?

Substantial evidence from animal research and a growing number of studies in humans indicate that marijuana exposure during development can cause long-term or possibly permanent adverse changes in the brain. Rats exposed to THC before birth, soon after birth, or during adolescence show notable problems with specific learning and memory tasks later in life.32–34 Cognitive impairments in adult rats exposed to THC during adolescence are associated with structural and functional changes in the hippocampus.35–37 Studies in rats also show that adolescent exposure to THC is associated with an altered reward system, increasing the likelihood that an animal will self-administer other drugs (e.g., heroin) when given an opportunity (see "Is marijuana a gateway drug?").

Imaging studies of marijuana’s impact on brain structure in humans have shown conflicting results. Some studies suggest regular marijuana use in adolescence is associated with altered connectivity and reduced volume of specific brain regions involved in a broad range of executive functions such as memory, learning, and impulse control compared to people who do not use.38,39 Other studies have not found significant structural differences between the brains of people who do and do not use the drug.40

Several studies, including two large longitudinal studies, suggest that marijuana use can cause functional impairment in cognitive abilities but that the degree and/or duration of the impairment depends on the age when a person began using and how much and how long he or she used.41

Among nearly 4,000 young adults in the Coronary Artery Risk Development in Young Adults study tracked over a 25-year period until mid-adulthood, cumulative lifetime exposure to marijuana was associated with lower scores on a test of verbal memory but did not affect other cognitive abilities such as processing speed or executive function. The effect was sizable and significant even after eliminating those involved with current use and after adjusting for confounding factors such as demographic factors, other drug and alcohol use, and other psychiatric conditions such as depression.42

Some studies have also linked marijuana use to declines in IQ, especially when use starts in adolescence and leads to persistent cannabis use disorder into adulthood. However, not all of the studies on the link between marijuana and IQ have reached the same conclusion, and it is difficult to prove that marijuana causes a decline in IQ when there are multiple factors that can influence the results of such studies, such as genetics, family environment, age of first use, frequency of use, having a cannabis use disorder, duration of use, and duration of the study. Key research in this area to date is described below.

A large longitudinal study in New Zealand found that persistent marijuana use disorder with frequent use starting in adolescence was associated with a loss of an average of 6 or up to 8 IQ points measured in mid-adulthood.43 Those who used marijuana heavily as teenagers and quit using as adults did not recover the lost IQ points. People who only began using marijuana heavily in adulthood did not lose IQ points. Two shorter-duration prospective longitudinal twin studies found that  youth who used marijuana showed significant declines in verbal ability (equivalent to 4 IQ points) and general knowledge between the preteen years (ages 9 to 12, before use) and late adolescence/early adulthood (ages 17 to 20); however those who went on to use marijuana at older ages already had lower scores on these measures at the start of the study, before they started using the drug. Also, no predictable difference was found between twins when one used marijuana and one did not.44

More research will be needed to answer definitively whether marijuana use causes long-term IQ losses and whether factors that weren’t measured in the prior research, such as the increasing amounts of THC in cannabis and the emergence of new cannabis products, are relevant.

Also, the ability to draw definitive conclusions about marijuana’s long-term impact on the human brain from past studies is often limited by the fact that study participants use multiple substances, and there is often limited data about the participants’ health or mental functioning prior to the study. Over the next decade, the National Institutes of Health is funding the Adolescent Brain Cognitive Development (ABCD) study—a major longitudinal study that will track a large sample of young Americans from late childhood (before first use of drugs) to early adulthood. The study will use neuroimaging and other advanced tools to clarify precisely how and to what extent marijuana and other substances, alone and in combination, affect adolescent brain development.

Marijuana, Memory, and the Hippocampus

Image

This is an image of a rat brain with the different parts of the brain labeled.

Image by NIDA

Distribution of cannabinoid receptors in the rat brain. Brain image reveals high levels (shown in orange and yellow) of cannabinoid receptors in many areas, including the cortex, hippocampus, cerebellum, and nucleus accumbens (ventral striatum).

Memory impairment from marijuana use occurs because THC alters how the hippocampus, a brain area responsible for memory formation, processes information. Most of the evidence supporting this assertion comes from animal studies. For example, rats exposed to THC in utero, soon after birth, or during adolescence, show notable problems with specific learning/memory tasks later in life. Moreover, cognitive impairment in adult rats is associated with structural and functional changes in the hippocampus from THC exposure during adolescence.

As people age, they lose neurons in the hippocampus, which decreases their ability to learn new information. Chronic THC exposure may hasten age-related loss of hippocampal neurons. In one study, rats exposed to THC every day for 8 months (approximately 30% of their lifespan) showed a level of nerve cell loss at 11 to 12 months of age that equaled that of unexposed animals twice their age.

Effects of Cannabis on the Adolescent Brain

Joanna Jacobus1,2 and Susan F. Tapert1,2

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The publisher's final edited version of this article is available at Curr Pharm Des

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Abstract

This article reviews neuroimaging, neurocognitive, and preclinical findings on the effects of cannabis on the adolescent brain. Marijuana is the second most widely used intoxicant in adolescence, and teens who engage in heavy marijuana use often show disadvantages in neurocognitive performance, macrostructural and microstructural brain development, and alterations in brain functioning. It remains unclear whether such disadvantages reflect pre-existing differences that lead to increased substances use and further changes in brain architecture and behavioral outcomes. Future work should focus on prospective investigations to help disentangle dose-dependent effects from pre-existing effects, and to better understand the interactive relationships with other commonly abused substances (e.g., alcohol) to better understand the role of regular cannabis use on neurodevelopmental trajectories.

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Introduction

According to the 2011 Monitoring the Future Study, marijuana remains the most commonly used illicit drug in adolescence in the United States, one of few increasing in prevalence. In fact, marijuana has been the most commonly used illicit substance for almost 40 years, and presently 23% of 12th graders in the U.S. report using marijuana in the past month [1]. Marijuana use in adolescence could have implications for academic functioning, as well as social and occupational functioning extending into later life. Maturational brain changes, particularly myelination and synaptic pruning, are occurring throughout adolescence, well into early adulthood [2]. These remodeling processes are purportedly linked to efficient neural processing, and believed to underlie specialized cognitive processing necessary for optimal neurocognitive performance.

Cannabinoid receptors (CB1) are widely distributed throughout the brain (e.g., hippocampus, prefrontal cortex), and play a role in neurotransmitter release and concentrations across neural systems (excitatory and inhibitory). It has been suggested that these receptors increase during adolescence, have a role in genetic expression of neural development, and that alteration of the endocannabinoid system during adolescence may results in a cascade of neurochemical and neurostructural aberrations, thus leading to poorer cognitive and emotional outcomes in adulthood [3, 4].

Disruptions in brain development related to neurotoxic effects of regular marijuana use could significantly alter neurodevelopmental trajectories by not only changing neurochemical communication and genetic expression of neural development, but causing a toxic effect on brain tissue. Such a marijuana-related effect on white matter and gray matter structures (e.g., changes in myelin, axons, and synapses) could have widespread implications for healthy brain development from childhood to young adulthood on subtle cognitive functioning and success in daily functioning. Studies exploring the neurocognitive consequences and structural and functional neuroimaging changes related to marijuana use in adolescence will be discussed, along with recommendations for future work.

Cognition

Adult studies of marijuana use often find subtle decreases in performance compared to controls in cognitive domains such as attention, memory, and processing speed; such effects have been discussed as transient in the literature given limited group differences after prolonged abstinence from marijuana [5, 6]. It is unclear if findings translate to adolescent populations. Ongoing cognitive development in the domains of memory and executive functioning, and particularly in specialized functions like cognitive control, is not only tightly associated with adolescence and neocortical tissue maturation, but is likely to have implications for school performance and engagement in risk/reward behaviors [7]. One of the earliest studies on the effects of marijuana on adolescent neurocognitive development evaluated verbal and nonverbal memory performance in cannabis-dependent adolescents (ages 14 to 16) compared to matched controls [8]. Schwartz and colleagues found that short-term memory impairment persisted after six weeks of monitored abstinence. In contrast, Teichner and colleagues (2000) found no relationship between marijuana use severity and cognitive performance among cognitively impaired and unimpaired adolescents referred for drug treatment [9]. There have been considerable additions to the literature over the last decade, yet the degree of impairment related to marijuana use in adolescence remains inconclusive. A pattern of subtle yet potentially detrimental effects in cognitive domains related to attention, learning, and memory are most often described.

A prospective study conducted in 2005 examined neurocognitive performance among 17–21 year olds with history of soft drug exposure in utero compared to prior performance at 9–12 years old. Current heavy cannabis users performed significantly worse on measures of processing speed and memory, controlling for pre-drug performance. Notably, former heavy users (reporting 3 months without regular use) had similar scores to non-marijuana using controls [10]. In regard to higher-order cognitive functioning, Lane and colleagues (2007) found adolescents (ages 14–18) with histories of heavy marijuana use performed worse on perseverative responding and flexible thinking compared to controls with limited histories of use. This same research group also found evidence of reduced motivation among marijuana users compared to controls [11, 12]. In 2007, Harvey and colleagues found adolescent marijuana users (age 13–18; use greater than once per week) performed worse on tests of attention, learning, and memory; furthermore, poorer performance on executive functioning in this sample was related to more days of cannabis use in the past month [13].

Studies from our laboratory have largely found differences in similar domains following four weeks of monitored abstinence. Our first prospective investigation found that cumulative marijuana use over the course of eight years (teens followed from ages 13–30) was related to poorer performance on measures of attentional functioning [14]. In a subsequent cross-sectional study of adolescent marijuana users ages 16–18, we found that marijuana users demonstrated slower processing speed, poorer verbal learning and memory, and sequencing abilities [15]. In order to better understand acute changes with abstinence, we examined neurocognitive performance over 3 weeks of monitored abstinence in marijuana users ages 15–19. Between-group differences in attention, learning, and memory were identified at baseline, however while learning and memory performance reached similar levels of performance to controls after 3 weeks of abstinence, attention differences persisted [16].

Group differences in our studies generally persist despite controlling for alcohol use present in both controls and marijuana users; but to further understand differential contributions of marijuana and alcohol to neurocognitive functioning in our sample, we examined unique associations between alcohol use severity and cognitive functioning in both marijuana users as well as controls. In a recent investigation, we found that more self-reported alcohol withdrawal symptoms predicted poorer performance on learning and memory in a sample of non-marijuana using teens with histories of episodic alcohol use, despite no relationship in our marijuana users with similar and/or heavier self-reported history of alcohol use [17]. This suggests differential relationships between marijuana, alcohol, and cognitive outcomes in our sample. We have observed similar relationships in magnetic resonance imaging (MRI) studies examining structural and functional brain alterations [18–20], which will be discussed in greater detail below.

In recent work, Tait and colleagues looked at young adult cannabis users (ages 20–24) and found memory deficits, however cessation of cannabis use was associated with improved performance with abstinence over the course of eight years [21]. Takagi and colleagues found that cannabis users (ages 13–24) performed worse on measures of immediate and delayed verbal memory compared to community controls. In a similar study by this team of investigators, no differences between cannabis users and community controls were found on measures of executive functioning [22, 23]. Similarly Gonzalez and colleagues (2012) found differences on immediate and delayed recall among young adult cannabis users (approximately age 20) compared to nonusing controls, however no differences were observed on measures of impulsivity. Despite no group differences on impulsivity, the authors found that worse performance on a decision making task was related to more cannabis use disorder symptoms [24]. Solowij and colleagues looked at 181 adolescents (ages 16–20) and found that cannabis users performed worse on learning and recall, and poorer performance was related to severity, frequency, and age of initiation of cannabis use [25]. A study on prospective memory evaluated undergraduates between the ages of 18 and 24 years old, while no differences in self-reported prospective memory was identified, cannabis users did recall fewer location-action combinations during the objective video-based prospective memory task [26]. A large-scale (N = 1037) longitudinal investigation from New Zealand evaluating individuals from birth to age 38 recently found a decline in intelligence quotient, particularly executive functioning and processing speed, with persistent cannabis dependence. Notably, those individuals with weekly use before age 18 demonstrated greater decline in cognitive performance [27].

Early/Late Onset of Use

Studies evaluating early- and late-onset marijuana users have provided considerable insight into the effects of cannabis use on adolescent neurodevelopment. For example, Ehrenreich and colleagues (1999) found that initiation of marijuana use prior to age 16 predicted impaired reaction time on a task of sustained attentional processing [28]. In 2003, Pope and colleagues also found that early-onset (or initiation prior to age 17) was related to poorer performance on verbal memory and fluency tasks, as well as verbal IQ [29]. Focusing on executive functioning, Fontes and colleagues (2011) examined 104 chronic cannabis users ages 18–55. All participants met criteria for DSM-IV cannabis abuse or dependence. The authors found that adolescent cannabis users reporting initiation prior to age 15 demonstrated poorer performance on tasks of sustained attention, impulse control, and executive functioning [30]. Overall, the majority of data support poorer cognitive performance on measures of attention and learning, and memory in adolescent users of cannabis, however frequency and severity of use is likely to play a role, particularly in those reporting younger age of initiation. Further, some evidence suggests that many of the subtle cognitive effects are likely to resolve after longer-term abstinence.

Structural NeuroImaging

Gray Matter Macrostructure

A large body of literature has shown dynamic changes in gray matter structures that are ongoing over adolescent development (e.g., cortical volume decline after about 6 years of age). For instance, dendritic pruning and elimination of synapses likely results in cortical thinning and decreased cerebral volume (e.g., subtraction of overproduced or weaker synaptic connections) to some degree, whereas some subcortical structures such as the hippocampus and amygdala have been shown to increase with age [2, 31, 32]. Studies show a high density of CB1 cannabinoid receptors in neocortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum [4]; therefore the degree to which cannabis use alters cortical and subcortical gray matter tissue development is being increasingly explored in the literature. While some alterations in gray matter macrostructure have been suggested, there has been inconsistent evidence of morphological changes as evaluated by structural MRI. For instance, Block and colleagues (1999) as well as DeLisi and colleagues (2006) found no differences in gray matter tissue volume between adolescent cannabis users and matched controls [33, 34].

In 2010, adolescent cannabis abusers (ages 16–19) were found to have decreased right medial orbital prefrontal cortex volume compared to non-using counterparts; volume was also found to be positively correlated with age of initiation of marijuana use in the sample (i.e., younger age of first use associated with reduced orbital prefrontal cortex volume) [35]. A second study published in 2010 found that while age was associated with changes in brain morphometry among non-users, there was no relationship between age and cortical gyrification in adolescent and young adult cannabis users. Cannabis users did show decreased concavity of the sulci and sulci thinning in frontal, temporal, and parietal lobes compared to non-users, highlighting the potential for cannabis to disrupt normal brain developmental trajectories [36]. Ashtari and colleagues (2011) found that heavy adolescent cannabis users abstinent for a minimum of 30 days had smaller bilateral hippocampal volumes compared to controls, and smaller right hippocampal volume was correlated with more self-reported cannabis use among users; no between group differences were observed in amygdala volume [37].

Several studies from our laboratory evaluating abstinent adolescent cannabis users (approximately ages 16–19) have found similar outcomes in regard to gray matter macrostructural changes. Medina and colleagues (2007 and 2009) found no difference in hippocampal volumes or prefrontal cortex volume in adolescent cannabis users compared to matched controls, despite observed differences in both hippocampus and prefrontal cortex in adolescent alcohol users compared to matched controls [19, 38]. We did observe a subtle gender interaction, as female cannabis users had a slightly larger prefrontal cortex compared to non-using female controls; while this trend did not reach statistical significance, it may suggest that female marijuana users are more vulnerable to macrostructural alterations (given smaller prefrontal cortex volume was related to better executive functioning among users). Similarly, in 2011, amygdala volumes were compared between adolescent cannabis users and non-users. Findings suggest increased amygdala volume in female users compared to female non-users. Increased amygdala volume was associated with more self-reported depression and anxiety (internalizing) symptoms [39]. In a study investigating differences in cerebellum volumes, we found that adolescent marijuana users demonstrated larger inferior posterior vermis volume compared to controls; larger cerebellar volume was associated with poorer executive functioning [40].

In recent investigation of temporal lobe structures, Cousijn and colleagues (2012) found that amygdala and hippocampal volume in a sample of young adults ages 18–25 correlated negatively with amount of cannabis use. Specifically, more weekly cannabis use in grams was related to smaller hippocampus volume in heavy users and increased severity of cannabis use was associated with smaller amygdala volume. The authors also found that anterior cerebellum volume was larger in adolescent heavy cannabis users compared to non-users [41].

A prospective study looking at gray matter volume at 12 years of age, prior to initiation of marijuana, found that smaller orbitofrontal cortex volume predicted initiation of cannabis use by 16 years of age, suggesting pre-existing structural abnormalities may play a role in both behavioral differences that lead to cannabis use as well as continued differences in the course of development [42].

There have been limited studies evaluating cortical thickness exclusively, however, Lopez-Larson (2011) evaluated 18 adolescents (ages 16–19) with histories of heavy marijuana use (at least 100 marijuana use episodes in the past year) compared to non-using controls. Decreased cortical thickness was reported in the right caudal middle frontal and bilateral superior frontal cortices; decreased thickness was also found in the bilateral insula. Marijuana users demonstrated increased cortical thickness in the bilateral lingual, right superior temporal, right parietal and left paracentral regions. Alterations of cortical thickness were related to severity of cannabis use and younger age of initiation of use in several brain regions. The authors suggest that marijuana may affect neurodevelopment (e.g., increased/decreased in cortical thickness) in two ways, 1) premature development and/or alterations in neurodevelopmental trajectories or 2) tissue loss or remodeling associated with marijuana-related toxicity [43].

Similar to findings by Lopez-Larson discussed above, the concept of deleterious effects related to early initiation of cannabis has been explored in the neuroimaging literature as well. According to Wilson and colleagues (2000), individuals reporting marijuana use prior to age 17 demonstrated decreased whole brain and cortical gray matter in addition to increased percent white matter volume. Findings also included higher cerebral blood flow in males reporting early initiation of marijuana use [44]. While findings do not necessarily support a clear and consistent pattern of changes in cortical/subcortical volume and thickness measurements, as emphasized by Lopez-Larson and colleagues, we can conclude that marijuana may influence the trajectories of appreciable gray matter changes in several ways. The compound may illicit premature tissue development, impose a marijuana-related effect on regressive changes (e.g., synaptic pruning, death of overproduced cells), and alter ongoing myelination of fiber tracts that are impacting gray matter estimates. Functional changes likely affect the mechanics that underlie structural brain changes, and interactions between these processes cannot be ruled out.

White Matter Microstructure

White matter tissue integrity (e.g., myelination, coherence of fiber tracts) is believed to be important for efficient cortical connectivity in the developing brain. The literature has shown linear increases in white matter over early development. As the brain becomes increasingly myelinated and fiber bundles mature from infancy to late adolescence, restriction of diffusing water molecules along the principal axis of an axon is commonly observed due to increasingly compact fibers and with more limited intracellular space [45, 46]. Diffusion tensor imaging (DTI) commonly utilizes two indices of white matter tract coherence to reflect water diffusion in white matter, fractional anisotropy (FA) and mean diffusivity (MD), which are thought to help to identify alterations in the health of white matter fibers. Increases in FA and decreases in MD are typically seen in healthy white matter development from young children to early adulthood [45]. In 2006, DeLisi and colleagues published one of the earlier studies to explore the potential for deleterious effects of cannabis on developing white matter.. The authors found higher FA and lower in MD in several tracts in MJ users compared to matched controls; they conclude no evidence of pathological white matter changes despite finding differences between groups [33]. Since this study, findings do suggest some evidence of alterations in white matter integrity in adolescent cannabis users. While DeLisi and colleagues suggest no evidence of pathology per se, subsequent studies have since shown changes in unanticipated directions [47]. While this may not represent a typical pathological process, group differences in either direction may still be reflective of a neural alterations.

For instance, increased MD in the prefrontal fiber bundles of the corpus callosum in heavy cannabis using adults (daily use for more than two years) who initiated use during adolescence suggest changes in white matter development associated with cannabis use [48]. Ashtari and colleagues (2009) found that adolescents with heavy cannabis use enrolled in residential drug treatment had reduced FA and increased MD in cortical association areas such as the temporal-parietal fiber tracts [49]. Recently, in a small sample of adolescents approximately 18 years of age, WM alterations were found in cannabis users compared to controls. Decreased FA in cortical and subcortical areas (e.g., hippocampal projections, superior longitudinal fasciculus) was found in cannabis users (weekly use for at least one year) compared to controls with no history of substance abuse [50].

In our laboratory, we have found white matter alterations in our abstinent teen marijuana users (ages 16–19) compared to controls. In two studies published in 2008 and 2009, we found poorer white matter integrity (e.g., decreased FA and increased MD) in several association and projection fiber tracts in adolescent cannabis users with concomitant alcohol use. Areas showing between group differences included tracts linked to fronto-parietal circuitry [51]. White matter integrity in several of these regions was linked to neurocognitive performance on measures of attention, working memory, and processing speed; we have also seen white matter linked to emotional functioning and prospective risk taking in our substance users [52, 53]. To better understand microstructural differences in tissue integrity among adolescent marijuana users as compared to binge drinkers, we looked at white matter differences between adolescent binge drinkers compared to binge drinkers with histories of heavy marijuana use (ages 16–19). While between group differences persisted between marijuana users and controls, surprisingly, teens engaging in binge drinking only looked significantly worse on indices of white matter integrity (i.e., decreased FA) in several areas (cortical and subcortical projection fibers) as compared to marijuana users, highlighting the need for further research to disentangle the effects of marijuana and alcohol on the developing brain [18].

In general, research points to poorer white matter integrity in adolescent marijuana users compared to non-substance using controls. While white matter findings are subtle in nature, we have observed poorer white matter integrity correlated with poorer neurocognitive functioning in our studies [47], which underscores the impact that slight alterations in white matter health during this time could have on optimal cognitive functioning. Interestingly, some preliminary evidence supports that marijuana-related toxicity on white matter integrity may be more modest compared to the impact adolescent alcohol use has on the developing brain, although more research in needed in this area.

Functional Imaging

fMRI Imaging

Changes in cognitive performance after acute and longer-term cannabis use are fairly well documented, even if residual effects are suspected to largely resolve. However, less is known on how brain functioning, or neural activation/signaling, may be changed by marijuana use and thereby reflected in declines in neuropsychological performance. Comparisons between blood oxygen dependent signal (BOLD) in adolescent marijuana users and controls in response to cognitive tasks have revealed subtle differences in brain activation patters in marijuana users. Jacobsen and colleagues (2004) were the first to pilot an auditory working memory (n-back) fMRI study comparing marijuana users (with tobacco use) compared to a tobacco using group and control group. The authors found cannabis users performed the task less accurately and failed to deactivate the right hippocampus across conditions. In another study by the same authors, nicotine withdrawal elicited increased activation across brain regions in the marijuana group, including parietal cortex, superior temporal gyrus, posterior cingulate gyrus, and the right hippocampus. The same effect was not found in the tobacco-only control group suggesting marijuana use may lead to developmental changes masked by nicotine use [54, 55]

We have conducted several BOLD fMRI studies evaluating differences in activation patters between our sample of abstinent marijuana users and matched controls. In 2007, we found marijuana users to have substantially more activation than non-using peers in response to an inhibitory processing task, particularly in parietal and dorsolateral prefrontal cortices, suggesting additional neural resources required to maintain adequate executive control during response inhibition [56]. In evaluating response patterns to a spatial working memory task, adolescent marijuana users exhibited increased activation in the right parietal lobe along with diminished activation in the right dorsolateral prefrontal cortex to achieve good task performance, which was not observed in controls [57, 58]. In a follow-up investigation using the same spatial working memory task, we evaluated teens with more recent abstinence (2–7 days abstinent) compared to prolonged abstinence (27–60) from marijuana, as well as matched controls. Recent users showed greater brain activation in prefrontal cortices, regions needed for working memory processes, and bilateral insula [59]. In response to a third task assessing verbal encoding, marijuana users demonstrated increased encoding-related activation in anterior brain regions as compared to decreased activation in posterior regions, despite no differences in task performance [20]; findings may suggest increased recruitment of neural resources in brain areas subserving task-related processing in marijuana using teens.

Several recent studies outside of our laboratory have shown similar findings. For example, Jager and colleagues (2010) evaluated boys with frequent cannabis use (more than 200 lifetime cannabis use episodes) compared to matched controls (ages 13–19) and found that cannabis users showed excessive activity in prefrontal regions in response to a working memory task [60], studies from this same research group with young adults have yielded similar, although modest, aberrant findings of the working memory system [61]. In 2010, an investigation comprising chronic marijuana users and matched controls (approximately 19 years old), suggest increased activity in the prefrontal cortex in response to a task requiring executive aspects of attention [62]. Cousijn and colleauges recently found increased activation in heavy cannabis users (ages 18–25) in response to the Iowa Gambling task during win evaluations in brain areas such as the insula, caudate, and temporal gyrus, which was also positively related to weekly cannabis use; win-related increase in brain activity also predicted increased cannabis use six months later [63] Lopez-Larson and colleagues (2012) found differences in cortico-cerebellar activity in older adolescents with heavy marijuana use. The authors describe decreased activation in response to a bilateral finger-tapping task, and motor function activation was negatively correlated with total lifetime marijuana use [64]. Age of onset also continues to play an important role, as early-onset cannabis users (prior to age 16) demonstrated increased activation in the left superior parietal lobe in response to a verbal working memory challenge (verbal n-back task), and earlier initiation of use was associated with increased BOLD activity [65]. The majority of findings suggest increased recruitment of neural resources (possibly reflecting compensation or changes in the efficiency of strategic neural processing) in brain areas subserving task-related processing in marijuana using teens.

Electroencephalogram (EEG)

There has been limited research on brain functioning using EEG among adolescent cannabis users. The strength in using EEG is the degree of temporal resolution that is not possible with BOLD imaging. Information on the degree of attentional bias to marijuana cues may provide some indication of brain-based differences in cue-reactivity resulting in heavier use of marijuana among certain teenagers. For instance, one lab based paradigm of cue reactivity found increased skin conductivity among teens diagnosed with cannabis use disorder [66]. Nickerson and colleagues (2011) found that among adolescents ages 14–17, P300 response (i.e., event-related potential response) was larger among cannabis users, and response increased (along with craving) in the user group after handling marijuana paraphernalia; findings suggest attentional bias, increased arousal, and possible neural differences (either pre-existing or altered by ongoing substance use engagement) that may elucidate discrepancies among teen substance use engagement [67].

Blood Perfusion

The neurovascular effect of marijuana use in adolescence has not been studied extensively. Understanding vascular changes in cerebral blood flow (CBF) can help us better understand neural signaling and vascular alterations that may be related to changes in neurocognitive functioning and/or changes in neural signaling related to the BOLD signal. Adult studies typically report increased CBF after acute exposure and lower or stabilized CBF after a period of abstinence in heavy users, although this has varied to some degree [68–70].

To our knowledge, there has only been one study in adolescent blood perfusion in heavy cannabis users. In a recent study in our laboratory utilizing arterial spin labeling (ASL), we found that heavy marijuana users (approximately 17 years old) assessed pre-and post 28 days of monitored abstinence showed reduced CBF in 4 cortical regions, including the left superior and middle temporal gyri, left insula, left and right medial frontal gyrus, and left supramarginal gyrus at baseline; users showed increased CBF in the right precuneus at baseline, as compared to controls. We did not observe group differences in neurovascular functioning after four weeks of abstinence, suggesting marijuana may influence cerebral blood flow acutely with a possible return to baseline with prolonged abstinence [71]. A study evaluating young adults (age range 21–27) found that acute THC administration increased blood perfusion in areas important for emotional and cognitive processing, such as the anterior cingulate, frontal cortex, and insula, and reduced perfusion in posterior brain regions. Resting state activity was also altered, as THC increased baseline activity [72].

Magnetic Resonance Spectroscopy

Very few studies have looked at neurochemical brain changes related to marijuana use in adolescence. Prescott and colleagues (2011) found decreases in metabolite concentrations (e.g., glutamate and N-acetyl aspartate) in the anterior cingulate, suggesting poorer underlying neuronal health in adolescent marijuana users [73], While the exact mechanisms by which cannabis would affect neuronal health is unclear, it is possible that modulation of neurotransmitters such as glutamate and GABA have adverse consequences on cellular development and neuron integrity; changes in neuronal health is one suggested mechanism which may underlie neuroimaging and neurocognitive findings discussed above.

Preclinical Studies

A fairly large amount of work can be found on animal models of adolescent cannabis exposure. A detailed analysis of the preclinical studies is beyond the scope of this review, however briefly discussing the existing literature is important for translation to human models. Studies also focus on various cannabinoids beside Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive component of marijuana; for example increasing attention is being given to cannabidiol, a nonpsychoactive cannabinoid that may have promising therapeutic effects independent of THC [74]. However, this brief summary will focus on models of exposure to the natural compound or cannabinoid agonists, which mimic the structure Δ9-THC. A great benefit of animal studies is lack of heterogeneity that corresponds with human consumption and substance use reporting.

In animals, postnatal days 28–49 correspond with human adolescent development (which can range from 21–59 for inclusion of early/late adolescent development) [75]. Studies during this postnatal time period in rats have evaluated both emotional behavior as well as cognitive/behavioral functioning. One of the first research groups to look at cannabinoid exposure found poorer performance on cognitive tasks, such as maze learning, in immature rats compared to mature rats treated with THC [76]. Schneider and Koch (2003, 2005) have reported alterations in pubertal rats treated with the receptor agonist WIN, discrepancies in performance range from sensorimotor functioning, object recognition memory, and social behavior [77, 78]. A more recent study by Schneider and colleagues (2008) found that chronic WIN treated pubertal rats demonstrated object/social recognition deficits, which the authors suggest is consistent with impairment in short-term information processing. Particularly, immature animals demonstrated more pronounced behavioral alterations as compared to mature animals after acute exposure to WIN, and more lasting deficits in social play and grooming behaviors [79]. Deficits in object recognition have also been reported in male and female pubertal rats treated with a cannabinoid receptor agonist as well as THC [80–82], and there is some support that findings are consistent across age groups.

Spatial functioning in adolescent rats has also shown affected by acute THC treatment [83]. In a recent investigation by Abush and colleagues (2012), chronic WIN treatment was found to result in both acute and longer term effects not only in spatial memory and object recognition, but interestingly, long term potentiation in areas such as nucleus accumbens pathways [84]. Studies are actively evaluating emotional functioning and neurochemical transmission in adolescent animals after exposure to cannabinoid agonists, as well as how cannabinoids moderate state-dependent learning based on brain regions [85, 86]. While this is not an exhaustive review of the preclinical findings, in general, the data suggest differential and often negative impact on adolescent animals compared to adult animals exposed to THC or other cannabinoid agonists in behavioral, emotional, and social outcomes. The animal work is particularly important to highlight, given the consistency in many adolescent neurocognitive and neuroimaging studies conducted with human subjects reporting regular use of marijuana, as the findings often point to the deleterious effects on brain functioning compared to non-using controls.

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Conclusions and Recommendations

Marijuana, second to alcohol, is the most widely used intoxicant. Approximately 25% of adolescents (8th, 10th, and 12th grade) report being drunk in the past month and close to the same (23%) report using marijuana in the past month [1]. As Gonzalez and Swanson point out in a recent commentary, annual prevalence rates of high school seniors have increased over the last decade (22% to 36%), while perceived risk of use has decreased from 80% of seniors reporting regular marijuana use as a “great risk” in 1992 to only 45% reporting marijuana use as risky in 2012 [1, 87]. The literature not only suggests neurocognitive disadvantages to using marijuana in the domains of attention and memory that persist beyond abstinence, but suggest possible macrostructural brain alterations (e.g., morphometry changes in gray matter tissue), changes in white matter tract integrity (e.g., poorer coherence in white matter fibers), and abnormalities of neural functioning (e.g., increased brain activation, changes in neurovascular functioning). Earlier initiation of marijuana use (e.g., before age 17) and more frequent use has also been associated with poorer outcome.

It is difficult to ascertain whether reported group differences reflect pre-existing brain architectural differences that lead to substance use and risk taking behaviors, and there is certainly some literature that suggests as such. Nevertheless, we have seen that differences in brain tissue integrity following heavier marijuana use does predict future risky behaviors such as increased marijuana use and aggressive and delinquent behaviors. This suggests imaging biomarkers may provide some clinical utility, despite the underlying pathological processes [53].

While the focus of this overview is on the existing adolescent literature, it is important to briefly touch on general findings in the adult literature. The amount of adult studies looking at the acute and non-acute effects of marijuana is large and investigations typically see changes in higher-order cognitive functioning and neural processes that are more pronounced immediately following THC administration and may persist after prolonged cessation of use; however current evidence suggests persisting differences are most likely subtle in nature [5, 6, 88–90]. In both the adult and adolescent literature abstinence periods and study designs vary widely (abstinence may vary from hours to years), and therefore making direct comparisons continues to be a challenge and the chronicity of cognitive alterations remains unclear. It is also unclear what defines acute versus longer-term effects (1 week compared to 6 months, etc). Findings from our laboratory discussed in this review reflect a “longer-term,” (residual) effect as adolescents are required to undergo a 28-day abstinence period confirmed by urine toxicology, yet in order to really understand the effects of this compound on the brain and cognition more rigorous study design needs to account for longer-term follow-up periods following monitored abstinence.

Early/late initiation of use as discussed in this review is also likely to interact with severity, frequency, and duration (and even administration) of use in both adolescent and adult studies. Similarly, there is emerging evidence on genetic vulnerability to cannabis, and more information on consumed cannabis is needed as studies move sole focus from THC to other cannabinoids (e.g., cannabidiol) that are likely to influence neural changes and in both adolescents and adults [91, 92].

More adolescent longitudinal studies are still needed to understand both pre-existing differences as compared to discrepancies that develop post-initiation of use. Large longitudinal research would also help clarify the degree to which pre-existing differences and/or chronic marijuana use during adolescence contributes to the development of psychiatric disorders and cognitive impairment in adulthood. Furthermore, we need to better understand the interactive relationships between alcohol and marijuana use as these substance are commonly used together and may result in differing structural, functional, and cognitive brain changes when used alone or in combination.

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Acknowledgements

This review was supported by the National Institute on Drug Abuse (R01 DA021182, PI Tapert; F32 DA032188, PI Jacobus) and the National Institute on Alcohol Abuse and Alcoholism (R01 AA013419, PI Tapert)

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Cannabis and the Developing Brain: What Does the Evidence Say?

Joanna Jacobus, Kelly E. Courtney, Elizabeth A. Hodgdon, and Rachel Baca

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The publisher's final edited version of this article is available at Birth Defects Res

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Abstract

Cannabis use during adolescence has been linked to deleterious effects on brain integrity. This article summarizes findings from two prospective investigations (3 years and 6-years, on average) on adolescent cannabis use from our laboratory that utilize structural neuroimaging and neurocognitive assessment approaches. Across most studies, findings suggest recency, frequency, and age of onset of cannabis use are likely key variables in predicting poorer neural health outcomes. There is some evidence that pre-existing differences in brain architecture may also contribute to vulnerability and outcome differences. Ongoing large-scale prospective studies of youth will be able to disentangle how both cannabis use as well as pre- and post-exposure differences play a role in divergent outcomes among youth who use cannabis.

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Background.

Adolescent brain development is dynamic, with changes in gray and white matter tissue and structural integration occurring well into young adulthood (Gonzalez, Pacheco-Colon, Duperrouzel, & Hawes, 2017; Stiles & Jernigan, 2010). There is a growing need to better understand how cannabis use impacts brain integrity throughout neurodevelopment, particularly as legalization of cannabis use increases throughout the United States and perception of cannabis-related harm declines among youth (Johnston et al., 2019; Lubman, Cheetham, & Yucel, 2015; Volkow et al., 2016). A clearer understanding of the neurobiological, environmental, and cannabis-related risk factors that contribute to health-related outcomes among adolescent cannabis users will help inform public health policy on cannabis as it pertains to youth.

Few prospective studies have followed adolescent cannabis users and assessed them at multiple independent time points, and/or assessed adolescents pre- and post-cannabis initiation (Gonzalez et al., 2017). Evidence that cannabis use may have deleterious effects on neurodevelopment and result in poorer neural health outcomes is mixed (Meier et al., 2012; Meier et al., 2017), particularly for neurocognitive outcomes (Jackson et al., 2016). For example, studies find heavier use patterns associated with poorer performance on tests of attention, learning and memory, and executive functioning (Gonzalez et al., 2017). However the relationship between cannabis and neural outcomes is often quite attenuated after accounting for recency effects and confounding sociodemographic factors (Scott et al., 2018). Systematic reviews suggest restored functioning with abstinence, poorer outcomes for those with more severe use histories, and shared risk factors (e.g., mental health, psychosocial factors) associated with cannabis initiation and brain-behavior based outcomes (Gonzalez et al., 2017; Scott et al., 2018).

Similarly, neuroimaging studies find structural and functional differences between adolescents reporting a history of cannabis use and those with minimal to no use histories, including differences in microstructural and macrostructural neural tissue indices (Baker, Yucel, Fornito, Allen, & Lubman, 2013; Orr et al., 2019), blood-oxygen level dependent signal responses and neural network integration (Lichenstein, Musselman, Shaw, Sitnick, & Forbes, 2017; Yanes et al., 2018), cerebral blood flow (Filbey, Aslan, Lu, & Peng, 2018; Jacobus et al., 2012), as well as behavioral and emotional functioning (Griffith-Lendering, Huijbregts, Mooijaart, Vollebergh, & Swaab, 2011; Moitra, Anderson, & Stein, 2016). Nevertheless, some studies find no association between cannabis use and brain integrity (Thayer et al., 2017; Weiland et al., 2015). There is strong research to suggest early brain-based vulnerabilities contribute to substance use initiation (Loeber et al., 2018; Spechler et al., 2018), leaving some individuals even more vulnerable to cannabis-related effects than others. Cannabis-related risk is likely moderated by many neural and environmental factors.

To date, our laboratory has conducted a series of prospective investigations that find evidence for both pre-existing brain differences as well as cannabis-related deleterious effects on neurostructural and neurocognitive development in youth. All participants (spanning ages 12–26) in the studies discussed below were recruited from San Diego area schools and screened for exclusion criteria that included major medical and/or mental health problems (e.g., Axis I DSM-IV diagnosis excluding substance use disorders).

Findings from two independent study designs are presented and include: (1) a three year investigation that identified cannabis users at baseline enrollment (>200 lifetime cannabis use episodes at baseline, on average) and demographically matched (e.g., age, socioeconomic status) non-cannabis using controls (< 10 lifetime cannabis use episodes at baseline, on average) and followed them every 18-months for 3 years (ages 17 at enrollment and 20 by last follow-up, on average; N=175 in cohort); and (2) a six-year investigation (on average) of youth at risk of substance initiation at baseline (pre-initiation, average age 13 at enrollment) and followed for 6–14 years (N=296 in cohort). Minimal illicit drug use and tobacco use was reported in both samples, however groups differed on lifetime alcohol use and therefore alcohol use was included as a covariate and/or subgroup analysis as appropriate. Comprehensive neurocognitive, neuroimaging, and substance use assessment was administered at all in-person visits for both studies. The following brief overview of our prospective work over the past decade focuses on associations between cannabis use, neurocognition, and structural brain integrity.

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3-Year Investigation.

Two cross-sectional studies of the first time point in this investigation found group differences between adolescent cannabis users and matched non-cannabis using controls (average age 17) in neurocognition and white matter fiber integrity. Poorer performance on tests of processing speed, attention, memory, and sequencing was observed in the cannabis group (Medina et al., 2007). Greater estimates of white matter fiber integrity were found for controls as compared to cannabis users in widespread bilateral white matter regions that included association and projection fiber tracts (Jacobus et al., 2009). Adolescents from this initial study were prospectively followed and assessed at independent time points 18 and 36-months later (average age 20 by last follow-up) to determine if those remaining cannabis users continued to show evidence of poorer white matter health. We found that controls consistently showed values reflective of better white matter integrity compared to cannabis users who continued to use cannabis over time, and that indices of poorer white matter health were related to poorer global cognitive status by 36-month follow-up (Jacobus, Squeglia, Bava, & Tapert, 2013).

Similarly, we investigated cortical thickness and neuropsychological performance to determine if gray matter refinement (i.e., cortical thinning) was impacted by cannabis use and to identify neurocognitive domains that may be more sensitive to frequent cannabis use. We found adolescents that continued to use cannabis from ages 17 to 20 had thicker cerebral cortices compared to matched controls across both hemispheres, but particularly in frontal and parietal regions. Dose-dependent associations were identified, as more cannabis use was associated with thicker cortices by age 20 (Jacobus, Squeglia, Meruelo, et al., 2015). Neurocognitive domains assessed included attention, learning and memory, processing speed, spatial functioning and executive functioning. Between-group differences between controls and cannabis users were observed across domains, as better cognitive performance was observed by controls over all three years of independent assessment. The largest average effect sizes were observed in attention and memory, as non-cannabis using controls performed substantially better on subtests in this domain over three years as compared to cannabis users (Cohen’s ds > 0.5). We saw positive associations between age of onset and performance on several tasks, particularly processing speed (Jacobus, Squeglia, Infante, et al., 2015), suggesting early age of regular use initiation is likely an important factor in predicting poorer outcomes.

To understand if neural health differences observed in this investigation were cannabis-related vs. pre-existing vulnerabilities, we examined neural tissue integrity and neurocognitive functioning among youth pre- and post-cannabis initiation. In a study conducted by our group in 2013, we observed equal to or greater white matter integrity estimates among cannabis initiators at baseline (pre-initiation, average age 17) compared to those who did not later initiate cannabis use. However, decreasing white matter integrity estimates were observed over time (ages 17–20) in cannabis initiators compared to those who did not initiate cannabis use. The data provide support for a deleterious effect of cannabis on white matter tissue development (Jacobus, Squeglia, Infante, Bava, & Tapert, 2013) independent of possible pre-existing vulnerabilities (see Table 1).

Table 1.

Summary of findings from our laboratory that includes primary results for each study, average age across time points, stage of cannabis initiation across time points, and methods (*= longitudinal analysis).

3-Year Investigation

Author (Year)

Average Age

Cannabis Initiation

Method/Analysis

Primary Result

Medina et al. (2007)

17

Post Initiation

Comprehensive assessment of 8 neurocognitive domains

↓ Attention and memory performance (cannabis)

Jacobus et al. (2009)

17

Post Initiation

Diffusion tensor imaging; Whole brain white matter tissue voxelwise analysis

↓ White matter integrity (cannabis)

Jacobus et al. (2013)*

17–20

Post Initiation

Diffusion tensor imaging; Whole brain voxelwise white matter analysis

↓ White matter integrity (cannabis)

Jacobus, Squeglia, Infante et al. (2013)*

17–20

Pre to Post Initiation

Diffusion tensor imaging; Whole brain white matter tissue voxelwise analysis

↓ White matter integrity (cannabis)

Jacobus, Sqeuglia, Meruelo et al. (2015)*

17–20

Post Initiation

3T MRI; 34 Cortical regions of interest

↑ Cortical thickness (cannabis)

Jacobus, Squeglia, Infante et al. (2015)*

17–20

Post Initiation

Comprehensive assessment of 5 neurocognitive domains

↓ Attention and memory performance; earlier age of onset= ↓ performance (cannabis)

6+ Year Investigation

Author (Year)

Average Age

Cannabis Initiation

Method/Analysis

Primary Result

Nguyen-Louie et al. (2015)*

13–17

Pre to Post Initiation

Comprehensive assessment of 5 neurocognitive domains

↓ Psychomotor speed

Jacobus et al. (2016)*

13–19

Pre to Post Initiation

3T MRI; 34 Cortical regions of interest

↓ Cortical thinning trajectory (cannabis)

Nguyen-Louie et al. (2017)*

13–20

Pre to Post Initiation

Comprehensive assessment of 6 neurocognitive domains

↓ Cognitive inhibition and memory performance

Infante et al. (2018)*

13–19

Pre to Post Initiation

3T MRI; 34 Cortical regions of interest

↓ Cortical surface reduction (cannabis)

Wade et al. (2019)*

13–22

Pre to Post Initiation

3T MRI; Orbitofrontal cortex region of interest

↑ Left lateral orbitofrontal cortex volume prior to cannabis use linked to cannabis use in young adulthood

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6+ Year Investigation.

Several studies conducted from 2016 to 2019 using structural imaging and neurocognitive assessment over a longer follow-up period (6+ years) captured cannabis users prior to initiation (age 13) to better disentangle the contribution of pre-existing differences on neural and behavioral outcomes by young adulthood. Findings suggest a more substantial decrease in cortical thickness (i.e., cortical thinning) and surface area (i.e., gray matter reduction) over time (ages 13–19) for individuals who remained abstinent from cannabis use by young adulthood (Infante, Courtney, Castro, Squeglia, & Jacobus, 2018; Jacobus et al., 2016). Notably, larger left lateral orbitofrontal cortex volume measured from ages 12–15 (prior to cannabis initiation) was linked to greater reward responsiveness and predicted classification as a regular cannabis user by age 22. (Wade et al., 2019). Hence, there is evidence to suggest that pre-existing differences are likely present prior to initiation, but that cannabis use during neuromaturation may also interfere with thinning and gray matter reduction trajectories that contribute to morphological differences by young adulthood (Infante et al., 2018; Jacobus et al., 2016). Nguyen-Louie and colleagues (2015, 2017) found that more recent cannabis use (e.g., past year use) was associated with worse neurocognitive performance during young adulthood after controlling for pre-initiation baseline differences in the sample (see Table 1.) Several associations between neurocognitive test performance and estimates of white and gray matter tissue integrity have been observed, such as increased white matter integrity and more substantial reductions in thickness (i.e., thinning) correlated with better cognitive performance by later follow-up time points (ages 17+) in widespread brain regions (Jacobus et al., 2016). Hence, characterizing early risk-related vulnerabilities and cannabis-related effects on the neural level are important to fully understand potential mechanisms of cannabis-related adverse behavioral outcomes.

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Discussion.

In summary of this brief review of our work, the findings represent a scientific basis that suggests the risks of adolescent cannabis use outweigh any potential benefit during typical development. As only few longitudinal studies outside of our laboratory have examined cannabis users pre- and post-initiation (Jackson et al., 2016; Meier et al., 2012; Meier et al., 2017; Mokrysz et al., 2016), our laboratory will continue to study how pre-existing vulnerabilities and cannabis-related brain changes interact and influence healthy outcomes. Currently, we have evidence to suggest recency, frequency, and age of onset of cannabis are likely key variables in predicting not only poor neural health and cognitive functioning, but emotional functioning as well (e.g., depression) (Jacobus et al., 2017). Larger prospective studies such as the newly launched Adolescent Brain Cognitive Development (ABCD) study will help us better understand the role of pre-existing childhood brain differences that contribute to substance use initiation and progression to problematic use, and ultimately poorer health outcomes for adolescents and young adults (Garavan et al., 2018; Lisdahl et al., 2018).

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Acknowledgements

We would like to thank the National Institute on Alcohol Abuse and Alcoholism (R01 AA013419); the National Institute on Drug Abuse (R01 DA021182; U01 DA041089; R21 DA047953); and the California Tobacco-Related Disease Research Grants Program Office of the University of California Grant 580264. The authors would like to thank participating schools in the San Diego Unified School District and participating families.

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The Neurocognitive Effects of Cannabis Across the Lifespan

Jarrod M. Ellingson, Ph.D.,1,2,* Jesse D. Hinckley, M.D.,1 J. Megan Ross, Ph.D.,1,2 Joseph P. Schacht, Ph.D.,1 L. Cinnamon Bidwell, Ph.D.,3,4 Angela D. Bryan, Ph.D.,3,4 Christian J. Hopfer, M.D.,1,2 Paula Riggs, M.D.,1 and Kent E. Hutchison, Ph.D.1

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Abstract

Purpose of review:

This review examines the neurocognitive effects of cannabis and relevant developmental factors across adolescence (age 13–21), adulthood (21–65), and older adulthood (65+).

Recent findings:

Cannabis use is robustly associated with poorer neurocognitive functioning; however, studies that carefully control for confounds have often not found any evidence for impairment. Notably, the endocannabinoid system may underly how cannabis use affects neurocognitive functions, including heightened vulnerability during adolescence. In contrast, the endocannabinoid system may underlie protective neurocognitive effects of cannabis in older adults. Notably, older adults have reported sharp increases in recent cannabis use.

Summary:

As legalization increases the accessibility, variety, and potency of cannabis, strong empirical evidence is needed to understand its neurocognitive effects across the lifespan. In particular, rigorous study designs are needed to investigate the neurocognitive effects of cannabis, including among vulnerable populations (adolescents, older adults) and mediating (e.g., endocannabinoid system) and moderating factors (e.g., alcohol use).

Keywords: Cannabis, Cannabinoids, Development, Lifespan, Cognitive, Neurocognitive

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Introduction

Recent decades have seen profound shifts in the attitudes, legality, accessibility, and potency of cannabis products, particularly in the United States (U.S.). Based on current state-level policies and U.S. census data, approximately one in three Americans have legal access to recreational cannabis. Further, public opinion polls suggest that most Americans support the federal legalization of cannabis [1]. Importantly, legal cannabis markets have increased the availability of a wide variety of cannabis products, including potent flower (20+% tetrahydrocannabinol [THC]), high-potency concentrates (80+% THC), and novel modes of administration (e.g., vaping, waxes/dabs). The potential public health effects of more potent cannabis products are unclear, but greater levels of cannabinoid exposure are associated with more adverse outcomes.

In addition to the potential public health risks of legal-market cannabis products, the adverse effects of cannabis may be heightened, particularly among adolescents. Adolescence is broadly marked by critical neurodevelopment in affective and cognitive substrates. Further, cannabinoids are thought to exert psychoactive effects via the endocannabinoid system, which may be uniquely susceptible to adverse effects during adolescence [2]. While the mechanisms of the neurocognitive effects of cannabis in adolescence are still being studied, much less is known about how the endocannabinoid system may be susceptible or resistant to similar effects during older adulthood. Whereas evidence is mixed about whether adolescents have increased use since legalizations, epidemiological evidence is clear that adults aged 65+ have had marked increased in cannabis use since legalization [3].

As the general public and scientific community navigate this pivotal period of increasing access to cannabis, evidence is needed to more clearly understand the public health effects of cannabis and cannabinoids across the lifespan. Thus, this review assessed empirical evidence on the neurocognitive effects of cannabis and mechanisms that may vary across the lifespan. Throughout this review, we focus on three primary components of cannabinoid system interactions. First, exogenous cannabinoids are compounds introduced into the body and typically derived from the cannabis sativa plant (e.g., THC). Second, endogenous cannabinoids are compounds produced by the body. Finally, cannabinoid receptors are a mechanism by which endogenous and exogenous cannabinoids exert their effects. This review assesses the neurocognitive effects and mechanisms of cannabis across adolescence (ages 13–21), adulthood (21–65), and older adulthood (65+).

Adolescence

Neurocognitive Effects of Cannabis in Adolescence

There are virtually no human studies examining the acute effects of cannabis in adolescence. Therefore, we focus on the short- and long-term effects of cannabis in adolescents that have been more widely studied.

Adolescent cannabis use is consistently associated with poorer neurocognitive outcomes, but a closer examination of the literature suggests that this association is nuanced. Scott and colleagues recently conducted an extensive meta-analysis on adolescent/young adult cannabis use and neurocognitive functioning. Significant effect sizes were observed for worse performance on tasks of learning (d=−0.33), executive functioning (EF)-abstraction/shifting, (d=−0.30), information processing speed (d=−0.26), delayed memory (d=−0.26), EF-inhibition (d=−0.25), EF-updating/working memory (d=−0.22), and attention (d=−0.21) [4]. Effect sizes were not significant in the domains of verbal/language, visuospatial, and motor functioning. However, across 15 studies that required cannabis abstinence for 72+ hours before assessment, there was no evidence of poorer impairments in any neurocognitive domain. Further, an earlier age of initiation did not influence the effect sizes; however, early initiation was defined inconsistently across studies (ranging from 15–18 years old). A more recent meta-analysis of longitudinal studies examined the effects of cannabis on IQ before and following cannabis initiation. Across the literature, there were minimal decreases in IQ (d=−0.13, ~2 IQ points) among those who initiated cannabis use; however, these decreases were significant among adolescents who frequently used cannabis or met cannabis dependence criteria [5]. Although recent meta-analyses indicate that chronic or frequent cannabis use during adolescence is associated with worse neurocognitive functioning, there is an ongoing debate about whether these decreases are clinically meaningful [6]. Thus, despite a broad link between adolescent cannabis use and poorer neurocognitive functioning, these effects are minimal, may be limited to residual effects within a few days after use, and are most pronounced with heavy use.

Mechanisms of the Neurocognitive Effects of Cannabis in Adolescence

Adolescence is characterized by substantial neurodevelopment, including neuronal differentiation, synaptogenesis, and synaptic pruning to establish mature neuronal networks. The endocannabinoid system is a highly evolutionarily conserved system [7] that is fundamental to adolescent neurodevelopment and modulates the nervous system throughout adulthood [8]. For example, synapses in the endocannabinoid system modulate neurotransmitter release [9], thereby regulating neuromaturation processes [10, 11]. Two components of the endocannabinoid system may be pertinent to the neurocognitive effects of cannabis during adolescence. First, endogenous cannabinoids are made “on-demand” in a precise temporospatial manner to modulate neurodevelopment [11]. Second, the cannabinoid 1 (CB1) receptor is widely expressed in the developing brain [8, 12]. In particular, there is a high concentration of CB1 receptors in white matter areas during adolescence, and CB1 receptor density diminishes in mature neural circuits once synaptogenesis is complete [12, 13]. Notably, CB1 receptor density and endogenous cannabinoid levels peak during early adolescence [14]. Importantly, exogenous cannabinoids (e.g., THC) act on the endocannabinoid system. For example, the psychoactive effects of THC occur specifically via its binding to the CB1 receptor. As a result of the endocannabinoid system modulating neurodevelopment and mediating the psychoactive effects of THC, the adolescent brain may be uniquely vulnerable to the adverse effects of cannabis use [15, 16].

Whereas endogenous cannabinoids affect neural activity in a temporally- and spatially-specific manner, exogenous cannabinoids (e.g., THC) affect neural activity for several hours and in a non-specific manner [8]. In addition, exogenous cannabinoids are lipophilic and readily cross the blood-brain barrier [17]. Thus, cannabinoid exposure during neurodevelopment may interfere with neuronal differentiation and survival, alter neurotransmitter system development, and diminish neurocognitive functioning as a result [18]. Notably, much of what is known about the biochemical impact of exogenous cannabinoid exposure on the adolescent brain has been elucidated from animal models. Additional information can be garnered from neuroimaging studies, including associations between cannabis use in adolescents and adults (see below).

Neuroimaging studies investigating the effects of cannabis in adolescents have received immense interest [19–24]. A recent review summarized findings across three neuroimaging meta-analyses of adolescent cannabis use [25–28]. Notably, the extant literature suggests altered brain activation among adolescents who use cannabis, compared to those who do not use cannabis, during neurocognitive tasks. However, findings are inconsistent regarding specific brain regions that differ as a function of cannabis use. For example, prefrontal regions and the insula may be affected by cannabis exposure, resulting in adverse neurocognitive effects. Further, as reviewed by Lu et al., exposure to cannabinoids may alter the development of crucial neurotransmitter systems, including dopamine, serotonin, gamma-aminobutyric acid (GABA), and the opioid system [8]. Neurotransmitter system anomalies in the prefrontal cortex, in particular, may increase disinhibition and underlie the cognitive decrements associated with long-term cannabis use [18].

In addition, neuroimaging evidence implicates the endocannabinoid system in the development of neurocognitive functioning [29]. For example, CB1 receptors are highly expressed in the hippocampus, and the endocannabinoid system is broadly implicated in memory acquisition, consolidation, and retrieval [18]. As a result of chronic cannabis use activating the endocannabinoid system, neurodevelopment and neurocognitive functioning may be adversely affected. For example, exogenous cannabinoid exposure during adolescence may decrease glutamatergic neurotransmission and contribute to learning impairment [30]. Further, exogenous cannabinoid exposure is associated with altered hippocampal long-term potentiation, glutamate release, and impaired neurocognitive functioning [31]. Thus, the endocannabinoid system affects the development of neural substrates that underlie neurocognitive functioning. Consequently, cannabis use may impair neurocognitive functioning during adolescence and potentially later in life.

Summary of Cannabis Effects in Adolescence

Cannabis is associated with neurocognitive decrements in adolescence across several domains, including learning, memory, and executive functioning. However, it is unclear whether cannabis impairs long-term neurocognitive functioning or whether any impairment persists with abstention. Study designs that reinforce abstinence amongst adolescent users and examine changes post abstinence could shed light on these questions.

Some mechanisms have been identified that may explain how cannabis use reduces neurocognitive functioning. In particular, the endocannabinoid system has received substantial attention, given its roles in neurodevelopment and the psychoactive effects of THC. Peripheral endocannabinoid markers partially reflect central processes and offer a possible window into the developing brain [32]. However, it is important to consider mechanistic studies in the context of findings from large-scale studies investigating the neurocognitive effects of cannabis. Although cannabis use introduces exogenous cannabinoids that may perturb the endocannabinoid system, evidence suggests that diminished neurocognitive functioning may only occur within a few days after last use or if these perturbations are frequent and chronic.

Adulthood

Neurocognitive Effects of Cannabis in Adulthood

The acute, neurocognitive effects of cannabis use have primarily been studied in young and middle-aged adults (i.e., 21–65). Placebo-controlled, laboratory-based cannabis administration studies consistently suggest that cannabis acutely impairs episodic and working memory, attentional processing, and executive functioning (shifting) in this age group (for review, see [33]). One of the most robust cognitive harms of cannabis use is acute memory impairment during intoxication [34–37], but regular users show minimal performance decrements [37, 38]. Similarly, cannabis acutely impairs divided attention among occasional users, but not heavy users [39]. Findings across these studies suggest that experienced cannabis users may be tolerant to the acute effects of cannabis. However, some evidence suggests a dose-response relationship on executive functioning may occur even among regular users. For example, performance on the Wisconsin Card Sorting Test is substantially impaired after 17 mg THC and less so after 13 mg THC [40]. Further, a recent study found acute effects on delayed verbal memory among tolerant high-potency concentrate users (i.e., THC ≥ 75%); however, effects were not seen in other cognitive domains [41]. Thus, tolerance may play a role in some of the acute neurocognitive effects of cannabis, but dose-response effects suggest that THC may acutely affect neurocognitive performance even among experienced users.

As with adolescents, there is a robust effect across the literature of chronic cannabis use and poorer neurocognitive functioning among middle-aged adults, but there are important caveats to these findings. In particular, cannabis use does not occur in isolation from other neurocognitive risk factors. Instead, cannabis use and adverse mental health outcomes co-occur with many environmental risk factors, including peer group deviance, familial psychopathology, family-of-origin marital instability, and lower family-of-origin socioeconomic status (SES) [42–44]. Controlling for covariates such as SES and other drug use has explained the effects of cannabis use on worse processing speed and executive functioning but not on verbal memory [43, 45]. Alternatively, family-controlled designs have provided a powerful way to control exhaustively for confounding genetic and environmental factors that make family members alike (e.g., siblings or twins). These studies have generally found that, among sibling/twin pairs, the heavier using family member does not tend to have worse neurocognitive functioning [46]. However, adverse effects have been observed for higher levels of cannabis use on delayed verbal recall [47]. Notably, the amount and duration of cannabis use and the length of abstinence are challenging to assess retrospectively, suggesting that prospective studies should be prioritized.

Mechanisms of the Neurocognitive Effects of Cannabis in Adulthood

After neuromaturation concludes in emerging adulthood, the endocannabinoid system regulates synaptic plasticity [9] and modulates neurocognitive functioning throughout adulthood [17]. Further, positron emission tomography research has found that CB1 receptors are downregulated in chronic cannabis users, indicating decreased CB1 receptor density. However, these effects are reversed by abstaining from cannabis for four weeks. Thus, the endocannabinoid system may continue to play a role in neurocognitive effects in adults.

Cerebral blood flow (CBF) is an important neurophysiological mechanism and may affect neurocognitive functioning [48]. Concerning the acute effects of THC, early neuroimaging studies of regional CBF demonstrated that acute THC administration affects brain function and increases metabolic activity, particularly in the frontal and parietal cortices [49–52]. These findings have been refined with increased spatial resolution. More recent findings suggest that THC increases CBF in the anterior cingulate cortex, bilateral insula, medial superior frontal, and left orbital frontal cortex [53–56]. Notably, only two studies, to our knowledge, have investigated the effects of CBD on CBF [57, 58]. These studies found CBF reductions in the left hippocampal complex (hippocampus, parahippocampal gyrus, amygdala) but conflicting effects in the posterior cingulate cortex.

In the last decade, studies have examined the effects of exogenous cannabinoids on resting-state connectivity. Two studies have suggested that THC disrupts resting-state networks in the superior frontal pole, middle and inferior frontal gyri, and dorsolateral prefrontal cortex (via inhalation; [59]) and in subcortical areas that include the PFC (via oral administration; [60]). Additionally, increased frontostriatal activity has been observed following a high dose of CBD (oral, 600 mg) but not following a low dose CBD (oral, 10 mg), suggesting a dose-dependent effect [61]. However, only a few studies have examined how THC and CBD affect neural connectivity, making it difficult to draw firm conclusions. Thus, additional studies are needed to understand how cannabis use affects connectivity more clearly.

Several recent studies have used magnetic resonance spectroscopy (MRS) to investigate whether acute and chronic cannabis use is associated with changes in neurotransmitter systems. MRS allows for investigating the molecular mechanisms by which THC exerts its effects on behavior, with a focus on glutamate. Preclinical studies suggest that acute THC dose-dependently reduces synaptic glutamate and neurotransmission [62]. Measurements of subcortical glutamate/glutamine (Glx) have also shown increases after THC administration in humans, which converges with preclinical work [62, 63]. CBD appears to have similar effects on subcortical Glx but decreases Glx in the anterior cingulate cortex [64]. Notably, baseline Glx levels may moderate the degree to which changes occur after acute administration, with higher Glx levels at baseline predicting greater changes after acute THC administration [62]. Among chronic cannabis users, MRS studies suggest that glutamate metabolites are 10–15% lower in substrates related to neurocognitive functioning (e.g., anterior cingulate cortex), and some findings suggest accompanying reductions in GABA (for review, see [53]). In summary, recent findings from MRS studies suggest that it represents a key translational methodology to identify potential targets for investigating individual differences in response to varying levels of exogenous cannabinoids.

Summary of Effects in Adulthood

The extant literature suggests that THC and CBD affect memory, but these effects may vary by tolerance, dose, timing, and form of administration [41]. Specifically, cannabis use is associated with acute impairment of memory, attention, and executive functioning, as well as persistent decrements in verbal memory in middle-aged but not younger adults. In addition, adverse effects of chronic exposure on memory and learning have been observed, even in some studies that carefully control confounds. Thus, rigorously designed prospective longitudinal studies that can measure and account for confounding factors are needed, as well as carefully conducted laboratory-based studies that investigate mechanisms.

Older Adulthood

Neurocognitive Effects of Cannabis in Older Adulthood

Recent epidemiological research (i.e., the National Survey of Drug Use and Health) indicates that cannabis use increased by approximately 10-fold between 2007 and 2018 among adults over age 65 [3]. While there are numerous public health questions related to the use of cannabinoids in this population, one crucial question is how cannabinoids might impact neurocognitive functioning in older adults, who are already at risk because of their age for mild cognitive impairment and dementia. The importance of this question is underscored by the rapidly aging global population and the mortality, morbidity, and socioeconomic costs of dementia (estimated $2 trillion by 2030; [65]). Unfortunately, while there has been substantial interest in the effects of cannabis use on neurocognitive functioning in adolescents, emerging adults, and even middle-aged adults, there have been very few studies in aging adults.

Despite the dearth of existing studies, there has recently been increasing interest in the role of cannabinoids and changes in neurocognitive functioning in aging in animal and human studies [for recent reviews, see 66]. While most animal studies on THC model these effects in young animals, there are now a few studies on the effects of cannabinoids in aging animals. In one study, chronic administration of low doses of THC was shown to reverse age-related cognitive decline. These effects were associated with molecular and neuronal changes in the hippocampus [67]. Similarly, in another study, a single low dose of THC improved neurocognitive functioning [68]. These results contrast with the deleterious effect of THC in brain development and neurocognitive functioning in young animals [67]. These intriguing initial findings highlight the need for further animal studies to better model and understand the impact of cannabis on aging in humans.

There are very few studies in humans examining the neurocognitive effects of cannabis in older adults. Two longitudinal studies in adults (~50 years old) reported that cannabis was associated with improved performance on cognitive tasks, and these improvements were accompanied by changes in brain activity [69, 70]. Another study in an older sample (age 60+) suggested no differences in neurocognitive functioning, positive or negative, between long-term cannabis users and non-users. In that same study, cannabis users had greater gray matter volume in the putamen than non-using older adults [71]. More recent studies with an aging population (age 60+) found that regular cannabis users, compared to non-users, had greater gray matter density (typically associated with increased abilities) in subcortical regions such as the putamen, pallidum, and caudate [72]. Additionally, frequent cannabis use in this sample was associated with greater functional connectivity in hippocampal and cerebellar areas [73]. Finally, a recent comparison of the acute effects of cannabis on cognitive measures indicated that a group of older adults (age >55) were less sensitive to the deleterious effects of THC as compared to a group of younger adults (age < 25) [74].

Mechanistic Changes of the Neurocognitive Effects of Cannabis in Older Adulthood

A crucial question is, by what mechanism do cannabinoids affect neurocognitive functioning in the aging population? There appear to be two basic candidates that might explain the beneficial neurocognitive effects of cannabinoids in an aging population. The first mechanism is related to the endocannabinoid system, consisting of receptors (CB1 and CB2) and endogenous ligands (2-AG and AEA). As discussed above, the endocannabinoid system plays a vital role in brain development, and CB1 receptors peak during adolescence. From adolescence through older adulthood, CB1 receptors decrease by about 50% (for review, see [75]). The loss of CB1 receptors and 2-AG in subcortical regions is associated with loss of gray matter density [76]. In contrast, increased levels of CB1 and 2-AG are associated with neurogenesis in these areas. It is unclear whether exogenous cannabinoids (e.g., THC) stimulate the endocannabinoid system in ways that enhance CB1 or 2-AG functioning, thereby delaying the neurodegeneration that coincides with aging.

A second possible mechanism is related to the effect of cannabinoids and the endocannabinoid system on neuroinflammation (for review, see Andrade et al., under review). Neuroinflammation has been implicated in aging on the loss of neurocognitive function. As we age, neuroinflammatory mediators (e.g., cytokines, chemokines, prostaglandins, free radicals) are upregulated in the brain, and these markers have been linked to age-related cognitive impairment and dementia [77–82]. For example, higher interleukin (IL)-6 levels have been associated with poorer auditory and working memory performance [83] and a general decline in neurocognitive function [84]. Furthermore, serum levels of cytokines are elevated in dementia and AD [85, 86], and IL-6 levels are negatively associated with gray matter volume [83]. Persistent neuroinflammation is also associated with Aβ plaques and neurofibrillary tangles, which signal neurodegeneration [87]. While the specific effects of the endocannabinoid system and cannabinoids still need to be carefully elucidated, the anti-inflammatory properties of cannabinoids have been widely documented [88, 89]. Cannabinoids exhibit immunomodulatory actions through several mechanisms impacting immune cell proliferation, migration, apoptosis, cell signaling, and cytokine production and release [90].

Summary of Effects in Older Adulthood

On balance, the few recent studies with humans suggest that cannabis may have long-term positive effects on brain structure and function among aging populations. Furthermore, the acute cognitive effects may be less deleterious in older adulthood. However, much remains unknown. For example, animal and human studies have primarily focused on the effects of THC. Virtually nothing is known about the effects of CBD in this population. In addition, other potential risks of cannabis may be more relevant to older adults compared to other ages (e.g., the psychomotor effects and risk of falling) and need to be more thoroughly examined. Finally, it is important to note that the age of initiation of regular use needs to be examined, as some studies have suggested that THC use in early development may have deleterious effects later in life, whereas later initiation may not [91]. Future human studies need to examine this variable more carefully.

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Conclusions

While there has been a swift shift in the legality, accessibility, and potency of cannabis in the last decade, rigorous research on the public health effects of these new products has lagged [92]. Here, we reviewed the state of the scientific literature on the neurocognitive effects of cannabis across the lifespan. Among adolescents and adults, there is a link between cannabis use and poorer neurocognitive functioning. Notably, well-controlled studies of adolescents and adults have generally found little evidence of adverse neurocognitive effects. In middle-aged adults, recent evidence suggests that neurocognitive effects occur but vary by tolerance, dose, timing, and form of administration. Finally, the empirical literature has largely overlooked the potential for neurocognitive effects of cannabis in older adults (e.g., age 65+), despite this age cohort reporting a 10-fold increase in cannabis use during the last 10–20 years. Further, the aging brain is at risk for mild cognitive impairment and dementia. Thus, there is a clear and pressing need to understand whether THC, CBD, and other cannabinoids affect neurocognitive functioning among older adults.

A review of the literature identifies at least three considerations for future research. First, evidence implicates the endocannabinoid system in the neurocognitive effects of cannabis across the lifespan, including the potential for deleterious effects in adolescents and beneficial effects in older adults. Thus, studies investigating mechanisms within the endocannabinoid system may help advance our understanding of the neurocognitive effects of cannabis across the lifespan. Second, most mechanistic studies investigating the endocannabinoid system’s role have focused on adults (age 21–65). As discussed throughout, there are important developmental changes in the endocannabinoid system, highlighting the need for similar mechanistic studies in adolescents and older adults. Finally, many studies that control for other substance use or familial confounds have often yielded negligible effects of cannabis use on neurocognitive outcomes. Even among these well-controlled studies, some findings remain consistent with a causal effect among heavy users; however, it is unclear whether these effects are clinically meaningful. Thus, as cannabis legalization appears likely to continue across the U.S. and worldwide, there is a particular need for studies that apply careful controls and investigate the mechanisms of how cannabis use may affect neurocognitive functioning across the lifespan.

Table 1.

Summary of key articles and findings on the effects of cannabis across adolescents, emerging/young adults, and older adults.

Study

Developmental Period

Study Design

Key Findings

Rubino et al., 2015 16

Adolescents & Emerging Adults (M age = 17.8 – 24.3)

Meta-analysis of neuroimaging studies of cannabis users vs. non-users

Cannabis users have altered neural activity during neurocognitive tasks.

Scott et al., 2018 4

Emerging Adults (M age = 20.6 – 20.8)

Meta-analysis, primarily of regular cannabis users

Cannabis users performed worse on learning (d=−0.33), shifting (d=−0.30), processing speed (d=−0.26), delayed memory (d=−0.26), inhibitory (d=−0.25), working memory (d=−0.22), and attention (d=−0.21). Effects do not continue after 72 hours since last use.

Bloomfield et al., 2019 53

Adolescents & Young Adults

Review of acute and chronic effects

Chronic cannabis users may have anomalous glutamatergic and GABAergic functioning in neurocognitive substrates, which may increase risk for neuropsychiatric problems.

Crane et al., 2013 33

Emerging & Young Adults

Review of acute and non-acute effects in regular users

Cannabis acutely impairs episodic and working memory, attentional processing, and executive functioning (shifting) in adults. Non-acute impairments in episodic memory are seen in adults, but level of use likely plays a role.

Broyd et al., 2016 35

Primarily Young Adults

Review of acute effects and chronic effects

Acute and chronic effects of cannabis on poorer verbal learning, verbal memory, attention, psychomotor functioning. Tolerance may not reduce acute neurocognitive effects of cannabis.

Di Marzo et al., 2015 7

Adolescents through Older Adults (primarily from animal models)

Review of the endocannabinoid system in aging and neurodegenerative disorders

CB1 receptor density decreases by 50% from adolescence through older adulthood. Endocannabinoid changes may broadly increase risk for neurodegenerative diseases.

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Note. Mean ages are listed for the meta-analyses that included this information.

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Acknowledgments

We thank Melissa Roark and Jamie Cavanaugh for their help in preparing this manuscript.

Financial Support

Funding for this study was provided by the National Institutes of Health Grants DA000357 (JDH), DA042755 (JMR), DA044131 and AT009541 (LCB), DA050515 and AG066698 (ADB), DA032555 and DA042755 (CJH), and DA048069 and DA039707 (KEH).

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