Approximately 147 million people across the world consume cannabis annually, making it the most commonly used illicit drug globally (1). Although the use of cannabis has generally become more accepted and perceptions of harm have been decreasing in recent years (2), negative effects of cannabis use on health and well-being have been identified. Cannabis use has been found to be associated with neurocognitive deficits in memory, learning, and attention and to contribute to alterations to both brain function and structure [see Volkow et al. (3) for review]. However, existing studies examining the neural correlates of cannabis use have produced mixed findings in relation to cannabis-specific effects. The question of whether–and to what extent–cannabis use produces unique neural detriments compared with other psychoactive substances remains largely unknown. A possible reason for this knowledge gap is that there are likely other variables at play, variables that are often unaccounted for, that confound direct associations between cannabis use and neural outcomes. Pulling from literature at the intersection of developmental science, addiction research, and neuroscience, two likely targets are age and polysubstance use.

In the current issue of Biological Psychiatry, Knodt et al. (4) incorporated these targets in their analyses examining the prospective influences of cannabis and other drugs on global and regional gray and white matter integrity measured at midlife. Analyses were conducted using data from the Dunedin Study, which is composed of a large-scale, population-representative sample with data on cannabis use and the use of other substances collected across 5 decades of development up to 45 years of age. Neuroimaging assessments were also conducted when participants were 45 years of age. One important finding from this work pertains to machine learning analyses used to create a brain age gap estimate. This estimate provided a measure of the difference between chronological age predicted from brain structure data and actual chronological age. Knodt et al. (4) reported that long-term cannabis users had older brain ages and thinner global and regional cortices compared with lifelong nonusers, and heavier cannabis use contributed to thinner global and regional cortices and smaller gray matter volume in the amygdala, hippocampus, thalamus, and ventral diencephalon. Interestingly, however, these results were no longer significant after adjusting for long-term use of other drugs. Knodt et al. (4) suggest that in midlife, long-term tobacco and alcohol use may lead to alterations in structural brain integrity to a greater extent than long-term cannabis use. Long-term alcohol users had older brain ages and greater detriments to both gray and white matter compared with long-term cannabis users; compared with both long-term cannabis and alcohol users, long-term tobacco users had even older brain ages and thinner cortices. Thus, cannabis use in itself may not be driving deficits in structural brain activity and accelerated brain age.

There are several key reasons why it is important for studies such as Knodt et al.’s (4) to account for the potential age-related impacts of substance use on neural indices, including brain structure. First, rates of substance use tend to vary by age, with initial experimentation beginning in adolescence, peak use occurring in young adulthood, and use then decreasing and leveling out through middle to older adulthood. According to the Monitoring the Future Survey, a national panel survey tracking substance use in the United States beginning in adolescence and continuing through older adulthood, nearly a quarter (24.5%) of adults 35 to 50 years of age used cannabis in the past year (2). Substances can also have differential effects on the brain at different phases of development. These impacts act in concert with normal developmental changes to the brain in middle to older adulthood. For example, in a healthy sample of adults 23 to 87 years of age in which structural brain integrity was measured approximately every 4 years, Storsve et al. (5) found increases in temporal and occipital cortices but decreases in prefrontal and anterior cingulate cortices as a function of age. Thus, age-related changes in the brain continue to occur throughout the lifespan.

In addition to developmental considerations, studies examining cannabis use in relation to neural outcomes, including impacts on structural brain integrity, often do not account for potential confounding effects of the use of other substances. On one hand, cannabis shares similarities with all drugs of abuse in that cannabis use elicits the release of dopamine in the mesocorticolimbic reward system. The highly rewarding properties of drugs of abuse then motivate continued use, which may lead to addiction. Indeed, about 9% of cannabis users meet the criteria for cannabis use disorder. Findings tend to be mixed, however, in terms of the unique effect of cannabis on neural indices (6). Advancing this existing body of research, Knodt et al. (4) leveraged substance use data across multiple data collection waves (ages 18, 21, 26, 32, 38, and 45 years) for cannabis, tobacco, and alcohol and 4 data collection waves (ages 26, 32, 38, and 45 years) for illicit drug use. Their sample was then categorized into long-term cannabis users and 3 other comparison groups–lifelong cannabis nonusers, long-term tobacco users, and long-term alcohol users. Regular cannabis use was exclusionary in long-term tobacco and alcohol user groups, but other substance use was allowed to vary for long-term cannabis users. In this way, regularity of use over time and use across substance types could be examined. Knodt et al. (4) also reported tests of dose-response associations to assess the effects of level of use on structural brain integrity. Indeed, more persistent use across substances and over time contributed to older brain age and a greater extent of impacts to structural gray and white matter.

The findings presented by Knodt et al. (4) are compelling, but future work is needed to expand upon their research and provide a more definitive answer regarding the unique role of specific psychoactive substances, including cannabis, on the aging brain. An important future direction is to examine associations between cannabis and other substance use on structural brain integrity beyond midlife and into older adulthood. The extent to which cannabis and other substances, especially when used chronically, impacts the aging brain is still relatively unknown, and findings are often mixed (7). Older adult substance users may be especially vulnerable to the neurotoxic effects of substances, considering that they metabolize substances more slowly and experience greater age-related impacts on brain plasticity and cognitive decline compared with younger adults (3). However, existing neuroimaging studies assessing cannabis use in older adults have often been limited by small sample sizes and the lack of adequate comparison groups (8).

Another avenue for future research to build upon findings presented by Knodt et al. (4) is to incorporate more nuanced measures of cannabis use. For example, additional research is needed that accounts for route of cannabis administration and Δ⁹-tetrahydrocannabinol concentration. Methods to administer cannabis can affect how rapidly intoxication occurs. For instance, orally administered products (i.e., edibles) tend to take longer to metabolize. Not feeling an immediate high may lead to additional consumption and, later, more amplified psychotropic effects. Furthermore, an increasing array of products with highly concentrated Δ⁹-tetrahydrocannabinol are available, especially in states and countries where cannabis has been legalized and dispensaries are easily accessible. Higher-potency cannabis is of particular concern, as it has been found to increase risk for the onset of first cannabis use disorder symptom (9). In addition, the extent to which concurrent use (i.e., the regular use of substances but not using more than one substance at a time) versus simultaneous use (i.e., the co-use of multiple substances at the same time, such as using alcohol and cannabis on the same occasion) may exert different influences on brain structure and function remains largely unknown. Simultaneous use of substances is relatively common, but its effects on the brain are complex and difficult to measure (10). Taken together, important future directions include using data from samples large enough to be able to account for comorbid substance use, leveraging longitudinal data that include imaging data as well as more nuanced information on quantity and frequency of use over time, and assessing developmental periods when cannabis use may be most detrimental to neuropsychological impairment (3).

In sum, Knodt et al. (4) advance the current literature in several important ways. Their work provides novel evidence that calls into question the unique role of long-term cannabis use on structural brain integrity in midlife and highlights the need to investigate the neural effects of other drug use, including alcohol and tobacco use. While it is likely that the cumulative effects of cannabis can include alterations to structural brain integrity, important questions remain. For instance, how expansive and long-lasting are the effects of Δ⁹-tetrahydrocannabinol on the endocannabinoid system, and what is the relative harmfulness of cannabis compared with other drugs of abuse? The results reported by Knodt et al. (4) pave the way for future studies to begin answering these questions and to disentangle the complexities of cannabis-specific effects on the brain.

Summary

An estimated 147 million individuals globally consume cannabis annually, making it a widely used substance. While public perception of its harm has decreased, research has identified potential negative impacts on health and well-being. These include associations with cognitive deficits in memory, learning, and attention, along with alterations to brain function and structure. However, studies examining the brain-specific effects of cannabis often yield mixed findings. A key challenge is distinguishing the unique neural effects of cannabis from those caused by other psychoactive substances, particularly given confounding variables such as age and the common practice of using multiple substances.

A recent study by Knodt and colleagues addressed these complexities by examining the long-term influence of cannabis and other drugs on brain integrity in midlife, utilizing data from the Dunedin Study, a large-scale, long-term research project. The study's innovative machine learning analyses generated a "brain age gap estimate," which measures the difference between an individual's actual age and their brain's predicted age based on structural data. Initially, long-term cannabis users showed older brain ages, thinner global and regional cortices, and smaller gray matter volume in areas like the amygdala and hippocampus compared to lifelong non-users. Crucially, these findings lost significance after adjusting for the long-term use of other drugs. The researchers concluded that in midlife, long-term tobacco and alcohol use might contribute to structural brain alterations more significantly than long-term cannabis use, with tobacco users showing the oldest brain ages and thinnest cortices among the groups studied. This suggests that cannabis use by itself may not be the sole cause of accelerated brain aging or structural brain deficits.

Understanding the interplay between substance use, age, and brain health requires careful consideration of developmental factors and polysubstance use. Substance use patterns change across the lifespan, and the brain itself undergoes continuous development and age-related changes. Furthermore, while cannabis, like other substances, affects the brain's reward system, its specific impact on neural pathways remains a complex area of study. The Knodt study significantly advanced this field by meticulously tracking various substance use patterns across multiple decades, allowing for the categorization of users and the assessment of dose-response relationships. Their findings indicate that more persistent use of any substance over time consistently contributes to an older brain age and greater impacts on both gray and white matter.

Future research should expand upon these findings by investigating the associations between cannabis and other substance use on brain integrity beyond midlife and into older adulthood. Older adults may be particularly susceptible to the neurotoxic effects of substances due to slower metabolism and greater age-related changes in brain plasticity and cognitive function. However, current neuroimaging studies involving older adults often have limitations, such as small sample sizes and a lack of adequate comparison groups. Additionally, future studies need to incorporate more detailed measures of cannabis use, including its route of administration and concentration of Δ9-tetrahydrocannabinol. Distinguishing the effects of concurrent (sequential) versus simultaneous (co-occurring) use of multiple substances is also critical, as simultaneous use is common but its complex effects on the brain are not well understood.

In summary, the work by Knodt and colleagues provides valuable insights, challenging the notion of cannabis having a unique, isolated role in midlife structural brain integrity. It highlights the critical need to investigate the neural effects of other commonly used drugs, particularly alcohol and tobacco. While cumulative effects of cannabis on structural brain integrity are probable, the study underscores significant questions that remain, such as the long-term impact of Δ9-tetrahydrocannabinol on the endocannabinoid system and the relative harmfulness of cannabis compared to other substances. This research paves the way for future studies to disentangle the complex effects of various substances on the aging brain.

Summary

Globally, cannabis is widely consumed, and while its acceptance has grown, concerns remain about its impact on health. Research has linked cannabis use to issues with memory, learning, and attention, as well as changes in brain function and structure. However, studies on the brain effects of cannabis often show mixed results, making it unclear whether cannabis uniquely harms the brain compared to other substances. This uncertainty may stem from other factors, such as a person's age and the use of multiple substances, which are not always fully considered in research.

A recent study by Knodt and colleagues examined the long-term effects of cannabis and other drugs on brain structure in middle age. The study used data from a large group of individuals tracked from birth to age 45, including their substance use history and brain scans at age 45. Researchers used a "brain age gap" estimate, which compares a person's predicted brain age based on their brain structure to their actual age. Initially, long-term cannabis users showed signs of older brain ages and thinner brain regions compared to those who never used cannabis. However, these findings changed significantly when the researchers accounted for the long-term use of other substances. The study suggested that long-term use of tobacco and alcohol may cause more significant changes to brain structure in midlife than long-term cannabis use. In fact, individuals who used alcohol or tobacco long-term showed greater signs of accelerated brain aging and damage than long-term cannabis users. This indicates that cannabis use by itself may not be the main cause of these brain changes or faster brain aging.

It is important for research to consider how both age and the use of multiple substances affect brain health. Substance use patterns change across a person's life, with peak use often occurring in young adulthood. Additionally, substances can affect the brain differently at various developmental stages, and these effects interact with normal brain changes that occur with aging. Furthermore, isolating the specific effects of cannabis on the brain is challenging because many individuals use multiple substances. Cannabis, like other addictive drugs, influences the brain's reward system. To address these complexities, Knodt and colleagues collected extensive data on the use of various substances over many years, allowing them to compare long-term cannabis users with non-users and long-term users of tobacco and alcohol. This detailed approach helped show that persistent use of multiple substances over time, rather than just cannabis, was linked to accelerated brain aging and greater changes in brain structure.

While the Knodt study provides valuable insights, more research is needed to fully understand the unique effects of cannabis and other substances on the aging brain. Future studies should investigate brain changes beyond middle age, especially in older adults who may be more vulnerable to the harmful effects of substances due to slower metabolism and age-related brain changes. It is also crucial for future research to include more detailed information about cannabis use, such as how it is consumed (e.g., smoking versus edibles), the concentration of its active compounds like THC, and whether it is used alone (concurrently) or with other substances at the same time (simultaneously). Understanding these nuanced aspects of substance use will help clarify their complex impacts on brain structure and function.

In summary, the work by Knodt and colleagues significantly contributes to current understanding by questioning whether long-term cannabis use uniquely affects brain structure in midlife. Their findings highlight the importance of considering the impact of other substances, particularly alcohol and tobacco, on brain health. While cannabis likely contributes to brain changes over time, critical questions remain about its long-term effects on the brain's systems and its overall harm compared to other drugs. This research opens the door for future studies to provide clearer answers and better understand the specific and complex ways cannabis affects the brain.

Summary

Globally, approximately 147 million people consume cannabis each year, making it the most frequently used illicit drug. While public acceptance of cannabis has grown and perceptions of its harm have decreased, research has identified negative effects on health and well-being. Cannabis use has been linked to problems with memory, learning, and attention, as well as changes in brain function and structure. However, studies on how cannabis specifically affects the brain have shown mixed results. It remains largely unclear whether cannabis use causes unique brain damage compared to other substances that affect the mind. One reason for this lack of clarity is that other factors, often not considered in studies, may hide the direct connections between cannabis use and brain outcomes. Two such important factors are a person's age and the use of multiple substances.

A study by Knodt and colleagues examined these factors by looking at how cannabis and other drugs influenced brain health over time. Their analysis used data from a long-term study that tracked substance use from adolescence up to age 45. Brain scans were also conducted at age 45. A key finding involved using a "brain age gap" estimate, which measured the difference between a person's actual age and the age their brain appeared to be based on its structure. The study initially found that long-term cannabis users had older-looking brains and thinner brain regions compared to those who never used cannabis. However, these findings were no longer significant once the researchers accounted for the long-term use of other drugs. The study suggested that, in midlife, long-term use of tobacco and alcohol may cause more significant changes to brain structure than long-term cannabis use. Those who used alcohol long-term had older-looking brains and more damage to brain matter than long-term cannabis users. Long-term tobacco users showed even more significant brain aging and thinner brain regions compared to both cannabis and alcohol users. This suggests that cannabis use alone may not be the primary cause of brain structure problems or accelerated brain aging.

Further research is necessary to build on these findings and gain a clearer understanding of how specific substances, including cannabis, uniquely affect the aging brain. It is important to study these associations beyond midlife, into older adulthood, especially since older adults may be more vulnerable to the harmful effects of substances due to slower metabolism and age-related brain changes. Current studies on cannabis use in older adults are often limited by small sample sizes and a lack of good comparison groups. Future research also needs to include more detailed information about cannabis use itself. For instance, studies should consider how cannabis is administered (e.g., edibles vs. smoking) and the concentration of its active compounds, like Δ9-tetrahydrocannabinol. Higher-potency cannabis is a particular concern, as it has been linked to an increased risk of developing cannabis use disorder. Understanding the differences between using multiple substances at different times versus using them simultaneously is also important, as their combined effects on the brain are complex and not well understood.

In summary, the work by Knodt and colleagues significantly advances existing research. Their findings provide new evidence that questions whether long-term cannabis use uniquely affects brain structure in midlife. It also highlights the critical need to investigate the brain effects of other drugs, including alcohol and tobacco. While it is likely that the ongoing use of cannabis can lead to changes in brain structure, many important questions remain unanswered. For example, how extensive and lasting are the effects of specific compounds like Δ9-tetrahydrocannabinol on the brain, and how harmful is cannabis compared to other addictive drugs? The results reported by Knodt and colleagues pave the way for future studies to begin answering these questions and to untangle the complex, specific effects of cannabis on the brain.

Summary

Many people around the world use cannabis each year. While more people now see cannabis as less harmful, using it can still cause health problems. For example, it has been linked to issues with memory, learning, and focus. It can also cause changes to the brain. However, studies do not always agree on how much cannabis use alone affects the brain. Other things, like a person's age and whether they use other drugs, often play a role and can make it hard to tell the exact effects of cannabis.

A recent study looked at how long-term use of cannabis and other drugs affects the brain in middle-aged people. The study used information collected from many people over many years. It looked at how "old" a person's brain appeared based on brain scans, compared to their actual age. People who used cannabis for a long time had brains that looked "older" and had thinner parts. However, the study found that when they considered the use of other drugs, such as tobacco and alcohol, the effects of cannabis on the brain were not as clear. The study suggested that long-term tobacco and alcohol use might cause more brain changes and make the brain seem older than long-term cannabis use. This means cannabis use by itself might not be the main reason for certain brain changes.

It is important for studies to consider a person's age when looking at how drug use affects the brain. People tend to use drugs differently at different ages, with more use often seen in young adulthood. Also, drugs can affect the brain in different ways as it develops and changes over a person's life. These drug effects can happen at the same time as the brain's natural aging process.

Studies often need to consider the use of other substances when looking at how cannabis affects the brain. All drugs, including cannabis, can affect the brain's reward system, which can lead to addiction. The study mentioned earlier carefully looked at how using different drugs for a long time affected the brain. It showed that using more drugs over time, or using them for longer periods, was linked to older brain ages and more changes in brain structure.

More research is needed to better understand how cannabis and other drugs affect the brain as people get older, especially beyond middle age. Future studies should also look at more specific details about cannabis use, such as how it is taken (like smoking or eating) and how strong it is. It is also important to study if using several drugs at the same time affects the brain differently than using them separately. The recent study helps guide future research to figure out the exact effects of cannabis on the brain, especially when compared to the effects of other drugs.