Long-Term Cannabis Use Linked to Dementia Risk Factors

Lolita Osorio

April 14, 2022

Long-term cannabis use is linked to hippocampal atrophy and poorer cognitive function in midlife — known risk factors for dementia.

A large prospective, longitudinal study showed long-term cannabis users had an intelligence quotient (IQ) decline from age 18 to midlife (mean 5.5 IQ points), poorer learning and processing speed compared to childhood, and self-reported memory and attention problems. Long-term cannabis users also showed hippocampal atrophy at midlife (age 45), which combined with mild midlife cognitive deficits, all known risk factors for dementia.

"Long-term cannabis users — people who have used cannabis from 18 or 19 years old and continued using through midlife — showed cognitive deficits compared with non-users. They also showed more severe cognitive deficits compared with long-term alcohol users and long-term tobacco users. But people who used infrequently or recreationally in midlife did not show as severe cognitive deficits. Cognitive deficits were confined to cannabis users," lead investigator Madeline Meier, PhD, associate professor of Psychology, Barrett Honors, Arizona State University, Tempe, told Medscape Medical News.

"Long-term cannabis users had smaller hippocampal volume, but we also found that smaller hippocampal volume did not explain the cognitive deficits among the long-term cannabis users," she added.

The study was recently published online March 8 in the American Journal of Psychiatry.

Growing Use in Boomers

Long-term cannabis use has been associated with memory problems. Studies examining the impact of cannabis use on the brain have shown conflicting results. Some suggest regular use in adolescence is associated with altered connectivity and reduced volume of brain regions involved in executive functions such as memory, learning, and impulse control compared with those who do not use cannabis.

Others found no significant structural differences between the brains of cannabis users and non-users.

An earlier, large longitudinal study in New Zealand found that persistent cannabis use (with frequent use starting in adolescence) was associated with a loss of an average of six (or up to eight) IQ points measured in mid-adulthood.

Cannabis use is increasing among Baby Boomers — a group born between 1946 and 1964 — who used cannabis at historically high rates as young adults, and who now use it at historically high rates in midlife and as older adults.

To date, case-control studies, which are predominantly in adolescents and young adults, have found that cannabis users show subtle cognitive deficits and structural brain differences, but it is unclear whether these differences in young cannabis users might be larger in midlife and in older adults who have longer histories of use.

The study included a representative cohort of 1037 individuals in Dunedin, New Zealand, born between April 1972 and March 1973, and followed from age 3 to 45.

Cannabis use and dependence were assessed at ages 18, 21, 26, 32, 38, and 45. IQ was assessed at ages 7, 9, 11, and 45. Specific neuropsychological functions and hippocampal volume were assessed at age 45. 

"Most of the previous research has focused on adolescent and young-adult cannabis users. What we’re looking at here is long-term cannabis users in midlife, and we’re finding that long-term users show cognitive deficits. But we’re not just looking at a snapshot of people in midlife, we’re also doing a longitudinal comparison — comparing them to themselves in childhood. We saw that long-term cannabis users showed a decline in IQ from childhood to adulthood," said Meier. 

Participants in the study are members of the Dunedin Longitudinal Study, a representative birth cohort (N = 1037; 91% of eligible births; 52% male) born between April 1972 and March 1973 in Dunedin, New Zealand, who participated in the first assessment at age 3.

This cohort matched socioeconomic status (SES), key health indicators, and demographics. Assessments were carried out at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, 38, and 45. IQ was assessed at ages 7, 9, 11, and 45. Specific neuropsychological functions and hippocampal volume were assessed at age 45. 

Shrinking Hippocampal Volume

Cannabis use, cognitive function, and hippocampal volume were assessed comparing long-term cannabis users (N = 84) against five distinct groups:

  • Lifelong cannabis nonusers (N = 196) — to replicate the control group most often reported in the case-control literature

  • Midlife recreational cannabis users (N = 65) — to determine if cognitive deficits and structural brain differences are apparent in non-problem users — the majority of cannabis users

  • Long-term tobacco users (N = 75)

  • Long-term alcohol users (N = 57) — benchmark comparisons for any cannabis findings and to disentangle potential cannabis effects from tobacco and alcohol effects

  • Cannabis quitters (N = 58) — to determine whether differences are apparent after cessation

Tests were conducted on dose-response associations using continuously measured persistence of cannabis use, rigorously adjusting for numerous confounders derived from multiple longitudinal waves and data sources.

The investigators also tested whether associations between continuously measured persistence of cannabis use and cognitive deficits were mediated by hippocampal volume differences.

The hippocampus was the area of focus because it has a high density of cannabinoid receptors and is also instrumental for learning and memory, which is one of the most consistently impaired cognitive domains in cannabis users, and has been the brain region that most consistently emerges as smaller in cannabis users relative to controls. Structural magnetic resonance imaging (MRI) was done at age 45 for 875 participants (93% of age 45 participants).

Of 997 cohort members still alive at age 45, 938 (94.1%) were assessed at age 45. Age 45 participants did not differ significantly from other participants on childhood SES, childhood self-control, or childhood IQ. Cognitive functioning among midlife recreational cannabis users was similar to representative cohort norms, suggesting that infrequent recreational cannabis use in midlife is unlikely to compromise cognitive functioning.

However, long-term cannabis users did not perform significantly worse on any test than cannabis quitters. Cannabis quitters showed subtle cognitive deficits that may explain inconsistent findings on the benefits of cessation.

Smaller hippocampal volume is thought to be a possible mediator of cannabis-related cognitive deficits because the hippocampus is rich in CB1 receptors and is involved in learning and memory.

Long-term cannabis users had smaller bilateral volume in total hippocampus and five of 12 structurally and functionally distinct subregions (tail, hippocampal amygdala transition area, CA1, molecular layer, and dentate gyrus), and significantly smaller volumes than midlife recreational cannabis users in the left and right hippocampus, and three of 12 subfields (tail, CA1, and molecular layer) compared with non-users, consistent with case-control studies.

More Potent

"If you’ve been using cannabis very long-term and now are in midlife, you might want to consider quitting. Quitting is associated with slightly better cognitive performance in midlife. We also need to watch for risk of dementia. We know that people who show cognitive deficits at midlife are at elevated risk for later life dementia. And the deficits we saw among long-term cannabis users (although fairly mild), they were in the range in terms of effect size of what we see among people in other studies who have gone on to develop dementia in later life," said Meier.

The study findings conflict with those of other studies, including one by the same research group, which compared the cognitive functioning of twins who were discordant for cannabis use and found little evidence of cannabis-related cognitive deficits. Because long-term cannabis users also use tobacco, alcohol, and other illicit drugs, disentangling cannabis effects from other substances is challenging.

"Long-term cannabis users tend to be long-term poly-substance users, so it’s hard to isolate," said Meier.

Additionally, some group sizes were small, raising concerns about low statistical power.

“Group sizes were small but we didn’t rely only on those group comparisons; however, we did find statistical differences. We also tested highly statistically powered dose-response associations between persistence of cannabis use over ages 18-45 and each of our outcomes (IQ, learning, and processing speed in midlife) while adjusting possible alternate explanations such as low childhood IQ, other substance use, [and] socioeconomic backgrounds.

"These dose-response associations used large sample sizes, were highly powered, and took into account a number of alternative explanations. These two different approaches showed very similar findings and one bolstered the other," said Meier.

The study's results were based on individuals who began using cannabis in the 1980s or ‘90s, but the concentration of tetrahydrocannabinol (THC) has risen in recent years.

"When the study began, THC concentration was approximately 4%. Over the last decade we have seen it go up to 12% or even higher. A recent study surveying US dispensaries found 20% THC. If THC accounts for impairment, then the effects can be larger [with higher concentrations]. One of the challenges in the US is that there are laws prohibiting researchers from testing cannabis, so we have to rely on product labels, which we know are unreliable," said Meier.

A separate report is forthcoming with results of exploratory analyses of associations between long-term cannabis use and comprehensive MRI measures of global and regional gray and white matter.

The data will also be used to answer a number of different questions about cognitive deficits, brain structure, aging preparedness, social preparedness (strength of social networks), financial and health preparedness, and biological aging (the pace of aging relative to chronological age) in long-term cannabis users, Meier noted.

"Fantastic" Research

Commenting on the research for Medscape Medical News, Andrew J. Saxon, MD, professor, Department of Psychiatry & Behavioral Sciences at University of Washington School of Medicine, Seattle, and a member of the American Psychiatric Association’s Council on Addiction Psychiatry, said the study "provides more evidence that heavy and regular cannabis use is not benign behaviour."

“It’s a fantastic piece of research in which they enrolled participants at birth and have followed them up to age 45. In most of the other research that has been done, we have no idea what their baseline was. What’s so remarkable here is that they can clearly demonstrate the loss of IQ points from childhood to age 45," said Saxon.

"It is clear that in people using cannabis long-term, cognition is impaired. It would be good to have a better handle on how much cognitive function can be regained if you quit, because that could be a motivator for quitting in people where cannabis is having an adverse effect on their lives," he added.

On the issue of THC potency, Saxon said that while it's true the potency of cannabis is increasing in terms of THC concentrations, the question is: “Do people who use cannabis use a set amount or do they imbibe until they achieve the state of altered consciousness that they’re seeking? Although there has been some research in the area of self-regulation and cannabis potency, we do not yet have the answers to determine if there is any causation," said Saxon.

Meier and Saxon report no relevant financial conflicts of interest.

American Journal of Psychiatry. Published online March 8, 2022. Full Text.

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