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 nonproblem 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 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 5 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 3 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 Dr. 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 polysubstance users, so it’s hard to isolate,” said Dr. 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 Dr. 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 U.S. dispensaries found 20% THC. If THC accounts for impairment, then the effects can be larger [with higher concentrations]. One of the challenges in the U.S. is that there are laws prohibiting researchers from testing cannabis, so we have to rely on product labels, which we know are unreliable,” said Dr. 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, Dr. Meier noted.
‘Fantastic’ research
Commenting on the research for this news organization , Andrew J. Saxon, MD, professor, department of psychiatry & behavioral sciences at University of Washington, 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 behavior.”
“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 Dr. 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, Dr. 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 Dr. Saxon.
Dr. Meier and Dr. Saxon reported no relevant financial conflicts of interest.
A version of this article first appeared on Medscape.com.