So in this lecture, we're going to cover cannabis and the brain. We're going to talk about our understanding of the short and long-term effects of cannabis exposure on the brain, which has been a research priority for a long time, especially at the National Institute of Drug Abuse, or NIDA, and which has sponsored many studies over the years, both in animals and in humans. Now, this slide's figure to the right comes from NIDA and basically illustrates where in the brain we find CB1 receptors and also where in the brain THC has its effects. In here, everything from the basal ganglia, the ventral striatum, the amygdala, hypothalamus, hippocampus, cerebellum, and of course the cortex, these are all important areas where THC can have effects. But now, let's talk about for a second morphology, that is how might or does cannabis or THC change the morphology of the brain. So if you go and look at the scientific literature on this question, there are lots of smaller studies and there are reviews of studies, that include the smaller studies, and they will suggest that the cannabis use is associated with changes in gray matter density. So when we talk about morphology, we're talking about the makeup of the brain, the shape of it, the density of it and how it changes. So these studies have suggested in the past, an association between cannabis use and reductions in gray matter density. However, when you look at only the large studies, remember we talked about grading different studies, these would be the studies with the best grade, studies that we have the most confidence in it. When you look at those studies, they tend to show no association between cannabis use and gray matter density. Also, there's a nice large sib pair or twin study out there, also suggesting no association between cannabis use and gray matter density, or if there is one, it's more of a shared vulnerability thing. So people with differences in brain morphology might be more likely to use cannabis. So there are also are a number of very large data sets out there, they have been out there for some time, yet no reports from those datasets of a possible association between cannabis use and gray matter density. So, why the discrepancies across studies? So we published a report back in 2014 where we compared 29 adult non users, so a control group of non-users, to a group of 29 daily users. We did the same thing with adolescents. These groups are very carefully matched in terms of alcohol use and other variables. So we want to basically exclude other explanations for any differences. What we found with these very carefully matched groups, we found no differences between those who reported marijuana use every day and those reported no use at all. So the brain morphology basically was the same between the two groups, both in adolescents and in adults. This is the important data figure from that study. What you see here basically, you see we're looking at different brain structures, the different shapes and colors on this chart and anything on this side of this vertical line means that marijuana users were greater than controls. Anything on this side means that controls are greater than marijuana users. But you can quickly just look at this figure and see the shapes are all over the map. When you look at the average of each shape, you find out they hover right around zero. Again, suggesting really no differences due to marijuana, or cannabis. We also did a follow-up study published in 2017, very large sample size, looking at the effects of alcohol, while controlling for cannabis and looking at the effects of cannabis while controlling for alcohol. We wanted to looked at the relative contribution of each in terms of brain morphology, and this are the results that we published. You can see here, where there's blue color in the cortex, that means that alcohol was showing an association with reductions in gray matter density. You see on the cannabis side of the equation, we're looking the effects of cannabis, we see no significant changes. So alcohol had a pervasive effect on gray matter density, cannabis showed no effect in gray matter density. When we look at white matter integrity, the white matter is basically the bundles or fibers connecting different parts of the brain, made of white matter. So looking at the integrity of these bundles is important for understanding how signals are passed from one area to another in the brain. Again, what you see here when we talk about alcohol use, we see significant reductions in white matter integrity, but when we look at cannabis we see no effects. So again, pervasive effects of alcohol, no effect with cannabis. Then with adolescents, we saw with effect of alcohol and no effect with cannabis on gray matter volume, and some slight differences here in adolescents with respect to white matter and alcohol, and basically no effect of cannabis on white matter. So, why the conflicting findings between what I just showed you and what I told you at the very beginning, which is that a lot of small studies find an association between cannabis and morphology? So part of this is an artifact of neuroimaging. It's easy to find an effect somewhere in the brain when you're doing a neuroimaging study. Studies do not often highlight the fact that they're not replicating previous findings in terms of the location. So the idea is that one study will be done and they'll find an effect of cannabis on the hippocampus, the next study comes around and they find an effect of cannabis in the amygdala, but not hippocampus, and the next study comes around in totally different brain region. The point here is that, studies that often don't highlight the fact that they're not finding effects in the same regions. Also there's likely some shared vulnerability, that is people with structural irregularities, may be more likely to use cannabis and this can be misinterpreted as causal, due to confirmation bias. So there's an association between irregularities and cannabis use, but it's not that cannabis use is causing irregularities, it could be that irregularities are actually leading to more cannabis use. Then of course is confirmation biases was probably pretty prevalent in the literature for many years and what that leads to is people sort of stretching the findings to define a positive effect. Okay. So, let's talk about older adults, regular users, versus control side of grad students. This paper actually was just published a month ago, who decided to look at adults over the age of 60, and she compared 28 regular users over the age of 60, with 28 controls had no history of use. She compared the membrane morphology and on neurocognition. Bottom line is, she found on very few differences between the active users and controls over the age of 60. So maybe in the left pallidum , one place where there might have been a difference, but otherwise and remarkably similar. This slide just shows you the kind of we're talking about here in terms of the samples. In the regular users over the age of 60, there's a subgroup of short-term users in a subgroup of long-term users. The long-term users had basically been using cannabis regularly for an average of 40 years, that's a long long time. Both groups where they've been using for four years or 40 years, basically we're showing almost zero symptoms of cannabis use disorder. So important to note. Also, they were using a fair amount in terms of number of days, outlast 90 days, and terms of milligrams of THC. So conclusions here, I would say right now there's no consistent evidence that cannabis use causes long-term pervasive changes in brain morphology unlike alcohol for which there is conclusive evidence. When we're talking about bring morphology, we're talking about gray matter density or white matter integrity. So there might be some confirmation bias and literature because it seems to keep coming up. Also, it's important that the absence of evidence is not necessarily evidence of absence. So just because we don't see right now in the data an association between cannabis use in gray matter morphology or brain morphology, it doesn't mean that we won't eventually find some evidence, right? It's entirely possible, there's something there and we're just not seeing it yet. Also important to note that products that are available today are mostly not represented in the literature. So all the edibles, the concentrates, the higher potency flower would not be represented in the older studies. Ultimately, the point here is that even though cannabis has not seemed to cause, or there's no evidence that it causes changes in gray matter density or white matter integrity, certainly doesn't mean that it's harmless. We'll talk it more about the potential for harm and the risks in the next few lectures.
