Staci Gruber: How Does Marijuana Affect the Brain?
WEED, ganja, pot, flower, dope, grass, bud: marijuana has many names, but an even greater number of chemical constituents, from THC, the psychoactive component, to cannabidiols such as CBD, often touted for its therapeutic potential. In this episode, Dr. Staci Gruber, an associate professor of psychiatry at Harvard Medical School who directs the longest-running study of medical cannabis use in the United States, discusses the effects of the plant’s components on human health. At a time when access to marijuana is progressively legalized, Gruber lays out the surprising ways in which its cognitive effects differ between youths and adults, and between medical marijuana patients and those who use the drug recreationally.
Transcript (the following was prepared by a machine algorithm, and may not perfectly reflect the audio file of the interview):
Jonathan Shaw: Weed, ganja, pot, flower, dope, grass, bud, reefer. Welcome to the Harvard Magazine podcast, “Ask A Harvard Professor.” I'm Jonathan Shaw. We'll spend today's office hours with Dr. Staci Gruber, Associate Professor of Psychiatry at Harvard Medical School and Director of the Marijuana Investigations for Neuroscientific Discovery Program or MIND at McLean Hospital. Welcome, Dr. Gruber.
Staci Gruber: Thank you.
Jonathan Shaw: You're running the only long-term observational study in the United States that looks at medical marijuana and its effects on cognitive performance, sleep, mood, brain structure, and function, quality of life, and conventional medication changes, post use. Separately, you also studied recreational marijuana use for more than 25 years, haven't you?
Staci Gruber: That is very true. Many, many years.
Jonathan Shaw: You've documented some really surprising differences between medical and recreational users. But before we get into that, I wonder if you could talk about the plant itself. Because, across the country, we're suddenly seeing claims for the health benefits of various marijuana derivatives. There's a restaurant here in Cambridge, in fact, where you can now add CBD to anything on the menu. Some people are apparently giving it to their pets. What is CBD? What else is in marijuana?
Staci Gruber: It's a great question. Marijuana is a casual term I think that's used these days to describe pretty much anything that comes from the plant Cannabis sativa. The plant itself has hundreds of constituents. The most common constituents or the most well-known really are Delta (9)-tetrahydrocannabinol or THC. This is the main psychoactive constituent from the plant that gets you high, mind altering. This is what our recreational users are looking for typically. The other main player, the country cousin I like to call it, is cannabidiol or CBD. This is the main non-intoxicating constituent of the plant. It does not get you high, but it's been touted for a potential bevy of therapeutic benefits. In fact, people do give it to their pets and take it in copious amounts of themselves. It's been proposed for use in lots and lots of different ways for lots of different indications.
Jonathan Shaw: What do you think of these commercially available CBD products? Do people know what's in them? Can they trust…?
Staci Gruber: That's another great question. There are lots of products available. There are cafes and restaurants and all sorts of places you can find these products, gas stations, convenience stores. Buy these gummy bears that are all CBD. People do. They plunk down lots of hard-earned money and they expect a certain level of product. First of all, I can tell you that a lot of our patients do exactly this. Laboratory analysis reveals that it's not exactly as it is advertised to be, which is very sad. They wonder why they're not necessarily "feeling" something. That's because instead of 25 milligrams per serving, they're getting two or one perhaps. There's also a difference in the source of the CBD. Whole plant-derived CBD, which is what our clinical trial users, is CBD with other accompanying cannabinoids, very small amounts perhaps of THC, CBG, CBN, THCV, CBC.
Staci Gruber: Other cannabinoids and terpenoids, the essential oils that give cannabis its characteristic flavor and scent profile that also exert their own bio behavioral effects most likely. That's very different from a product that has been made with what we call an isolate. A single extracted compound like CBD, isolated, purified and then added into something. I don't think we have any real data on isolate-based products versus whole-plant derived products. Then there are research studies that have used non-plant derived CBD. These are things that are crafted and manufactured in a lab. Is that really analogous to what we expect to see from a whole-plant derived source product? I don't know.
Staci Gruber: When you read these reports, you must have to be mindful of the source of the CBD. The take home-message, can consumers trust the CBD products they're buying? I would love to say yes. I would suggest and advise everyone buying one, especially online, ask for laboratory analyses. Most of the better, more reputable brands will give you a CEA or certificate of analysis. There are some great brands out there that are tried and true, and some not so great ones. So buyer beware.
Jonathan Shaw: What sorts of conditions are people treating with CBD?
Staci Gruber: The very first thing that comes to mind with regard to cannabidiol I think that's most timely, are pediatric onset intractable seizure disorders, things like Dravet syndrome and Lennox-Gastaut. These unbelievably devastating illnesses of children. I think the world was made aware of these types of things years ago when the very first documentary on CNN called WEED with Sanjay Gupta. It highlighted a little girl named Charlotte Figi, who has Lennox-Gastaut syndrome. This child went from having hundreds of seizures a week, hundreds, to having a normal life. This kid could not walk or talk. She's an identical twin.
Staci Gruber: The other twin's unaffected. It was quite a striking contrast. This young girl's parents gave her cannabidiol basically, especially Bread strain. They're very high in CBD. Again, non-intoxicating constituent in the plant, very low in THC. From this, they extracted an oil, administered this to Charlotte., and her seizures all but abated. Now, she walks and she talks and she looks pretty much like any normal, I think at this point, child, which is amazing.
Jonathan Shaw: Wow.
Staci Gruber: That's one indication, seizure disorders. Lots of different indications, things like anxiety. We actually have a clinical trial to look at the potential role of cannabidiol for folks with anxiety, threshold or sub threshold? Lots of different mood-related symptoms. Some people are taking cannabidiol for things like pain, PTSD, you name it.
Jonathan Shaw: I've heard of people taking it for inflammation too. Is that…?
Staci Gruber: Absolutely. One of the things about pain is that very often pain is caused by inflammatory processes. If we can get behind or in front of actually the inflammatory process, maybe we can help alleviate the pain. CBD is a particularly good anti-inflammatory.
Jonathan Shaw: I see. How are people taking marijuana these days? Are they not smoking it necessarily?
Staci Gruber: It's a great question, too. Whether you are a recreational consumer or a medical patient, as it turns out, there are lots of different modes of use. In the old days, people used to ... Well, very, very oldest days, thousands and thousands of years ago, people often chewed leaves or brewed it as tea. I'm thinking more about old is like 60, 70s. People often smoked cannabis. They were rolling it in a joint or blunt or spliff, whatever pipe. These days, people smoke or they vaporize so they actually aren't smoking if they're vaporizing cannabis. They often vaporize oil. Again, extracted oil using any number of different extraction techniques, all of which, by the way, impact the final product.
Staci Gruber: They smoke flower product. They vape flower product, they vape oil. They use sublingual tinctures. They use topicals. They use suppositories. There's lots of different ways that you can use cannabis. Most recreational consumers, by the way, are not necessarily using things like suppositories or sublingual tinctures.
Jonathan Shaw: Is there credence to the claims for CBD? You mentioned this girl who was miraculously treated. Is there other evidence that shows that cannabidiol is effective?
Staci Gruber: For cannabidiol , we have far less hard data, I would say. For THC, there was a report that came out in 2017 from the National Academy of Science, Engineering and Medicine, the health effects of cannabis and cannabinoids. What the report concluded was that there were three main conditions for which cannabis or cannabinoids were. There was substantial conclusive evidence. It was pain, muscle spasticity as a function of MS or chemotherapy induced nausea and vomiting. Very soon after the publication the report, the lead author also added pediatric onset seizure disorder. I guess more evidence had come in at that point.
Staci Gruber: The company that is now credited with formulating something called Epidiolex. GW Pharma had just published these data right around the time that the report came, I think. There's actually evidence that there is a drug now that sits in Schedule 5 called Epidiolex, which is approved by the FDA for the treatment of some of these pediatric onset seizure disorder. I would say that there's evidence for that as well.
Jonathan Shaw: Great. Now turning to THC, the psychoactive ingredient that recreational users are pursuing, how has the level of THC in the plant changed over time?
Staci Gruber: Another great question. I think compared to cannabis of 15 to 20 years ago, we'd like to say, this isn't your daddy or your granddaddy's weed. Lots of people say that. Back in the day, THC levels, which is basically how we describe potency, although there are other factors, but potency really relates to how much THC is in a product, somewhere around 4%. These days, you're talking about a national average of around 12%. That data is based on government seizures. That is, seizure of product—and then they analyze it. It's gone up just under 200%, which is striking. I will say, here in Massachusetts, we get samples analyzed by our consumers of both recreational and medical products. I can tell you that our average is higher than 12. It's about 16 or 17 as far as I can tell.
Staci Gruber: Along with THC levels going up and cannabis becoming more potent over the last 10 or 20 years, we've also seen a huge drop in CBD. Remember that CBD is non-psychoactive, non intoxicating I should say. It's also been proposed to mitigate some of THC's less desirable effects, the negative effects of THC. We can actually reduce some of the psychoactive effects. CBD levels in cannabis has gone down almost 60% in the same time period. So THC levels are rising, CBD levels are going down. Any potential protective effect we might have had from CBD is also being minimized.
Jonathan Shaw: This is presumably the result of selective breeding.
Staci Gruber: Absolutely.
Jonathan Shaw: Are there differences in the effects of THC on children and adolescents whose brains are still developing and its effects on adult brain?
Staci Gruber: That's a great question. Absolutely, fantastic question. The answer in short is yes. Simple as that. The brain develops throughout adolescence and into adulthood, right? We know from the pioneering efforts of lots of folks that, again, we develop throughout the second and the third decade of life. In adolescence or emerging adulthood, when we are confronted with things like substances of abuse, or all sorts of behaviors and things that we might not necessarily have been exposed to before because we're little. The brain is neuro developmentally vulnerable. It's not just vulnerable to cannabis. It's vulnerable to other drugs, to alcohol, to illness, to injury. The brain is "under construction". It doesn't really become fully-developed again until you're talking about the 20s.
Staci Gruber: Exposure to what we call exogenous cannabinoids or cannabinoids that are not part of our own endocannabinoid system, which is yet another topic may impact the developmental trajectory. In fact, we know the endocannabinoid system is critical for development. So exposure to outside cannabinoids, things like THC, appears to change the way things work. We have a number of studies that have looked specifically at adolescent and emerging adult users of cannabis. There's definitely an age-of-onset effect. The earlier you use cannabis, the more likely you are to show differences on tasks relative to those who don't use cannabis at all or those who begin using later. That's very different from someone who begins using cannabis in their 30s or 40s most likely. In fact, we don't have a ton of data, for example, in the medical cannabis realm, but I can tell you from our own ongoing studies, some of which we've now begun to publish, these folks looked different, which is encouraging.
Jonathan Shaw: The young users then have brains that look different on for example, an fMRI as well.
Staci Gruber: I think in the aggregate, the overarching statement I would make is that individuals who use cannabis at an early age, in our studies, we've looked at lots and lots of cannabis users. We typically use heavy chronic cannabis users. These are folks who are using cannabis pretty much every day, a minimum of four or five days a week, they have to have used a certain amount to get into the study. These are not people who use once a week, once a month. These are heavy-hitters. By and large, these people look a little bit different on tasks requiring what we call executive function.
Staci Gruber: Tasks mediated by the very frontal part of your brain, which happens to be the last part of your brain to become fully developed. What types of processes are we talking about? Things like inhibitory function, the ability to inhibit or suppress or response tendency. You really wanna say something but you know you shouldn't, because it's wrong to do it. Things like being able to make decisions under pressure, the ability to utilize feedback to change your behavior. These are all executive functions. Tasks requiring executive function appear to be slightly less good in those folks, who begin using early. Again, in our studies, prior to age 16, early onset folks have more difficulty with these types of tasks than those who begin using after age 16. The same is true for, you mentioned fMRIs. I run an imaging lab in our hospital.
Staci Gruber: During tasks that require things like executive function, we can actually watch the brain "at work". What we see a very different patterns of activation. That is, which parts of the brain are more active during these types of tasks. We definitely see different patterns of activation. It's not just our data. That's my colleagues across the country. We see differences. We've actually also noted some structural brain differences predominantly in things like white matter integrity. The earlier you use cannabis, the more likely you are to see some differences in the ability to do these cognitive tasks, differences and activation patterns within the brain, and perhaps even structural brain measures. Interestingly, what we found, which I think is very important is in the early onset users, we saw a very clear relationship between lower white matter fiber tracts integrity of the brain. White matter's what connects brain regions to each other.
Staci Gruber: Good, clean communication from one region to another, dependent on white matter. The earlier folks start using cannabis, the lower the white matter integrity. The lower the white matter integrity, the higher the behavioral impulsivity. We only saw that relationship in the early onset folks which is very important. It certainly gives us concern or reason to be mindful of folks who were using early, especially since cannabis now is a little bit different from cannabis of years past. Types of products that are used now concentrates, things designed have potency levels of north of 35, 45, 55. We tested one and it was I think 88% THC, that are designed to be administered to your user in a single bolus. Instead of passing the joint, or a pipe, or a blunt or a bong.
Staci Gruber: Folks are often dabbing so the heat this product, this wax, shatter, glass, whatever they're using. Very high temperatures, and they inhale. They get this giant bolus of a very high THC product all at once. We don't have much in the way of studies to tell us what that does long term. I'd like to know. I’d hazard a guess it may be different from folks were using lower-potency products or even higher-potency products, but not in that way. That's certainly something to be mindful of.
Jonathan Shaw: It's too risky for children, adolescents to be exposed to marijuana.
Staci Gruber: We always say just not yet. We never say just say no, because that didn't work. We say just not yet. Let your brain develop. There are certainly more things to be mindful of during the development of the brain than later on.
Jonathan Shaw: That's amazing that the brain is developing into the 20s.
Staci Gruber: Throughout the second, maybe even in the third decade of life. Go ahead and tell someone not to do something until their 30, let's see what they'll do. Not gonna happen.
Jonathan Shaw: All right, putting aside the definition of an adult, how long does it take before an adult recreational users' brain returns to baseline on a cognitive test?
Staci Gruber: That's a great question, too. I think there have been studies that have looked at what we call extended abstinence periods. Certainly, we've done some of that work. In some studies, there's certainly a return that is "recovery of function", whether it's a cognitive performance. Or we've done some studies looking at regional cerebral blood flow and things like that. After about 30 days of abstinence, you begin to see a normalization. Does that happen for everyone in the same time course? I don't know. I don't think there are tons and tons of data on this. Certainly, it's not the same for everyone. Much of that is going to depend, I think, on how often they use, how long they've been using, what they use, and what they started off as.
Jonathan Shaw: Now let's get to the meat of this. Let's talk about what your studies of medical marijuana have found and how that compares to what you found about recreational users, because I think this is really going to surprise our listeners.
Staci Gruber: Sure. In general, as I mentioned, recreational cannabis use has primarily been associated with decrements in cognitive performance, changes in brain structure and function. There are lots of other psychosocial measures that people were looking at. The assumption for most would be, "Look, if you're gonna use cannabis for medical purposes, obviously, you're gonna have the same outcome." Right? I could not find much in the data when I went to address this question because medical cannabis was legalized here in Massachusetts many years ago. It took a while for it to take off, but I wanted to know what to expect. Lots of people were asking really good questions. Medical cannabis, by the way, was legalized in California in 1996. There have been some studies of medical cannabis.
Staci Gruber: Predominantly, though, focused on the effect of medical cannabis on whatever symptom or condition was being studied, not necessarily on cognitive performance. What I found in the literature were spurious references here and there to a one off-test here, or one-off test there. Nothing that looked at folks before they started and followed them over time. Nothing that was what I would call a comprehensive neurocognitive assessment really designed for the sake of looking at cognitive function. So, we started the MIND program. This program was designed literally to look at the effects of medical cannabis use and cognitive performance, brain structure, brain function, conventional medication use, sleep, quality of life, you name it, we wanted to know. In general, what we've seen and, again, this is early days. We've been at it just about five years. The way these studies work is we bring folks and before they begin using cannabis. Very important for everyone to know. They are negative at baseline. These are not recreational cannabis users, okay?
Staci Gruber: If they have a history of recreational cannabis use, they have to be free of recreational use for quite a while. By quite a while, I mean years, not weeks, days, not months. Although I would consider that in a separate cohort, years. They are not using cannabis. We assess them in terms of all these things I just mentioned and then we follow them over time. When they settle on a regimen, they began using medical cannabis. We bring them back and we look at them again at three months, six months, 12, 18 and 24. We have interim visits too and we talked to them very often. They keep logs of the products that they use, where they got it, what's in the product or what I like to call the what's-in-your-weed factor based on where they got it. Then they submit a sample of their most commonly used products for an outside laboratory analysis that we pay for, so that we can see what's in their weed.
Staci Gruber: 10 major cannabinoid constituents now 12, actually, which really helps us. We look at this change over time. What we've seen so far, and I think we are the first to publish any longitudinal data on this, medical cannabis users, first of all, are not the same age range as our recreational cannabis users, at least in our studies, which were really early 20s. These folks are older. They're in their early 50s, by and large. They go all the way up to their 70s and beyond. What we find is, instead of seeing decrements in cognitive performance, relative to baseline, after three months of use, we're seeing improvements on measures of executive function. That's a bit of a surprise to a lot of people. They're not getting worse, they're getting better. In addition, we're seeing improvements in lots of different clinical measures, specifically measures of mood and sleep. We see reductions in conventional medication use predominantly opioids. A very significant reduction in the use of opioids after the initiation of medical cannabis.
Staci Gruber: But the improvement in cognitive performance is really something quite striking. Rather than getting worse, they're getting better. That not only holds at six months, it seems to continue to improve. That's really important. We're also now starting to see, we have not published this yet, but we just looked at this data, the white matter data that we see in recreational users. Just as a quick refresher, we see lower white matter integrity in those with earlier onset of cannabis use. The earlier you start, the lower the white matter integrity. Then we saw this relationship between lower white matter integrity, higher impulsivity. In our medical cannabis users, we're actually seeing increases in white matter integrity between baseline and three months and baseline six months. I did not expect that. That will bear a lot of watching over time. That's very interesting, but it may go hand in hand with the fact that they are now having a clinical response.
Staci Gruber: Some folks were using for mood-related conditions, for example. The precedent I could find in literature is that treatment refractory patients with psychosis, for example. They finally find something that works. They actually see an increase in white matter integrity. This is not particularly dissimilar from that. Maybe that's what we're seeing. It could be that we're seeing symptom reduction. So folks can focus a little bit more effectively on cognitive tasks. It may be the reduction in conventional medications. They don't have a cognitive hangover in the morning. They're not taking their benzodiazepines at night. They're not taking their opioids. They're not taking as much in the way of mood stabilizers or antidepressants that may impact it. I have a sneaking suspicion this also has to do with the age of the person under study.
Staci Gruber: These folks are in ,on average, the early 50s. I hate to say it, but we're no longer neuro developmentally vulnerable at that age. We're on the other side. We're now looking at the other side of aging, right? It may be that the brain when fully-developed responds very differently to small amounts. The amount and frequency with which these people are using product is also a little bit different from our recreational cannabis users. All of these things are important and all of them are a bit counterintuitive based on what we know from recreational users. I think it's important sometimes to look at preclinical data. There's an interesting study that was published in mice that looked at three groups of mice. Basically adolescent mice, let's say, adult mice, and then what would be analogous to older mice, older adults. They looked at these mice at baseline during cognitive tasks. Not surprisingly, the youngest mice outperform the adult and, let's just say, older adult mice.
Staci Gruber: Biology is cruel. We don't get better at cognitive tasks as we get older, very sad. Then, they implanted these tiny little pumps and allowed very small amounts of THC to be administered. Now, the adults and older mice outperformed the young mice without any THC on board. The young mice with THC on board did very poorly. Very similar to what we see, perhaps, in our human data. I think this speaks volumes, again, to the importance of the age of the organism under study.
Jonathan Shaw: What were the differences in what was actually in the marijuana that the medical users were taking versus what you would see in a typical recreational user? You're probably trying to maximize the THC exposure.
Staci Gruber: Recreational samples are typically very high in THC. As I mentioned, we see relatively low levels of CBD and other cannabinoids although they're there. They're whole full spectrum product, so they're there, but they're very small amounts, almost undetectable CBD. In our medical cannabis patients, very often, they're choosing products with, I would say, considerable amounts of THC, nothing close to the rec people. Although, some may have high THC levels. We see a very large proportion of our folks with very high CBD levels in their products. They are looking for them intentionally. Also, they look for products that are high in CBM or cannabinol, cannabigerol, tetrahydrocannabinol. I mean other constituents. I would say there's a much wider array of cannabinoids. Overall, they're looking for less of the bang for the buck from THC.
Jonathan Shaw: Right, that makes sense. 33 US states, and the District of Columbia have legalized cannabis for medical use. And 10 states, including Massachusetts, have legalized marijuana for recreational use. But despite growing acceptance by states, marijuana is listed by the federal government in the same Schedule 1 category as heroin and LSD. What impact does that have on research?
Staci Gruber: I think that's a very important point to make, and I would just add one caveat. You're right. 33 states plus DC have fully legalized medical cannabis programs. Another 14 have partial medical cannabis programs. By partial, what I mean is they allow the use of cannabidiol for very specific indications in some states, but that means there are 47 states, 47 states where some form of medical cannabis is available. That leaves only three without access. First, let's wrap our heads around that. What does that mean? Okay. Then there's the 10 states plus DC with recreational. The fact that it sits in Schedule 1 and all constituents from the plant are treated equally has been difficult.
Staci Gruber: Very recently, there was a ruling that basically stated any product with less than point 0.3% THC by weight, these things were typically termed industrial hemp, are no longer subject to the Controlled Substance Act. They now fall outside. How that will affect what we do may be very important, actually, in the very near future for some of us who are very invested in looking at these types of products. Lots of our patients are taking these products. But the fact that it sits in Schedule 1 does complicate things a bit. Even in states where we have legal medical cannabis programs, I am not able to give our patients medical cannabis products that they could get themselves at a dispensary. I cannot. It is against federal regulations. For clinical trials, I must use products that are approved for use. At the moment, those products exclusively come from the National Institute on Drug Abuse supply [NIDA].
Staci Gruber: The drug supply program has expanded exponentially over the last several years. They do not have products that resemble what is available to our patients in dispensaries. They do not have products that are turnkey, that are already formulated as, let's say a sublingual tincture optimized, for this condition or that. They do not have products that are concentrates like dabs or wax or shatter that lots of recreational folks are using. It's a little bit more difficult because it sits in Schedule 1. There are some restrictions that we have to abide by, that make things a little more complicated.
Jonathan Shaw: Thank you. To wrap up, what are the policy takeaways from your work? It seems that on the one hand, the drug should be classified differently to facilitate research. On the other, legislators should perhaps be thinking about ways to persuade children, adolescents and even older cohorts to postpone recreational use, if they're ever gonna use it, until after their brains are fully developed. Is that right?
Staci Gruber: I think it's there's a lot of take home messages. I think that from the public policy perspective, the policymakers' perspective, there's a lot of things to keep in mind. States that have legalized recreational use have often discussed the possibilities of doing things like limiting the amount of THC in products to consumers who are between certain ages. Like 21 to 25, you can only have 8% to 10% THC, whatever it is. That has not been well-received. Higher tax levels on products that have higher THC, also not well received. But I think people are struggling pretty hard with what to do and policy really outpaced science here. Most of the time, science and data allow us to set a policy in accordance with what we know and what we expect.
Staci Gruber: We don't know everything we perhaps should know at this point. Although, many of us are trying very hard to play catch up. I think the overwhelming take-home message is that, for many, cannabis has been an absolute salvation. I would say cannabis most importantly is not one thing. We need to consider the constituents. Again, CBD is not the same as THC. Most will tell you that whole plant derived products are likely, perhaps, we don't have a ton of data on this either, more efficacious than single, extracted compounds that are used in isolation. What we need is a lot more data. I think most policymakers who are proposing bills, for example. There are specific bills being debated these days that allow researchers specific, and exclusive access to certain things that would allow us to actually use products that are in the mainstream. I mean, it's great for me to be able to use products that NIDA supplies. It's great for me to look at observational data from patients using their own regimen and then retrospectively, I can go back and analyze it.
Staci Gruber: But wouldn't it be better if I could do studies of products that they're actually using, that are available to countless thousands in the real world? Wouldn't that have much greater external or ecological validity? I think there's a real push to try to get some of us some access until the legislation shifts in such a way that makes a little bit more sense for us.
Jonathan Shaw: Well, good luck with that.
Staci Gruber: Thank you.
Jonathan Shaw: Thank you for being with us today.
Staci Gruber: Sure. It's been a pleasure.