So in this lecture, we're going to talk about what sort of summarize what we've learned so far, and we're going to start with THC, and we're going to start with high doses. So here's the thing. I can't think of any single study suggesting that high doses of THC do something good for people. So what is a high dose? Well, that's an arbitrary thing. It really depends on the individual, but generally speaking, more than 1-2 grams of flower per day or 35 milligrams of an oral form of THC is a higher dose. So again, no studies I can think of this suggests that higher doses do something important. There are higher stage I can point to the suggests that consistently taking a higher dose of THC can be problematic, and it's going to have obviously a bigger impact on terms of altering the endocannabinoid system, in terms of downregulating CB1 receptors, intentionally in terms of impairing cognition, and obviously in for young people increasing risk of psychosis. Also once you start taking higher and higher doses there's a question there although we don't have the research yet, about whether you're going to start producing tolerance to the beneficial effects. You don't want the beneficial effects to go away. So dose is important, and again not a lot of evidence to suggest that high doses are good for anything and certainly some evidence to suggest they have some risks. On the flip side of this, if you think about literature with respect to load a moderate doses of THC, I can't think of any studies suggesting that a low dose of THC does something bad. So low doses, we're talking quarter gram, maybe a flower, 2.5 milligrams of THC in oral form. There are even some studies suggesting low doses have a pretty powerful positive effect too. There's the paper we talked about with the in the mouse model looking at very very low doses protecting the brain against the effect of aging. So there's a few studies suggesting actually low doses are good thing, and also again very few insights suggesting low doses are harmful. Then you look at the side effect literature, these are all these clinical trials and surveillance that was done on side effects available via prescription in Europe, and we see again very little evidence of adverse or harmful effects with side effects when taken as directed. Again, this is a more moderate dosing, but again, mild to moderate doses not a lot of evidence for harmful effects. Also at the same time evidence suggests to maybe useful and important. So for example, a side effect we see effects with pain, this is suggestions that more moderate dose of THC are important for the opiate reduction effect you saw at Zita Cooper's work. So again, THC a mild to moderate doses clearly has some benefits and harm is pretty low. So CBD, what about CBD? You don't start seeing harm from CBD until you get to super high doses. There's been some evidence, there's a little bit coming out from the epidemics trials showing elevation of liver enzymes and really high doses were talking 1,500 milligrams per day. Also the beginning of some studies coming out on drug metabolism and high doses of the CBD may impact metabolic pathways, which then may impact or interact with other medications. This is just we're just beginning to see this research. Obviously, we need more research on how high doses may impact, how other drugs work. But otherwise, in terms of acute effects there's at least one important literature, 4,500 milligrams being given to people with very little in the way of acute effects that would be seen as risky. One curious point, when these guys come out with a super high doses of CBD and would have been interesting to see how much THC actually is in the blood but there's no report of that, so that's unfortunate because even if THC is almost completely purified out of the CBD that's produced by GW Pharma, it would be interesting to see how much actually is in makes it into the blood vessel of high doses. This some data that came out in 2018, just comparing CBD at three different doses to dronabinol which just THC to Alprazolam which is a benzodiazepine. This is again some of the harmful abuse liability kinds of variables. But what you see here basically is that the CBD in the blue super low on all of these measures, and THC and Alprazolam higher on these measures. Then this is also looking at cognitive or psychomotor effects. What you see again, CBD has almost zero cognitive psychomotor effects, even THC is pretty low, Alprazolam though is definitely producing some cognitive and psychomotor effects, this is like a pharmacokinetics CBD, so looking at blood levels for example. What's fascinating here is that definitely an increase in blood level from the 1,500 milligram dose over the 750 milligram dose but going up to 4,500 milligrams, you actually have less than the blood, so that's a fascinating thing that might be some ceiling effect here in terms of the maximum dose that you can take because you're obviously getting anymore in the blood with a super high dose. Then what we have here, we have looking at the combination of cannabidiol and fentanyl which is a powerful powerful opioid. This is the first step in knowing whether it's safe for people to take cannabidiol in combination with opioids. So for example, for people who want to cut down opioids, they're going to be taking initially both at the same time, and this is just looking at blood levels over time and nothing much going on there. This actually from the same study that was looking at positive aspects, and I found this interesting little pearl buried in the paper. Here, we're looking at zero CBD with fentanyl, then 400 milligrams and a milligram of fentanyl. What you see here is that there actually is some reduction in positive affect and after a fentanyl administration. So CBD seems to have some impact at 400 milligrams but not 800 milligrams. So that's a fascinating thing. Mirrors some of the anxiety, the few excited studies out there showing that a medium dose has an effect but a high dose like 300 milligrams has an effect but 600 doesn't, for example, so it's interesting. So in general though, dosing is super important for CBD, we don't have a lot of data on this. In the same module, we talked about a study with a 160 milligrams producing a positive effect on sleep. Again, with anxiety studies 300 milligrams shows an effect but maybe 600 doesn't. Yasmin Hurd's work in looking at craving for opioids. In the 400-800 milligram range, we've had psychosis, and psychosis where we talked about in. That module looking at 800 milligrams and having a positive effect and epilepsy literature, we're talking 1,500 milligrams. So there's a huge range of doses that seemed to be effective, and maybe the dose is different for each of symptom or disorder, but the lowest dose I've seen literature as a 160 milligrams. The point we're trying to make here is that, the nation has been undergoing the CBD craze, it's everywhere. The people who were involved in marketing will tell you it does everything, all the possible good things you can think of. Mostly it's sold in doses of 5 to 20 milligrams. But yet, there's no evidence that 5 to 20 milligrams does anything, at least not in terms of the research literature. Not anything I can think of, and so that's an important point. So as a counterpoint that though, what's important to notice that no scientists have been studying those doses, and that's a disconnect too, right? A lot of people are taking doses in this range of whatever around 20 milligrams, you think we should be, somebody should do a study to see if it does anything. But instead, scientists are studying the higher doses, and it just seems to me we should include a condition with a lower dose. We would know whether a low dose does anything or not. The last thing, the suit important to point out CBD, I can't think of a single study that suggests it doesn't mean bad for you, unless it's super super high doses. So it does seem pretty benign crop pretty much across the board. So the job of a scientist is more than just understanding the research has been done, it's about synthesizing research in ways that leads to new theories, new hypotheses, and new knowledge. So just looking at the literature, it does seem that lower doses THC seem to be important. THC seems to be important, it does something important, it's useful but mostly lower doses and also not harmful lower doses. Higher doses of CBD more than a 100 milligrams seemed to be important and not harmful. There's no studies that are suggesting that combining CBD with THC is a bad idea, so nothing that's suggested CBD takes something away from THC. So the point here is that, if you put those three things together and it makes sense that combining lower doses of THC and higher doses of CBD is like a good starting point. To sort of take a step further, the issue with the combination of course is that you're limited by how much THC is in the combination. Assuming you don't want to be high, you don't want to be intoxicated, then you're limited somewhere in that 1-10 milligrams of THC per dose, but that can be combined with a 100-1,000 milligrams of CBD, and that's kind of a I think probably in general good starting point for where we should be looking for the most benefit and least harm in terms of these products. So just some ideas of how that might work is just a quick table to show you. What does a 20 to 1 ratio CBD-to-THC look like. One milligrams of THC and 20 milligrams of CBD or 5 in 100, that's what that product would look like. Important to note here, that hemp-derived products unless they're taking a second step to really separate out the THC, most of those hemp-derived CBD products we'll have some THC and that ratio is going to be somewhere around 20 to 1 like this, or 30 to 1. Some of the growers can get in their hemp plant, it's a ratio of 30 to 1 CBD-THC. But that's the range, 20 to 1 or 30 to 1 is how hemp works. Instead, if you're extracting cannabinoids from hemp, that's probably going to be the ratio you're going to see in terms of THC-to-CBD. So if you take if you're taking a hemp-derived CBD product that's got 30 milligrams of CBD. You're probably getting one milligram of THC, unless they took up extra steps that really separate out, purify out the THC. So 50 to 1 looks something like this. Again, the limiting factor of THC, if it's 2.5 milligrams of THC, it would be a 100 milligrams of CBD, and you can see how that works through the different dose range there, and a 100 to 1, 2.5 milligrams of THC and 250 of CBD. So in summary, we understand the risks and benefits pretty well, and they seem to vary by the dose of THC. We don't know so much about CBD dosing yet, although, the doses that are commonly sold are probably so low, that they're close to a placebo effect, but again, scientists really haven't studied those logos and so we don't know for sure. The dose effects likely vary by condition, but the effect of doses are probably in a 100 to 1,000 milligram range depending on the condition, and I must say this is total speculation on my part, but that's what so far the study suggests as I mentioned, we have a 160 milligram showing an effect for sleep and then it goes up from there and nothing really less than a 160 milligrams showing an effect in the research literature that I can think of. So yeah, so THC is important, and a low doses are probably safe and so a good starting point is combining low to moderate dose of THC with higher doses CBD and it seems to be I think a good starting point in terms of how we should be looking at this going forward.
