Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science

00:00:03.760 | and science-based tools for everyday life.

00:00:05.920 | I'm Andrew Huberman,

00:00:10.260 | and I'm a professor of neurobiology and ophthalmology

00:00:13.400 | at Stanford School of Medicine.

00:00:15.440 | My guest today is Dr. Matthew Hill.

00:00:17.840 | Dr. Matthew Hill is a professor of cell biology and anatomy

00:00:21.300 | at the University of Calgary.

00:00:22.880 | His laboratory studies cannabis and its effects on stress,

00:00:26.200 | its effects on feeding,

00:00:27.720 | and its effects on the behavioral impacts

00:00:30.080 | of cannabis exposure at different stages of development.

00:00:33.760 | The origin of today's podcast episode is a bit unique,

00:00:36.800 | so I'd like to share a little bit

00:00:37.920 | of that background with you.

00:00:39.220 | Previously, I did a solo episode

00:00:41.200 | of the Huberman Lab Podcast about cannabis,

00:00:43.800 | the biology of cannabis,

00:00:45.200 | some of its medical applications and uses,

00:00:47.480 | as well as some of its potential harms.

00:00:49.680 | That episode came out several years ago now,

00:00:52.040 | and remains a very popular episode.

00:00:53.800 | It's had millions of views and millions of listens.

00:00:56.880 | Several months ago, we posted a clip of that episode

00:01:00.320 | to X, formerly known as Twitter.

00:01:02.800 | And Dr. Matthew Hill responded to that clip on X

00:01:06.140 | with criticism about the specific points

00:01:08.680 | made within that clip.

00:01:10.200 | Most notably, my discussion of the data

00:01:12.440 | that cannabis use can, in some individuals, cause psychosis.

00:01:16.720 | He also took issue with some of the specific points

00:01:18.680 | I made in that clip related to potential differences

00:01:21.760 | in the biology of the effects

00:01:23.480 | of different strains of cannabis,

00:01:25.080 | most notably indica versus sativa strains,

00:01:28.200 | and a few other points as well.

00:01:29.900 | Now, as somebody who's been in the field of science

00:01:31.600 | for several decades now,

00:01:32.960 | I'm very familiar with the fact that every field,

00:01:35.920 | every single field within science,

00:01:38.160 | has debates within it, controversies,

00:01:40.160 | and sometimes outright battles.

00:01:41.880 | And to me, that's part of what makes science interesting.

00:01:43.840 | It's an evolving process.

00:01:45.240 | It's something for which we should all be very curious

00:01:47.920 | to try and understand what we know, what we don't know,

00:01:51.200 | and try and get to the real answers.

00:01:53.160 | So right off the bat on X, I invited Dr. Hill

00:01:56.240 | onto the podcast, and he accepted the invitation.

00:01:58.840 | So today's episode is really a unique one

00:02:01.240 | in that, first of all, we cover an enormous amount

00:02:04.800 | of biology and clinical data as it relates to cannabis,

00:02:09.280 | meaning today's discussion is not a debate.

00:02:11.880 | It is really an up-to-date discussion

00:02:13.920 | about how cannabis works.

00:02:15.360 | So we talk about THC versus CBD.

00:02:17.760 | We address the question

00:02:18.800 | of whether or not indicas versus sativas

00:02:21.080 | have different biological and subjective effects or not.

00:02:25.060 | We, of course, talk about the potential correlation,

00:02:27.200 | maybe even causation, between cannabis use and psychosis.

00:02:30.500 | I think you'll find that discussion very interesting.

00:02:32.440 | And we talk about how cannabis relates to hunger,

00:02:35.920 | to memory, to anxiety, and to the treatment of anxiety.

00:02:39.580 | I'm certain that given the widespread use

00:02:41.420 | of cannabis nowadays, that you'll find the discussion

00:02:44.060 | to be both an informative and potentially useful one

00:02:47.600 | that could help guide decisions

00:02:48.960 | as to whether or not you or others should

00:02:50.940 | or should not use or avoid cannabis,

00:02:53.800 | as well as one that can simply inform

00:02:56.160 | about this very interesting compound.

00:02:57.840 | And of course, you'll learn a lot of neuroscience

00:03:00.200 | and biology along the way.

00:03:02.140 | Before we begin, I'd like to emphasize

00:03:03.960 | that this podcast is separate

00:03:05.520 | from my teaching and research roles at Stanford.

00:03:07.680 | It is, however, part of my desire and effort

00:03:09.800 | to bring zero-cost to consumer information

00:03:11.740 | about science and science-related tools

00:03:13.800 | to the general public.

00:03:15.160 | In keeping with that theme,

00:03:16.440 | I'd like to thank the sponsors of today's podcast.

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00:07:14.240 | And now for my discussion with Dr. Matthew Hill.

00:07:17.320 | Dr. Matt Hill, welcome.

00:07:19.080 | - Thanks for having me.

00:07:20.600 | - Delighted to have you here

00:07:21.680 | because you're an expert in the biology of cannabis,

00:07:26.380 | a topic that many, many people are curious about

00:07:29.500 | for a variety of reasons.

00:07:30.940 | So just to kick things off,

00:07:33.360 | maybe we can get people up to speed on what cannabis is,

00:07:38.280 | a little bit about how it works in the brain and body

00:07:40.800 | to produce the various effects that it produces

00:07:43.440 | and how some of that comes to be.

00:07:45.120 | And then we can dig into some of the nuance.

00:07:47.260 | I have a lot of questions about different types,

00:07:49.800 | if you will, of cannabis,

00:07:51.840 | the relationship to mental health,

00:07:53.860 | potentially to mental illness.

00:07:55.280 | We're gonna drill into all of that.

00:07:56.920 | So just to kick things off, what is cannabis?

00:08:00.080 | - I mean, cannabis is a plant

00:08:01.520 | that has been around for some time.

00:08:03.180 | It's kind of got like a very rich history

00:08:05.960 | of use around the world for different cultures,

00:08:09.720 | for both kind of medicinal and spiritual

00:08:12.120 | and recreational purposes over several centuries.

00:08:14.820 | The plant has kind of become, I mean, in the West,

00:08:19.120 | it really wasn't a thing mainstream-wise

00:08:21.320 | until about the '60s.

00:08:23.000 | And then it became kind of introduced

00:08:25.440 | as like a drug of choice that a lot of people started using

00:08:27.960 | during the rise of the hippie era.

00:08:29.680 | And I think that was a lot of the time

00:08:30.920 | that cannabis got popularized.

00:08:32.600 | And then I'd say more recently,

00:08:35.160 | cannabis has, into the '90s and on,

00:08:37.240 | has become kind of a very heavily used drug

00:08:39.560 | by a large swath of people, ranging from teenagers on up.

00:08:43.680 | In terms of what it is inside it,

00:08:45.600 | I mean, it's a plant with a lot of very complex chemistry

00:08:48.800 | and biology behind it.

00:08:49.680 | So there's a lot of molecules that it carries in it.

00:08:52.120 | We call these cannabinoids.

00:08:54.240 | And they come in a lot of different flavors,

00:08:56.680 | but the main one that's the most important one

00:09:00.080 | when we talk about cannabis

00:09:01.080 | and what drives the kind of intoxicating

00:09:04.120 | and what I would refer to as psychoactive effects

00:09:06.320 | of cannabis is delta-9 tetrahydrocannabinol,

00:09:09.280 | or what we call THC.

00:09:10.680 | And that really is what dictates the psychoactive

00:09:15.080 | and intoxicating properties of the plant.

00:09:16.440 | And so the amount of THC that is within the cannabis plant

00:09:19.920 | will influence how high a person's gonna get

00:09:23.000 | when they consume it.

00:09:24.760 | There are probably 70 to 100 and some odd other cannabinoids

00:09:29.440 | that are within cannabis.

00:09:30.360 | Most of them are pretty trace levels,

00:09:32.800 | and they vary from different types to cannabis

00:09:35.240 | from one another.

00:09:36.080 | But the other one that's had a lot of attention

00:09:38.480 | is cannabidiol, or what we call CBD.

00:09:41.080 | CBD is structurally looks pretty similar to THC,

00:09:44.560 | but doesn't behave anything like THC.

00:09:46.440 | It's not intoxicating at all.

00:09:49.000 | Not sure, I would probably say it's not psychoactive

00:09:52.200 | in the sense that people can't tell

00:09:53.520 | if they're on it or not.

00:09:55.200 | But I would, some people still say it's psychoactive

00:09:57.440 | because people claim it can affect anxiety state

00:10:01.400 | or mood state or other things.

00:10:02.600 | So in that context, maybe psychoactive

00:10:05.080 | is still somewhat appropriate of a word to use.

00:10:07.840 | And then there's a whole bunch of other things

00:10:10.320 | like cannabinol, cannabigerol,

00:10:12.200 | and these other minor cannabinoids,

00:10:13.680 | most of which we really don't understand

00:10:15.600 | any of the biology of.

00:10:16.640 | We don't know what they're doing.

00:10:18.540 | They may influence some of the effects of THC,

00:10:20.600 | they may not, but they're there.

00:10:23.280 | And they vary in their composition from different flavor

00:10:26.280 | of different cannabis to different flavor.

00:10:28.440 | And then there's those other things called terpenes,

00:10:30.520 | which are kind of highly volatile compounds,

00:10:33.120 | but they're not specific to cannabis.

00:10:34.520 | They're found in tons of other plants.

00:10:36.400 | So this is a lot of which seems to contribute

00:10:38.560 | at least to some of the smell and the flavors of cannabis.

00:10:40.680 | So these are things like limonene,

00:10:42.560 | which gives some cannabis kind of a citrusy odor

00:10:46.600 | or flavor to it.

00:10:48.360 | Pinene, which gives things more of like a earthy tree

00:10:51.320 | kind of smell.

00:10:52.760 | Beta-caryophyllene, myrcene, and these terpenes

00:10:56.320 | are also, some of which do have known biological activity,

00:10:59.940 | some don't, and they vary quite heavily

00:11:02.040 | across different kinds of cannabis as well.

00:11:03.760 | And again, there's some thought that they may be influencing

00:11:07.920 | some of the psychoactive or intoxicating properties

00:11:09.960 | of cannabis, but the reality is we really don't know

00:11:13.000 | a lot about them at this point.

00:11:14.280 | There's kind of some emerging work that's starting

00:11:16.240 | to come out now that kind of plays with, you know,

00:11:19.480 | giving someone THC and adding in one other terpene

00:11:22.880 | or one other minor cannabinoid

00:11:24.200 | and seeing how it influences things.

00:11:25.640 | And so you can imagine with the plethora of molecules

00:11:29.840 | that exist in cannabis, doing this in a piecewise manner

00:11:33.440 | could take decades to kind of really get to a point

00:11:35.960 | where we understand all the interactive components

00:11:38.580 | of cannabis.

00:11:39.420 | But people tend to refer to this as like an entourage effect.

00:11:42.560 | That's kind of a phrase that gets used quite widely

00:11:44.680 | in the cannabis world.

00:11:45.680 | And the idea behind that is that if you took pure THC,

00:11:50.440 | and so there are some like distillate pens and things

00:11:53.040 | that exist out there now in the product market,

00:11:55.160 | which are basically isolated THC with trace levels

00:11:58.080 | of anything of other stuff, would be very different

00:12:00.620 | than if you had THC in combination

00:12:02.280 | with some of these other molecules

00:12:03.840 | and how they might influence how THC itself

00:12:06.800 | is working or not, so.

00:12:08.200 | - Fascinating plant.

00:12:12.160 | You mentioned the psychoactive effects.

00:12:15.120 | Some people listening to this and watching this

00:12:17.680 | presumably have experienced those psychoactive effects.

00:12:20.400 | Others perhaps have not.

00:12:22.600 | How could we describe for both groups

00:12:26.680 | what the quote-unquote psychoactive effects are?

00:12:28.880 | You mentioned the higher the concentration of THC,

00:12:32.760 | the quote-unquote higher someone will get, right?

00:12:35.360 | The greater the intensity of the high.

00:12:37.260 | What is the high?

00:12:39.660 | And I know people are probably chuckling saying,

00:12:43.040 | does Huberman not know because he's never done it?

00:12:45.720 | I mean, that's my own business.

00:12:46.920 | I just want people to understand

00:12:48.240 | what you mean by psychoactive effects.

00:12:49.800 | - So, I mean, the way that people would usually describe

00:12:53.080 | the intoxicating effects of cannabis is,

00:12:56.040 | they would, I mean, people often refer to it

00:12:57.720 | as there being some euphoria or some positive mood.

00:13:00.640 | Not on the same order as what people would describe

00:13:02.820 | with say cocaine or some other stimulants,

00:13:04.760 | but there certainly is some kind of positive aspect.

00:13:07.400 | I mean, if there wasn't, people wouldn't be using it

00:13:09.520 | if they didn't feel positive about it afterwards.

00:13:12.200 | There can be other aspects

00:13:17.000 | in terms of changes in feeding behavior.

00:13:18.920 | People might find things funnier than they found things.

00:13:21.320 | It might change the way they perceive

00:13:22.720 | various environmental stimuli.

00:13:25.720 | But it can also, for some people,

00:13:27.360 | create a bit of a dissociative state to some degree

00:13:29.520 | where people might feel a little bit out of body.

00:13:32.000 | So, it's kind of a complicated,

00:13:35.400 | intoxicating state to describe, I would say,

00:13:37.460 | because usually if someone's referring

00:13:39.440 | to something like a stimulant, they're just like,

00:13:40.800 | oh, people feel like they're God.

00:13:42.400 | They're like, you know.

00:13:43.880 | - Possibility everywhere.

00:13:45.120 | - Yeah, exactly.

00:13:45.960 | Like they're very happy and they're kind of jacked up.

00:13:47.920 | And I think with cannabis,

00:13:49.520 | the way people would describe it would be very different.

00:13:51.360 | It's like kind of an introspective state.

00:13:53.240 | You might be more aware of your bodily feelings

00:13:56.080 | and states that are going on inside of you,

00:13:58.400 | your kind of internal state.

00:13:59.900 | But you also have like a different perspective

00:14:01.520 | on external stimuli.

00:14:02.960 | You might process information a bit differently,

00:14:05.040 | focus on things a bit differently.

00:14:06.440 | So, it's kind of a complicated state to describe,

00:14:09.480 | I would say.

00:14:10.320 | Usually when people are assessing if someone's intoxicated,

00:14:13.080 | like the kind of lab work where people get someone high,

00:14:16.600 | they just kind of use what we call a visual analog scale,

00:14:19.600 | which is like a one to 100 or something,

00:14:21.360 | or a zero to 100 and say, do you feel high?

00:14:24.180 | Do you enjoy this?

00:14:25.680 | Would you say you feel euphoric?

00:14:27.120 | Is your mood elevated?

00:14:28.240 | So, they're kind of scaling things like that.

00:14:29.840 | So, I think that's more typically in a lab setting,

00:14:32.440 | how you would define if someone's high or not from it.

00:14:35.040 | And this is why when people do studies

00:14:37.440 | with something like a placebo cannabis

00:14:39.180 | or a very low THC cannabis, you'll see kind of a scaling.

00:14:42.120 | So, even if you give someone a placebo cannabis,

00:14:45.560 | if they think that they're getting cannabis,

00:14:47.120 | a lot of people still respond by saying

00:14:48.920 | they feel a bit high.

00:14:49.880 | - That's interesting, is that true

00:14:51.520 | even if they've never used cannabis before?

00:14:54.560 | - I'm not actually certain if you are allowed

00:14:58.040 | to have someone in a drug study

00:14:59.760 | if they've never done something before.

00:15:01.160 | I think they have to have had some previous experience

00:15:03.800 | with a drug to be enrolled.

00:15:04.880 | - And they pay you, so now pot smokers everywhere

00:15:07.760 | are running to look at subjects.

00:15:08.600 | - Yeah, but I think, yeah,

00:15:09.720 | I don't think you can use drug naive people.

00:15:11.680 | I mean, I don't run human clinical lab studies,

00:15:13.720 | so I can't explicitly say it,

00:15:14.960 | but that's my understanding is that someone has to have had

00:15:17.320 | even limited, like, you know, not much,

00:15:19.700 | but at least once or twice.

00:15:20.720 | They have to have experienced the drug before.

00:15:22.280 | So, I don't know if you would take someone

00:15:24.920 | who was completely blind,

00:15:26.000 | 'cause I don't know how they would replicate that state

00:15:29.320 | if they're not expecting it.

00:15:31.160 | - What about the effects of cannabis on time perception?

00:15:36.000 | You know, there's this reputation that cannabis has

00:15:41.000 | for disrupting time perception,

00:15:42.480 | that people will think a long period of time has passed

00:15:44.840 | when in fact very little time has passed.

00:15:46.940 | Maybe it's sometimes even the reverse.

00:15:49.840 | Is the mechanism by which cannabis

00:15:52.380 | can adjust time perception known?

00:15:55.340 | - I wouldn't say it's well worked out.

00:15:56.900 | There definitely seems to be some, like,

00:15:58.420 | temporal dilation, like you're saying,

00:15:59.860 | where people think things of, you know,

00:16:01.780 | someone will be high and someone will ask them,

00:16:03.820 | "How long do you think time has passed?"

00:16:05.300 | They would report usually longer periods of time

00:16:08.220 | have passed than actually have.

00:16:09.720 | I feel like there is some older work I could dig up

00:16:13.460 | to see if I could find that is either in, like,

00:16:15.260 | it might even be in pigeons, but it might be in rodents.

00:16:17.700 | It's looking at, like, temporal ordering,

00:16:19.120 | and they give animals cannabinoids,

00:16:20.600 | and that's kind of a cleaner way of seeing,

00:16:22.880 | 'cause they are very good at learning,

00:16:24.680 | like, if I wait 10 minutes

00:16:25.840 | and then I engage in a behavior, I get a reward.

00:16:27.920 | And so you can really train animals

00:16:30.120 | to have this ordinal timing

00:16:31.520 | where they kind of know distinct periods of time.

00:16:34.040 | And if they give them cannabinoids,

00:16:35.600 | they respond differently.

00:16:36.580 | So in that context,

00:16:38.040 | it does still seem to produce some state

00:16:40.240 | where there's an altered perception of time passing.

00:16:43.560 | And so I think if we were gonna really understand

00:16:46.160 | the mechanism of it,

00:16:47.000 | that would probably be the way to go,

00:16:48.120 | but I'm not super familiar with the work,

00:16:50.720 | 'cause no one's, I mean,

00:16:52.260 | anything I can think of is pretty old.

00:16:53.840 | I can't think of anything modern

00:16:55.080 | where people have actually looked at this.

00:16:56.440 | - Interesting.

00:16:57.400 | You mentioned effects of cannabis on appetite,

00:17:00.240 | and I know one of the medical uses of cannabis

00:17:03.840 | is in people that are undergoing treatment for cancer

00:17:07.080 | in order to stimulate appetite,

00:17:08.520 | because oftentimes they have very low

00:17:11.320 | or even no appetite due to the cancer treatment.

00:17:14.920 | Is the mechanism by which cannabis

00:17:16.720 | can stimulate appetite known?

00:17:18.400 | And if so, what is the general trend of effect?

00:17:22.200 | Makes people hungrier, obviously,

00:17:24.720 | but we hear again in kind of recreational terms

00:17:29.080 | of people getting the munchies,

00:17:30.800 | becoming exceedingly hungry.

00:17:31.960 | Is that related to some cannabis induced effect

00:17:34.760 | on say blood sugar, like insulin or glucose regulation,

00:17:37.760 | or is it happening at a different level?

00:17:39.880 | - I think we almost need to take a step back actually

00:17:41.600 | to talk about how cannabis works in the brain

00:17:43.440 | before we kind of go into that.

00:17:44.500 | So THC as a molecule exerts almost all its effects

00:17:48.520 | through acting at this one receptor for the most part

00:17:51.440 | that's widely expressed through the brain

00:17:52.840 | called the cannabinoid type one receptor.

00:17:55.720 | - CB1.

00:17:56.560 | - Yeah, CB1 is the shorthand for it.

00:17:58.600 | And I think as people tend to create analogies

00:18:02.920 | to describe what receptors are,

00:18:04.200 | for those of you who don't know,

00:18:05.200 | most people use like a lock and key analogy

00:18:07.080 | that a receptor would be a protein that sits on a cell

00:18:10.120 | and a molecule that binds to it like THC

00:18:11.720 | is the key that fits in that lock.

00:18:13.440 | When it activates it, it triggers some biological process

00:18:16.260 | in the cell, in this case, a neuron

00:18:17.980 | that changes its activity in some capacity.

00:18:20.540 | And so THC acts on these CB1 receptors,

00:18:23.580 | which are very widely expressed.

00:18:26.100 | In fact, outside of like kind of ion channels

00:18:28.980 | that are expressed in the brain,

00:18:29.820 | the CB1 is I think one of the most,

00:18:31.860 | if not the most widely expressed receptor in the brain.

00:18:33.860 | It's everywhere.

00:18:35.100 | So it's really important.

00:18:37.340 | And I think as kind of you had alluded to previously,

00:18:41.580 | it doesn't exist in the, you know,

00:18:43.400 | this didn't evolve in humans in the hopes

00:18:45.420 | that one day humans would find cannabis.

00:18:46.980 | This is just-

00:18:47.820 | - Although cannabis users everywhere use that argument.

00:18:50.900 | - I know people love to leverage things.

00:18:53.180 | If it's a plant, it's, you know, it's natural and safe.

00:18:55.540 | And there's obviously issues we'll talk about with that.

00:18:58.680 | But I mean, really, this is just biological redundancy.

00:19:01.000 | I mean, you know,

00:19:01.840 | nature only has so many ways to create something.

00:19:04.660 | And so there's gonna be things that end up overlapping

00:19:07.020 | in the way that they function.

00:19:07.980 | And so the receptor that's in the brain

00:19:10.760 | and throughout the body, the CB1,

00:19:12.580 | and there is also a CB2 receptor.

00:19:14.220 | It's not really expressed in the brain.

00:19:16.340 | It's in some of the immune cells in the brain

00:19:17.780 | and maybe some limited distribution

00:19:20.480 | in actual brain cell neurons.

00:19:22.940 | - Where in the body is it expressed?

00:19:24.060 | - It's mostly immune cells.

00:19:25.300 | So you'll see CB2 is mostly on like macrophages

00:19:28.180 | or other kinds of immune cells.

00:19:29.380 | - Cells that gobble up debris.

00:19:30.980 | - Yeah, and that basically, you know,

00:19:32.900 | regulate inflammatory processes.

00:19:34.660 | And so the main role of CB2 seems to be much more

00:19:37.180 | about like regulating inflammation.

00:19:39.660 | So that's kind of a separate role

00:19:41.300 | that can certainly impact the brain in different ways.

00:19:43.300 | But when we talk about the effects

00:19:45.400 | on the central nervous system and the brain and behavior,

00:19:47.460 | we're talking almost entirely about CB1.

00:19:49.580 | And so both the CB1 and CB2 receptors, like I said,

00:19:52.300 | don't exist because nature was like,

00:19:53.940 | "Humans are gonna find cannabis.

00:19:56.140 | This will all work together now."

00:19:57.780 | So there are molecules our body produces,

00:19:59.660 | which we call endocannabinoids.

00:20:01.320 | And they are kind of funny little molecules

00:20:05.380 | 'cause they don't really behave.

00:20:06.840 | Like certainly in the brain,

00:20:07.740 | they don't behave like a normal neurotransmitter.

00:20:09.780 | So, I mean, I assume most people who listen to your podcast

00:20:13.140 | are relatively adept with the basic idea

00:20:15.060 | of how neurons work.

00:20:16.180 | So you have neuron A, let's call it the presynaptic neuron

00:20:20.300 | because you have that gap between the two cells

00:20:22.420 | where they communicate called the synapse.

00:20:23.740 | So neuron A releases a transmitter

00:20:26.460 | and it can be something that excites the neighboring cell,

00:20:29.420 | neuron B, or it can inhibit it.

00:20:31.100 | And so the way that we always kind of talk

00:20:34.920 | about neurotransmission in the brain

00:20:36.240 | is neuron A releases a chemical that crosses the synapse,

00:20:39.660 | acts on neuron B, and it can either jack

00:20:42.020 | that neuron's activity up or it can scale it down.

00:20:44.380 | And that affects brain-wide patterns of activity.

00:20:48.340 | And we call that anterograde

00:20:50.500 | because it moves from neuron A to neuron B,

00:20:52.520 | which is kind of the general flow of things

00:20:54.980 | and how we usually think about it.

00:20:56.060 | So endocannabinoids are kind of this little bit

00:21:00.020 | of an oddity in the sense that they could do the reverse.

00:21:02.220 | And so endocannabinoids are actually made in neuron B

00:21:04.840 | on the postsynaptic side, and then they go backwards

00:21:07.780 | and act on neuron A to regulate

00:21:09.660 | how much transmitter is released.

00:21:11.220 | And so in many ways, this is like,

00:21:13.900 | I kind of liken it to a thermostat model for the most part.

00:21:16.900 | Certainly if we're talking about something

00:21:17.740 | like excitability.

00:21:18.660 | So if neuron A is dumping out something

00:21:20.820 | that excites neuron B, like glutamate,

00:21:23.020 | which is an excitatory neurotransmitter,

00:21:25.420 | as neuron B gets too excited,

00:21:27.780 | it's gonna start releasing endocannabinoids

00:21:29.940 | to go back and tell neuron A to stop driving it.

00:21:32.500 | - So sort of a homeostatic scale

00:21:34.220 | trying to maintain a middle range.

00:21:35.720 | - Yeah, I mean, at the end of the day,

00:21:37.320 | no matter how you discuss it and what system you discuss it,

00:21:40.200 | I think the majority of people in the cannabinoid field

00:21:42.960 | would agree that the primary physiological role

00:21:45.680 | of endocannabinoids is to maintain homeostasis.

00:21:47.840 | That's what they do.

00:21:48.680 | They keep everything in its happy place, let's say.

00:21:51.160 | So like-

00:21:52.240 | - And that's probably why the CB1 receptor

00:21:54.440 | is so widely distributed is that neurons can excite

00:21:57.200 | or inhibit each other.

00:21:59.000 | That is, raise or reduce the amount of electrical activity

00:22:01.400 | in the, let's say, nearby neuron.

00:22:03.480 | 'Cause we're talking about retrograde signaling.

00:22:05.080 | But ultimately you don't want runaway excitation

00:22:08.840 | 'cause that looks like epilepsy.

00:22:09.920 | - Exactly.

00:22:10.760 | - And you don't want runaway inhibition

00:22:12.240 | because that looks like suppression

00:22:15.560 | of ability to think, move, et cetera.

00:22:17.440 | - Exactly.

00:22:18.280 | So you wanna keep things in where they should be.

00:22:19.960 | And so you want neurons to get excited,

00:22:21.480 | but you don't want them to get overexcited.

00:22:23.200 | So endocannabinoids in kind of a very prototypical sense

00:22:25.680 | act as this circuit breaker, essentially,

00:22:27.940 | where they go back and gate how much is coming in.

00:22:30.240 | And they do this by, through various mechanisms,

00:22:33.640 | essentially turning off the electrical activity

00:22:35.880 | of that presynaptic neuron

00:22:36.920 | so that it stops releasing neurotransmitter.

00:22:39.880 | They can also regulate, though,

00:22:41.880 | inhibitory neurotransmitter release as well.

00:22:44.480 | And this is usually done through a little bit more

00:22:46.360 | of a complex process where it's driven by excitation,

00:22:49.520 | but then it regulates the inhibitory pathway.

00:22:51.780 | - So inhibiting the inhibitor leads to more excitation.

00:22:54.600 | - Exactly.

00:22:55.440 | I usually liken it to basically taking the brakes off

00:22:57.500 | of a car while you're going downhill kind of thing.

00:22:59.280 | Like you'd use your braking system

00:23:01.200 | to keep things in check, but if you want to go faster,

00:23:03.480 | you take the foot off the brakes

00:23:04.720 | and you let things accelerate.

00:23:05.860 | And so this can be really important for things

00:23:08.280 | like forms of synaptic plasticity or neuroplasticity,

00:23:12.440 | let's say, where you want synaptic strengthening to happen.

00:23:15.440 | So like under a learning event or something,

00:23:17.560 | you want that synapse to really hardwire better.

00:23:20.160 | And so having endocannabinoids kind of turn off

00:23:22.800 | the inhibitory component is one of the mechanisms

00:23:25.040 | to facilitate that.

00:23:26.360 | But at the same time,

00:23:27.800 | if you want to have a bit more adaptive flexibility,

00:23:31.040 | endocannabinoids can weaken that synapse at the same time

00:23:34.040 | by acting right at the excitatory terminal itself.

00:23:36.640 | And so their ability to kind of play

00:23:38.920 | with the relative activity of a circuit

00:23:40.920 | is really dependent on which neuron they're acting on.

00:23:43.280 | And so they can regulate excitation

00:23:45.440 | or inhibition differentially.

00:23:47.480 | And I mean, CB1 receptors are found

00:23:50.000 | on virtually every single kind of neuron in the brain,

00:23:54.280 | except one.

00:23:55.120 | I think you'll find this interesting 'cause it's dopamine.

00:23:58.040 | And dopamine neurons are basically the only neurons

00:24:01.640 | in the brain that don't really,

00:24:03.480 | at least as far as we've been able to characterize to date,

00:24:05.680 | express cannabinoid receptors.

00:24:07.320 | - Interesting.

00:24:08.280 | If I may, earlier you mentioned

00:24:10.800 | one of the potential psychoactive effects

00:24:13.160 | of cannabis is euphoria.

00:24:15.680 | Does that mean that the euphoria associated

00:24:17.840 | with cannabis use is independent of dopamine

00:24:20.880 | and is more reliant on something like perhaps

00:24:23.360 | the opioid receptor system

00:24:25.200 | or the serotonergic receptor system?

00:24:27.040 | - I wouldn't say that cannabinoids don't affect dopamine

00:24:29.560 | because what we understand in the ventral tegmental area,

00:24:34.520 | which is kind of the hotspot of dopamine neurons,

00:24:36.720 | or at least the ones that are involved

00:24:37.880 | in motivation and stuff,

00:24:39.160 | those neurons are regulated by a lot of inhibitory neurons

00:24:44.360 | that dump out inhibitory transmitter

00:24:46.080 | and keep those neurons kind of quiet.

00:24:47.600 | - So there's an opportunity for indirect regulation.

00:24:49.200 | - Exactly.

00:24:50.040 | So what you have is those neurons

00:24:51.160 | that regulate the dopamine neurons

00:24:52.560 | are very rich in cannabinoid receptors.

00:24:54.480 | This is actually kind of similar

00:24:55.520 | to how mu-opioid receptors work

00:24:57.080 | for things like morphine or heroin.

00:24:59.440 | And essentially what the cannabinoid receptors will do

00:25:01.840 | is when they're activated,

00:25:02.840 | they'll turn off that inhibitory control.

00:25:04.760 | And that allows dopamine neurons

00:25:06.320 | to kind of move into a state where they're more prone

00:25:08.640 | to go into burst firing and have big dumps of dopamine.

00:25:11.440 | Whether or not that relates to the positive affect

00:25:15.160 | or the euphoria,

00:25:16.000 | I don't think anyone has cleanly demonstrated that.

00:25:18.400 | I mean, obviously dopamine's very complicated

00:25:21.280 | in terms of its relation to endpoints

00:25:23.080 | and whether it's reward or motivation,

00:25:25.840 | but cannabinoids definitely do have an influence

00:25:27.800 | on dopamine transmission.

00:25:28.800 | They just don't tend to do it directly.

00:25:30.320 | And I think that's this very bizarre

00:25:33.200 | and interesting component of cannabinoid signaling

00:25:35.800 | is why the brain would have evolved in a way

00:25:38.000 | to allow every other neurotransmitter system

00:25:39.880 | to be actively and directly regulated by endocannabinoids,

00:25:42.720 | but dopamine is kind of spared from this.

00:25:44.520 | So I don't know.

00:25:46.040 | No one, I mean, obviously you can always

00:25:47.360 | just theoretically guess as to why someone would do that.

00:25:49.400 | I don't know what the reason for it would be,

00:25:50.720 | but it is something that has kind of intrigued

00:25:53.760 | a lot of people because every other system in the brain

00:25:56.160 | is so tightly controlled to some degree by endocannabinoids

00:25:58.920 | and then this one circuit is kind of free of it.

00:26:00.920 | So, but yeah, so the main role of endocannabinoids

00:26:04.400 | is really to regulate plasticity or homeostasis,

00:26:07.080 | allow flexibility of circuits

00:26:08.440 | to either goose up their activity

00:26:10.320 | or ramp it down if they need to,

00:26:11.760 | depending on the environment,

00:26:13.440 | depending on the experience of the organism.

00:26:15.800 | So there's a lot of kind of roles

00:26:17.480 | that endocannabinoids play in that domain,

00:26:19.280 | but even within the endocannabinoids,

00:26:21.980 | I mean, there's two primary endocannabinoids.

00:26:25.160 | And again, this is one of the weird things

00:26:27.200 | about how endocannabinoids work,

00:26:28.440 | because if you talk about things like serotonin or dopamine,

00:26:31.800 | you have a single molecule that gets released

00:26:34.320 | in the typical anterograde way

00:26:36.440 | and it diversifies at the level of a receptor.

00:26:38.740 | So serotonin has like, I don't know,

00:26:40.280 | like 15 receptors or 20 or something, no.

00:26:43.000 | Dopamine has at least five.

00:26:44.880 | And so the different actions

00:26:46.480 | that serotonin or dopamine will have

00:26:48.080 | is all driven by the diversification of the receptors.

00:26:50.440 | It's one molecule.

00:26:51.320 | Whereas cannabinoids are the reverse.

00:26:53.200 | Not only do they work backwards across the synapse

00:26:55.480 | and work in this retrograde fashion,

00:26:57.560 | but really you have one receptor

00:26:59.180 | that is regulated by two molecules.

00:27:00.920 | So the diversification happens more at the level

00:27:02.880 | of the molecule than at the receptor,

00:27:05.260 | which is, again, very unique.

00:27:06.960 | And the two molecules that we know

00:27:09.240 | are kind of the bona fide endocannabinoids.

00:27:10.920 | There could be more.

00:27:12.720 | They're called anandamide,

00:27:13.840 | which is actually kind of a funny name

00:27:17.760 | because it comes from the Sanskrit word anand for bliss.

00:27:21.400 | And so Rafi Mashulam, who was in Israel

00:27:24.280 | when he discovered the molecule, you know,

00:27:26.740 | 30 odd years ago, wanted it to reflect inner bliss.

00:27:31.000 | And so he named it anandamide.

00:27:32.480 | So it's like inner bliss with an amide bond

00:27:34.440 | is kind of the joke he had for it.

00:27:35.840 | And so-

00:27:36.680 | - He discovered anandamide and decided to call it bliss

00:27:39.560 | because he had familiarity with cannabis

00:27:41.600 | or because he took anandamide as a direct experience.

00:27:45.320 | - No, no, I mean-

00:27:46.160 | - It takes a lot for a scientist to discover a molecule,

00:27:48.560 | but then for a scientist to discover a molecule

00:27:50.600 | and then name it bliss for a particular reason,

00:27:52.680 | you have to speculate that they had some familiarity

00:27:56.160 | with the compound.

00:27:57.000 | - Rafi Mashulam was also the guy who isolated

00:27:58.800 | and discovered THC.

00:27:59.880 | So, I mean, he has a very,

00:28:01.120 | he's kind of the grandfather of the whole cannabinoid field.

00:28:03.200 | So he has a landmark paper from 1964,

00:28:06.800 | which ironically,

00:28:08.520 | and this is one of these weird pop culture things.

00:28:10.200 | I don't know if this is true.

00:28:11.600 | That paper was published on April 20th, 1964.

00:28:14.520 | And so the joke is, is this where 420 came from?

00:28:17.360 | Because the original like birth date

00:28:19.240 | of the first THC paper was 420, 1964.

00:28:22.520 | - Well, now that potential myth

00:28:26.160 | is definitely gonna propagate.

00:28:27.560 | - Yeah, but yeah, so he'd been in the field for a while.

00:28:30.800 | And so he had studied cannabis on that side.

00:28:32.840 | And then in 1990, his lab isolated anandamide

00:28:36.040 | as being the first molecule

00:28:37.480 | that activated the receptor endogenously.

00:28:39.280 | And so it was kind of, yeah,

00:28:43.240 | I think it was a little tongue in cheek

00:28:44.400 | that he named it the way he did.

00:28:45.800 | A few years later, the second molecule,

00:28:47.600 | which is just called 2-arachidonylglycerol,

00:28:49.360 | or what we call 2-AG,

00:28:50.480 | that was discovered kind of in tandem,

00:28:52.320 | both again by Mashulam, but also by a Japanese group.

00:28:55.000 | And so we understand these two molecules

00:28:58.280 | don't do the same thing.

00:28:59.760 | Like they are a bit different.

00:29:00.840 | So the way anandamide binds the receptor

00:29:03.680 | is it's what we would call a high affinity,

00:29:06.160 | but low efficacy agonist, or molecule at least.

00:29:09.480 | And what I mean by that is very low levels of anandamide

00:29:13.080 | are required to actually bind to the receptor.

00:29:15.320 | But once it binds,

00:29:16.400 | its ability to stimulate a biological response

00:29:19.040 | in that neuron kind of caps out pretty fast.

00:29:21.800 | So it doesn't have like a sledgehammer effect.

00:29:24.720 | Whereas 2-AG seems to require

00:29:27.520 | a bit more concentration in the synapse

00:29:30.160 | to be able to bind to the receptor.

00:29:31.640 | So it has a lower affinity for the receptor.

00:29:33.880 | But once it binds to the receptor,

00:29:35.520 | it's like pretty heavy duty.

00:29:37.320 | So it evokes a very robust

00:29:40.120 | intracellular signaling response.

00:29:41.560 | And so why we have two endocannabinoids,

00:29:44.840 | we're not totally sure.

00:29:46.120 | Some of us have theories.

00:29:47.160 | I'm of the camp that I think

00:29:48.720 | they may play somewhat differential roles,

00:29:50.640 | either based on the synapse or the circuit

00:29:52.840 | that they're working in,

00:29:54.040 | or this idea that maybe anandamide

00:29:56.320 | might be more of a tonic molecule.

00:29:58.080 | And what I mean by that is,

00:29:59.720 | we'll say it's like a stage setter.

00:30:01.200 | So like anandamide might just be kind of

00:30:03.760 | made by neurons on an ongoing basis

00:30:05.960 | and just released.

00:30:06.800 | And its job may be to kind of keep

00:30:09.400 | the steady state of a brain circuit

00:30:11.560 | in a desired range.

00:30:12.680 | So that under resting conditions,

00:30:14.600 | it's not too active or too quiet.

00:30:16.760 | - Your thermostat analogy is perfect here.

00:30:18.760 | - So in that context,

00:30:19.760 | it kind of is like just the thermostat of the house.

00:30:22.520 | Whereas 2-AG is like,

00:30:25.040 | let's say the pinch hitter,

00:30:26.480 | who gets brought in to do the heavy lifting.

00:30:28.480 | And so 2-AG during a situation,

00:30:31.000 | like let's say something like even like a seizure

00:30:33.520 | is an extreme example,

00:30:34.520 | where you have a huge amount of neural activity.

00:30:36.760 | Those neurons that are getting heavily activated

00:30:39.200 | during massive amounts of neural activity,

00:30:41.880 | start dumping out huge amounts of 2-AG.

00:30:44.000 | And that acts as the,

00:30:45.400 | okay, we really need to turn off this circuit

00:30:47.320 | very quickly in this situation.

00:30:49.440 | And in most of these forms of like synaptic plasticity,

00:30:52.400 | like I was saying earlier,

00:30:53.240 | where you need to either strengthen or weaken a synapse

00:30:55.840 | in response to a change in the environment

00:30:58.320 | or in response to an experience

00:30:59.800 | or something that's going on.

00:31:01.440 | Most of that is driven by 2-AG signaling.

00:31:04.340 | And so, you know,

00:31:06.480 | all these forms of like turning things up or down

00:31:09.000 | in a kind of rapid and on-demand manner,

00:31:11.320 | that's mostly 2-AG.

00:31:13.000 | So most people who study like neurophysiology

00:31:16.480 | and like record activity in neurons

00:31:18.960 | and look at endocannabinoids,

00:31:20.040 | they're almost entirely talking about 2-AG

00:31:21.720 | when they play with stuff.

00:31:23.020 | So yeah, that's kind of one of the ways we do it.

00:31:26.480 | We say that anandamide may be more tonic

00:31:28.760 | and 2-AG might be more phasic.

00:31:30.800 | And like brought online when needed,

00:31:32.800 | but doesn't do a lot.

00:31:33.840 | There is some evidence that 2-AG may also have a role

00:31:36.120 | to regulate some circuits

00:31:37.160 | under kind of resting conditions as well.

00:31:38.760 | And there certainly are some situations

00:31:40.440 | where anandamide might get brought into play

00:31:42.640 | to affect plasticity,

00:31:44.780 | but as kind of like an umbrella idea of how we look at it,

00:31:48.720 | that's often how we divide those two up.

00:31:50.620 | So we kind of have these two molecules,

00:31:53.120 | they end of the day do the same thing.

00:31:54.580 | They're regulating neurotransmitter release

00:31:57.060 | through retrograde signaling,

00:31:58.120 | but what stimulation brings them online

00:32:00.720 | or what drives their activity may differentiate.

00:32:03.040 | And we don't really understand all the details behind that

00:32:06.240 | outside of the fact that we very clearly know

00:32:08.360 | 2-AG is activity dependent.

00:32:09.880 | So as that neuron becomes more active,

00:32:11.380 | it's gonna make 2-AG to regulate its inputs.

00:32:13.700 | So yeah, you have this very complex system

00:32:17.200 | and it's really widely distributed in, you know,

00:32:19.720 | it's everywhere.

00:32:20.560 | There's cannabinoid receptors

00:32:21.400 | and the endocannabinoid molecules are in the cortex,

00:32:23.400 | they're in the hypothalamus,

00:32:24.240 | they're in the striatum, the hippocampus, the cerebellum.

00:32:26.240 | - All over the place.

00:32:27.160 | - Except the one area where it's really interesting,

00:32:28.860 | actually, where you don't really see much receptor

00:32:32.040 | is in brainstem populations that regulate, you know,

00:32:35.800 | kind of unconscious cardiac and respiratory function.

00:32:38.840 | So this is one of the things that really differentiates

00:32:41.600 | cannabis from opiates,

00:32:42.840 | because a lot of the signaling mechanisms

00:32:44.680 | between opioid receptors and cannabinoid receptors

00:32:46.560 | are quite similar.

00:32:47.760 | But as it's been well-established,

00:32:50.160 | people can overdose and fatally and die from opiates

00:32:53.840 | relatively easily.

00:32:54.680 | And the way that that tends to happen is

00:32:56.880 | when you activate the opiate receptors

00:32:58.520 | in the kind of cardiorespiratory parts of the brainstem,

00:33:00.520 | it depresses neural activity.

00:33:02.200 | So as the person loses consciousness,

00:33:04.600 | they also unconsciously will stop regulating

00:33:07.960 | their own heart and breathing

00:33:08.800 | and it can be a fatal response.

00:33:11.480 | Because cannabinoid receptors

00:33:12.840 | don't really exist in those regions,

00:33:14.800 | you don't get the same kind of impact

00:33:17.160 | in terms of suppressing heart rate and breathing function.

00:33:21.080 | And so that's, I mean, you know,

00:33:23.820 | there's always the saying, like,

00:33:24.660 | there's never been an account of someone actually dying

00:33:27.160 | from a cannabis overdose or a THC overdose.

00:33:29.240 | I mean, certainly people can do stupid things

00:33:30.840 | while they're intoxicated that result in their death,

00:33:32.660 | but in the same manner that someone can die

00:33:35.040 | from consuming too much opiates,

00:33:36.280 | that doesn't seem to be physically possible

00:33:38.120 | with cannabinoids as far as we've seen so far.

00:33:40.660 | And a lot of that is just because of the localization.

00:33:43.860 | Like for some reason,

00:33:44.700 | it's just not the receptors in that part of the brain, so.

00:33:47.400 | - Very interesting.

00:33:48.440 | A lot of kind of a aficionado questions

00:33:53.520 | about the receptor biology.

00:33:54.640 | I'll just spare everyone the details

00:33:57.460 | by just highlighting something that you already said

00:34:01.000 | far more eloquently than I will,

00:34:02.920 | which is, I think it is fascinating

00:34:04.600 | that this whole system has both a tonic,

00:34:06.760 | like a steady release capability and a phasic, you know,

00:34:10.760 | so the ability to spike, forgive the pun,

00:34:13.520 | the neuroscientists will know what I'm talking about,

00:34:15.000 | to spike more activity of the system

00:34:17.360 | superimposed on that tonic activity,

00:34:19.120 | because this is something that you see

00:34:20.200 | in the dopamine system.

00:34:21.520 | This is something that you see

00:34:22.880 | in essentially every neuromodulator, neurotransmitter system,

00:34:26.920 | but it seems that the endocannabinoid system

00:34:29.800 | has accomplished this quite a bit differently.

00:34:31.800 | So very interesting, unique system in a number of ways

00:34:36.160 | that raise a number of key questions.

00:34:37.960 | - So yeah, if you go back

00:34:38.800 | to the munchies question you had,

00:34:40.980 | so if we tie into that, one of the,

00:34:43.200 | so there's a few ways, I mean,

00:34:45.040 | cannabinoids and feeding are a really interesting thing,

00:34:48.120 | because proto, like if you ask people,

00:34:51.020 | like kind of the prototypical responses to consuming cannabis

00:34:53.440 | most people would usually say munchies

00:34:55.140 | is one of the things that pops up pretty regularly.

00:34:57.720 | And so, you know, the cannabinoid receptors are very,

00:35:02.720 | they are expressed in these feeding circuits

00:35:05.720 | in the hypothalamus, and, you know,

00:35:08.200 | there's a lot of complex circuitry there

00:35:10.440 | that can regulate food-seeking behavior.

00:35:12.760 | - Yeah, we just had an episode with Zach Knight

00:35:14.600 | from HHMI and UCSF, where he talked about

00:35:17.600 | like the AGRP neurons and different neurons

00:35:20.280 | of the hypothalamus, we can link to that

00:35:21.800 | in the show note captions.

00:35:23.100 | Nowadays, a rich understanding of the neurons

00:35:27.040 | that stimulate food-seeking, craving, and then eating.

00:35:30.440 | - And so we know that like cannabinoids,

00:35:32.240 | they regulate, again, those inhibitory inputs

00:35:34.220 | around AGRP neurons, for example.

00:35:36.120 | And so one thing they can do is disinhibit

00:35:38.520 | those AGRP neurons, so they become more active,

00:35:40.560 | and that can drive food-seeking behavior.

00:35:42.240 | So that's certainly one mechanism of it,

00:35:44.000 | but there's also a huge reward component to this

00:35:47.040 | in terms of the munchies.

00:35:47.960 | And so we know that like you can also

00:35:51.320 | just dump anandamide, for example.

00:35:53.200 | This is, you know, Steve Mahler and Kent Berridge

00:35:54.960 | did this work years ago, where they just put anandamide

00:35:56.980 | into the nucleus accumbens, and that can also stimulate

00:35:59.000 | palatable food intake.

00:36:00.000 | So you also have this ability to integrate

00:36:01.860 | with the reward circuitry.

00:36:03.520 | And then there was also this fascinating paper

00:36:05.960 | from a Japanese group in PNAS, I think about 12 years ago.

00:36:09.160 | And what they found was they would give a rodent

00:36:12.720 | a cannabinoid, and then they would stimulate

00:36:14.380 | different taste bud populations.

00:36:16.200 | And then they would look at the gustatory cortical response

00:36:18.560 | to stimulating the populations.

00:36:19.840 | And what they found is under the influence of a cannabinoid,

00:36:23.800 | if you stimulated sweet taste buds,

00:36:25.960 | you got an enhanced response in the gustatory cortex,

00:36:28.680 | but not if you did salty, bitter, or sour.

00:36:31.240 | I don't know if they did umami in that one,

00:36:32.800 | but it was very explicit to sweet tasting.

00:36:35.360 | And so you have this kind of ability to like jack up

00:36:39.360 | the way the brain is processing sweet-tasting foods.

00:36:41.720 | You have this engagement of the reward circuitry,

00:36:43.680 | and then you also have this ability to regulate

00:36:46.080 | AGRP neurons, as well as the POMC neurons.

00:36:48.720 | There's kind of both sides to that in the arcuate nucleus,

00:36:52.100 | to regulate multiple components of feeding.

00:36:55.160 | But a big question is like,

00:36:57.320 | my lab has become kind of interested in this as well,

00:36:59.820 | because we have a component of my lab

00:37:01.500 | that studies feeding behavior.

00:37:03.020 | And one of my postdocs has been doing these projects

00:37:05.560 | for years now trying to understand,

00:37:07.480 | almost like at a behavioral mechanism level,

00:37:09.400 | what the munchies are.

00:37:11.160 | And what she's been looking at is,

00:37:12.880 | we kind of started thinking about the idea that,

00:37:15.380 | what is it that, because it's not just food seeking,

00:37:18.480 | and it's not just, like just want to consume something.

00:37:21.940 | There's a maintenance of eating.

00:37:24.240 | And so we know from humans and animals,

00:37:26.200 | you can satiate them, you can make someone full,

00:37:28.260 | and then get them high on cannabis,

00:37:30.020 | and they'll re-initiate eating.

00:37:31.500 | So that's an interesting thing in and of itself,

00:37:34.500 | because that means you're disrupting either

00:37:36.560 | the ability of the brain to detect satiety,

00:37:38.760 | or you're messing with a process we call reward devaluation.

00:37:42.480 | And so reward devaluation is like,

00:37:45.080 | if you haven't eaten for a day,

00:37:46.200 | and you see like a picture of a pizza,

00:37:48.240 | someone brings a pizza in front of you,

00:37:49.780 | it just looks delicious.

00:37:51.000 | That first slice tastes amazing.

00:37:52.520 | It's salty, it's fatty, it's delicious.

00:37:54.440 | You eat five of those slices, it feels greasy and nasty.

00:37:56.900 | And so that process of how you perceive the food,

00:38:00.200 | and its reward salience degrades as you eat,

00:38:02.840 | and as your brain basically shifts into a thing of,

00:38:05.640 | we don't need to consume calories and food anymore,

00:38:07.640 | we're okay, we're full now.

00:38:09.340 | And so we've done a series of experiments in the lab

00:38:12.180 | where you'd get the animals and either satiate it in advance

00:38:15.300 | where they have already devalued the food,

00:38:17.420 | and under a normal state, they won't eat it anymore,

00:38:19.280 | they won't work to get access to it.

00:38:21.320 | And you get them high on like a cannabis extract.

00:38:23.880 | We have these vape chambers that are like,

00:38:27.460 | I don't know how else to describe it

00:38:28.620 | outside of like a little hot box.

00:38:30.200 | It's probably the best way to,

00:38:31.320 | 'cause it's essentially a kind of a locked airtight box

00:38:36.080 | that the rat goes in and it gets like vapor puffs,

00:38:38.400 | and it fills up, and then they inhale this,

00:38:40.880 | and then it clears out, and they get another puff,

00:38:42.520 | and then it fills up, and we do this for like 15 minutes.

00:38:45.040 | And we've titrated all this to get exactly

00:38:47.520 | blood levels of THC that you would achieve

00:38:49.760 | in someone who's consuming cannabis through smoking.

00:38:52.400 | And so we get them to that point,

00:38:55.280 | and then give them access to food,

00:38:56.960 | and they will go gangbusters.

00:38:58.800 | They eat food, doesn't matter what you give them.

00:39:00.400 | You give them plain chow, they go to town,

00:39:02.120 | you give them fatty, you give them sweet, they love it all.

00:39:04.400 | But you pre-satiate them, and they get 'em stoned,

00:39:06.980 | they will re-initiate eating again.

00:39:08.980 | And you make 'em work for it

00:39:10.480 | where they have to like lever press,

00:39:12.400 | and you get 'em stoned, and they will go to town on that,

00:39:15.700 | and they will work, and--

00:39:17.040 | - Proof that even under the influence of cannabis,

00:39:19.640 | animals will work hard.

00:39:21.880 | - Yeah, they, for food, I don't know about other stuff,

00:39:25.040 | but for food, they certainly will.

00:39:26.160 | I mean, and at least Weiritz and Cassie Moore

00:39:27.800 | have done this at Hopkins as well.

00:39:29.000 | They've shown similarly,

00:39:30.240 | using what we call progressive ratio,

00:39:31.960 | which is essentially a thing where it's like

00:39:34.320 | the first time you press a lever,

00:39:35.500 | you immediately get a sugar.

00:39:36.480 | Next time you gotta hit it twice to get a pellet,

00:39:38.320 | then you have to hit it four times to get one.

00:39:40.420 | Yeah, then you gotta hit it 16,

00:39:41.820 | and then, and it kind of scales exponentially up.

00:39:44.680 | I mean, we've had this one female

00:39:46.440 | we kind of joke about in the lab,

00:39:47.800 | this one female rat, and you get her high,

00:39:49.440 | and she'll do like 300 lever presses

00:39:51.240 | to get one sugar pellet, like she really wants it.

00:39:53.880 | So you can really kind of goose up their motivation to eat,

00:39:56.680 | and so there's clearly a rewarding aspect to this

00:39:59.400 | because they're motivated to engage enough

00:40:01.560 | in working to get access to the food,

00:40:03.660 | but you can also do another way of testing this question,

00:40:06.780 | which is you can pair a food with something

00:40:10.080 | that will make the animal feel nauseous,

00:40:11.560 | like lithium chloride.

00:40:13.080 | This is kind of the way that you would test

00:40:15.040 | conditioned taste aversion.

00:40:16.080 | So you give them access to a food,

00:40:18.020 | and then you give them something

00:40:18.860 | that makes them feel nauseous,

00:40:19.720 | and the animals will avoid that food.

00:40:21.720 | And so that's another way to kind of devalue a food

00:40:25.720 | is by pairing it with a nauseant

00:40:27.080 | so the animal no longer likes it.

00:40:28.600 | So again, same situation, you can get the animal stoned,

00:40:31.200 | and it will re-engage in eating that food

00:40:33.480 | that it had devalued through being paired with a nauseant.

00:40:36.280 | So through either satiety

00:40:38.360 | or making it kind of a negative associated flavor

00:40:42.520 | because the animal got nauseous before,

00:40:44.880 | you can kind of override these effects by giving THC.

00:40:47.680 | And so that could be a complex process

00:40:50.600 | that either involves changes in the reward circuitry.

00:40:53.840 | This could be something that's like

00:40:54.760 | from the orbitofrontal cortex,

00:40:56.160 | which is a very important part of the brain

00:40:58.100 | that scales reward and kind of assesses

00:41:01.000 | how much someone wants to work

00:41:02.480 | or an organism wants to work to achieve a reward at the end.

00:41:05.200 | So we haven't figured out the circuitry of this

00:41:07.520 | and where exactly it's acting,

00:41:08.760 | but I would say a lot of the stuff

00:41:10.820 | that we and others have done kind of supports this idea

00:41:14.080 | that a lot of what the munchies is

00:41:15.680 | is this ability to kind of almost lock in

00:41:18.680 | the reward value of food so that it doesn't decay.

00:41:21.460 | Despite satiety, despite eating over time,

00:41:23.920 | it just keeps it highly salient

00:41:25.960 | so that they want to work for it still.

00:41:28.200 | And then similarly, we've also,

00:41:30.120 | we and others have also done work to show

00:41:31.560 | we can block satiety signals.

00:41:32.920 | So we know endocannabinoids at least

00:41:35.200 | are capable of overriding leptin.

00:41:37.760 | So leptin is an anorectic molecule,

00:41:41.040 | comes out from the fat,

00:41:42.440 | and usually we release it when we've eaten a lot,

00:41:44.720 | and it's one of these things

00:41:46.040 | that tells our brain, "Stop eating."

00:41:47.320 | You know, it works through, again,

00:41:49.240 | populations in the arcuate nucleus

00:41:50.680 | and changes the way those neurons function

00:41:52.800 | to drive food-seeking behavior.

00:41:54.880 | And we and others have shown previously

00:41:57.120 | that if you elevate endocannabinoids,

00:41:59.080 | you can override that.

00:42:00.200 | And actually, one of the mechanisms

00:42:01.720 | by which leptin seems to suppress feeding

00:42:03.320 | is actually by turning on

00:42:05.680 | the metabolism of endocannabinoids

00:42:07.280 | so that their levels decline.

00:42:08.840 | And so as you lose that endocannabinoid function,

00:42:11.680 | the animal is less interested in eating.

00:42:13.360 | And so you can prevent these anorectic effects of leptin

00:42:16.160 | by, like, goosing up endocannabinoid activity.

00:42:20.000 | As many of you know,

00:42:20.880 | I've been taking AG1 for more than 10 years now.

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00:43:02.600 | that we all need for physical and mental health.

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00:43:24.600 | meant to augment, not replace quality food.

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00:44:09.240 | You're talking about increasing endocannabinoid activity,

00:44:13.080 | and we've said all this in the context of cannabis.

00:44:16.100 | So maybe we could talk a little bit

00:44:17.280 | about how the components in cannabis,

00:44:19.560 | THC mainly, but also CBD,

00:44:22.320 | impact these receptors, the CB1,

00:44:24.760 | and let's just leave CB2 out for the moment

00:44:27.020 | because it sounds like it's more of an immune system thing.

00:44:30.020 | But just to make it very clear,

00:44:31.560 | is there a way to increase the activity of endocannabinoids

00:44:37.280 | without ingesting THC?

00:44:41.000 | - Yes, I mean, they dynamically change all the time, so-

00:44:44.080 | - But you're talking about,

00:44:45.520 | you're talking about experimentally

00:44:46.780 | or recreationally adjusting their levels,

00:44:48.960 | but how does one do that without using THC?

00:44:52.600 | - So, okay, few things there, we'll take a step back.

00:44:55.280 | So THC itself isn't going to,

00:44:59.520 | it does its thing by acting directly

00:45:02.240 | on the cannabinoid receptor, not-

00:45:03.760 | - So it sort of mimics the anandamide and 2AG.

00:45:07.360 | - Yeah, so THC,

00:45:09.280 | going back to kind of the pharmacology of this.

00:45:11.360 | So THC, if you look at how it interacts with the receptor,

00:45:14.840 | it's not a heavy duty molecule.

00:45:18.480 | So, I mean, this was kind of one of the things

00:45:20.480 | that came up before as well,

00:45:21.760 | is this idea that THC is a sledgehammer

00:45:23.600 | and it overrides endocannabinoids.

00:45:25.200 | - By the way, Matt's referring to the fact

00:45:26.680 | that I said that in a previous solo episode about this,

00:45:29.560 | and there I was nesting it in the concentrations of THC

00:45:32.600 | that can be found in high THC cannabis.

00:45:35.120 | - Yeah.

00:45:35.960 | - So essentially what I was saying

00:45:37.520 | is that at very high THC concentrations,

00:45:40.400 | the amount, maybe not the binding affinity,

00:45:43.800 | but the amount of THC that is available to the CB1 receptors

00:45:48.400 | is going to exceed what's normally found

00:45:51.000 | in terms of the amount of anandamide

00:45:52.920 | that can bind to CB1 receptors,

00:45:54.400 | because what you're talking about

00:45:55.280 | is a super physiological condition.

00:45:57.120 | - Yeah, I mean, you don't really actually need

00:45:59.080 | much THC in the brain to produce psychoactivity.

00:46:01.560 | Like it's a little bit of a mystery,

00:46:03.880 | to be honest, exactly how it works.

00:46:06.040 | I mean, I think the main way that most people

00:46:09.280 | in the cannabinoid theory field would look at this

00:46:11.320 | is that THC is not like a very strong agonist.

00:46:15.800 | I mean, even if you look at its ability

00:46:17.160 | to trigger an intracellular response,

00:46:18.880 | it's much lower than 2-AG.

00:46:21.000 | So it's actually more like anandamide.

00:46:22.920 | - So you said anandamide is high affinity, low efficacy.

00:46:25.640 | - Yeah, so THC is the same.

00:46:27.080 | THC is actually only a partial agonist.

00:46:28.920 | It's not even a full agonist at CB1.

00:46:30.880 | - But it is high affinity.

00:46:32.120 | - It's high affinity, so it has the ability.

00:46:34.680 | So, but the tricky thing with that is

00:46:36.680 | it can out-compete 2-AG,

00:46:40.160 | but because it's a lower efficacy agonist than 2-AG,

00:46:43.400 | in that sense, it's almost blocking the effects,

00:46:45.600 | not amplifying them.

00:46:47.880 | - Blocking the effects of 2-AG,

00:46:49.200 | but does it block the effects of anandamide?

00:46:51.560 | - THC and anandamide, I would kind of,

00:46:55.320 | the way I would visualize it is

00:46:56.440 | because they seem to have relatively similar affinities

00:46:58.760 | and efficacies of the receptor,

00:47:00.720 | they might, let's say, dance around.

00:47:02.360 | So it would be somewhat interchangeable.

00:47:04.000 | The difference there is,

00:47:05.520 | and this, I think, is the big point

00:47:06.800 | about what THC does versus endocannabinoids,

00:47:09.200 | because we know now,

00:47:11.200 | through the pharmaceutical development of drugs

00:47:13.180 | that can boost anandamide levels, which exist,

00:47:15.680 | we have inhibitors that prevent their metabolism,

00:47:17.520 | we can elevate them.

00:47:18.360 | There's no intoxication and no psychoactivity

00:47:20.640 | associated with elevating anandamide.

00:47:22.640 | - That's a very interesting point that we should highlight.

00:47:24.800 | So there are drugs that now exist

00:47:26.300 | that can block the breakdown of anandamide,

00:47:28.160 | make more available,

00:47:29.280 | presumably by disrupting some enzymatic breakdown,

00:47:31.960 | and therefore lead to more binding

00:47:34.360 | of the now elevated levels of anandamide

00:47:37.760 | that are available to CB1,

00:47:38.960 | and you see no psychoactive effect.

00:47:41.440 | People are not aware that they-

00:47:42.820 | - Yeah, you can do, no one can guess.

00:47:44.780 | Yeah, no one can guess.

00:47:45.620 | - What is it used for?

00:47:46.740 | - Well, I mean, it was developed,

00:47:48.780 | the first molecule really was developed by Pfizer

00:47:50.900 | to look at if it could work on pain.

00:47:53.580 | The first trial that was done did not work.

00:47:55.180 | It was like a kind of strange osteoarthritic knee pain trial

00:47:59.920 | that was like, even in that trial,

00:48:01.780 | the positive control of naproxen barely worked,

00:48:04.220 | but because the pha inhibitor, which is,

00:48:07.380 | take a step back,

00:48:08.220 | pha is the enzyme that chews up anandamide.

00:48:10.500 | So the drug that is developed inhibits that enzyme.

00:48:13.760 | So you prevent the enzymatic breakdown of anandamide.

00:48:15.760 | So we just call them pha inhibitors.

00:48:18.280 | So this drug will boost anandamide levels quite high,

00:48:22.160 | and in animal research showed some efficacy

00:48:24.800 | in modulating pain.

00:48:25.960 | And so they put it in a trial

00:48:27.480 | and it didn't work

00:48:28.320 | against the positive control of naproxen,

00:48:30.200 | which is like an NSAID, just like Advil, basically.

00:48:32.440 | - Aleve.

00:48:33.280 | - Yeah, essentially, yeah.

00:48:34.120 | So, and that drug didn't work that great to begin with.

00:48:37.080 | So it was maybe some issues with the trial,

00:48:38.760 | but it essentially killed the development of the drug

00:48:41.680 | from that point on,

00:48:42.520 | because everyone's like, oh, it's not gonna work.

00:48:43.540 | So it kind of shelved for a while.

00:48:45.240 | A colleague of mine, Marcus Heilig and Leah Mayo,

00:48:50.520 | Leah is now a colleague of mine in Calgary,

00:48:52.720 | but at the time she was a postdoc with Marcus in Sweden,

00:48:56.080 | and they were able to get access to this molecule

00:48:58.800 | right before COVID, essentially.

00:49:00.480 | And they did a trial in just healthy controls with it,

00:49:05.240 | which again, this is kind of jumping the gun

00:49:07.360 | on some of the other stuff I'll talk about,

00:49:08.480 | so I'll tether back to that.

00:49:09.720 | But what they did was they dosed people for 10 days

00:49:13.440 | on this drug, and then we looked at stress and fear,

00:49:16.280 | because this is something that I study,

00:49:18.100 | this is something that they were interested in.

00:49:20.040 | And we did find that boosting anandamide with this drug

00:49:23.840 | over 10 days was sufficiently capable

00:49:27.240 | of dampening stress-induced autonomic responses.

00:49:29.840 | So like looking at heart rate or skin conductance.

00:49:32.640 | I think skin conductance was the measure we did in there,

00:49:34.360 | but it's a proxy for like adrenaline release.

00:49:37.200 | So it blunted that, and it blunted subjective feelings

00:49:39.600 | of stress as well, so people had lower levels

00:49:41.400 | of saying they actually felt stressed.

00:49:43.280 | And it kind of helped remove this conditioned fear memory

00:49:47.600 | that they had trained people to do.

00:49:49.640 | And so I worked with them on kind of doing

00:49:51.240 | the biochemistry of this to make sure

00:49:52.500 | the drug was working properly.

00:49:54.200 | But it was very interesting because we did see

00:49:56.040 | in that situation where elevating anandamide

00:49:58.160 | produced kind of like a reduction in stress perception,

00:50:01.800 | a reduction in stress physiology responses,

00:50:04.020 | and kind of helped kind of reduce fear.

00:50:07.820 | And so that is kind of an interesting outcome

00:50:11.060 | because it tracks with some of the stuff

00:50:12.640 | we know about cannabis.

00:50:13.480 | And I'm sure we'll talk about some of the PTSD stuff

00:50:15.260 | and anxiety later.

00:50:16.220 | But so that's kind of one of the things.

00:50:18.300 | The drug has not really been used that widely yet.

00:50:20.460 | It's still, it's one of the frustrations I have

00:50:23.860 | as a scientist who does a lot of translational work

00:50:26.480 | and with clinical partners like Leah,

00:50:29.280 | is that getting access to these molecules is not easy

00:50:32.340 | when they're not kind of wide, they're not like

00:50:34.900 | out in the market.

00:50:35.740 | So you can just go and get them.

00:50:36.580 | You really have to try and get access

00:50:39.040 | from the drug companies to be able to do trials with them.

00:50:41.700 | And so we are in the midst of trying to do that.

00:50:44.700 | We did just complete a trial that Leah and Marcus ran

00:50:47.540 | that I worked with them on as well, that was on PTSD.

00:50:50.440 | And so there are various potential indications for this.

00:50:55.520 | I mean, Johnson & Johnson developed one as well,

00:50:57.500 | and they looked at it in social anxiety disorder.

00:50:59.180 | They had some moderate efficacy in their trial.

00:51:01.620 | So I'd say the jury's still out on exactly

00:51:04.260 | what we're gonna do with these,

00:51:05.540 | but they have some potential.

00:51:08.260 | I think in certain clinical settings,

00:51:09.560 | we just have to figure that out exactly.

00:51:11.300 | But I think going back to where we started this from,

00:51:14.100 | they're not psychoactive.

00:51:15.300 | And so, I mean, when Pfizer first made the drug,

00:51:17.820 | they were actually initially concerned

00:51:20.140 | that it wasn't getting in the brain

00:51:21.540 | because no one could tell they were on the drug.

00:51:23.460 | I mean, this was the Wild West at this point.

00:51:25.420 | No one had any idea what endocannabinoids

00:51:27.220 | were actually gonna do.

00:51:28.340 | People were basing it on what we knew about THC.

00:51:30.600 | So the assumption was people would have psychoactivity,

00:51:33.580 | but they didn't.

00:51:35.180 | Pfizer then actually had to do,

00:51:36.380 | they did a sleep study to show

00:51:37.620 | that it did have some effects on sleep cycle,

00:51:40.120 | the same way THC does.

00:51:41.420 | And then they also did like an in vivo pet binding study

00:51:44.580 | to show that they could displace a radioactive molecule

00:51:47.940 | that would bind to the enzyme in the brain.

00:51:49.900 | - Seems like a lot of gymnastics

00:51:51.420 | to basically confirm what they already knew,

00:51:53.820 | which is that even greatly elevating the anandamide

00:51:56.740 | by blocking this enzymatic breakdown of anandamide

00:51:59.420 | leads to, at least from what I'm understanding,

00:52:02.080 | vastly different subjective experience

00:52:04.960 | than ingesting or smoking THC,

00:52:07.760 | which brings us back to THC and cannabis.

00:52:11.880 | Like, you know, it seems that this thing

00:52:15.440 | that we call cannabis and THC are overlapping

00:52:20.160 | with the endogenous effects of anandamide.

00:52:23.000 | But here you're not talking about endogenous normal levels.

00:52:25.820 | You're talking about pharmacologically

00:52:27.080 | greatly increasing anandamide,

00:52:28.640 | no psychoactive effect, no euphoria,

00:52:30.640 | no munchies, you know, et cetera.

00:52:32.740 | Then people smoke or take an edible of THC or cannabis

00:52:37.740 | and you get a vastly different set of effects.

00:52:40.680 | So maybe we could talk about THC and the CB1 receptor.

00:52:44.720 | And since we're here, we might as well talk about CBD

00:52:48.320 | and the, I think you're going to tell us,

00:52:50.320 | the lack of interaction with CB1 receptor, right?

00:52:53.800 | And what is cannabis doing at the level of these receptors?

00:52:57.960 | Because it makes me wonder whether or not

00:53:00.280 | these receptors are the whole story

00:53:02.200 | or whether or not cannabis is, you know, as you mentioned,

00:53:05.280 | you know, 70 plus active molecules in there,

00:53:08.480 | terpenes and a bunch of other things

00:53:09.800 | that may modify their action.

00:53:11.320 | But this thing we call cannabis has many more actions

00:53:15.420 | than just mimicking the endogenous cannabinoid system.

00:53:18.640 | - Yeah, I mean, I think, I would say the main way

00:53:21.480 | that we think about this is the difference

00:53:23.280 | between endocannabinoids and THC

00:53:24.800 | is endocannabinoids are going to be released

00:53:26.600 | in a very specific spatial and temporal manner.

00:53:30.120 | So-- - They evolve to do that.

00:53:31.600 | - Yeah, so there's going to be, and I think like,

00:53:33.520 | it's very clear that like anandamide, for example,

00:53:36.220 | is not active at every synapse that has CB1.

00:53:39.040 | And so when we boost anandamide signaling

00:53:41.800 | by inhibiting its metabolism,

00:53:43.440 | all we're doing is amplifying anandamide signaling

00:53:45.680 | at the synapses it already exists.

00:53:48.120 | Whereas THC, when you consume it orally or inhalation wise,

00:53:52.300 | and it gets into your blood and into your brain,

00:53:56.100 | it's just blanket activation.

00:53:57.440 | You're just carpet bombing the whole system

00:53:59.160 | indiscriminately, and so--

00:54:00.660 | - You're introducing the ligand,

00:54:02.080 | the thing that binds the receptor.

00:54:03.500 | This is far and away different than say like

00:54:06.000 | the actions of amphetamines,

00:54:08.320 | which are disrupting the normal biology

00:54:10.240 | in a way that's giving you an amplification

00:54:12.040 | of an endogenous mechanism, right?

00:54:14.680 | If that was all just nerd speak for those listening.

00:54:17.640 | It's one, in the context of amphetamines,

00:54:20.200 | what you're doing is you're taking an endogenous system,

00:54:22.280 | a naturally occurring system,

00:54:23.600 | and you're greatly amplifying the amount of dopamine,

00:54:26.080 | the amount of norepinephrine that's available.

00:54:28.400 | With what we're discussing today,

00:54:31.860 | the endocannabinoid system seems to be producing

00:54:35.260 | a set of effects that might overlap with the THC effects,

00:54:39.160 | but THC is doing a bunch of other things,

00:54:41.960 | and that's because THC, and we'll talk about CBD,

00:54:44.840 | but at least THC is acting as the ligand.

00:54:48.240 | It's in some sense, we don't wanna say replacing,

00:54:50.380 | but it's masking the effects of anandamide.

00:54:52.560 | - I think the problem is when you just blanket activate

00:54:55.100 | all the CB1 receptors in the brain indiscriminately,

00:54:58.140 | like you do when you consume cannabis with THC,

00:55:00.720 | the resulting effect is the intoxicating state,

00:55:03.680 | and it's probably because there's a lot of CB1 receptors

00:55:06.400 | in the cortex, and those are gonna be

00:55:08.480 | differentially regulated at different times

00:55:10.600 | by endocannabinoids, whereas when THC hits them,

00:55:13.520 | all of them are gonna get affected at once,

00:55:15.040 | and if you think of the way that I had described

00:55:17.640 | how cannabinoid receptors work by essentially,

00:55:20.200 | I mean, at its simplest form,

00:55:21.760 | what cannabinoid receptors do is they change the way

00:55:23.920 | that two neurons talk to each other, and so--

00:55:27.040 | - So you're changing all the networks simultaneously.

00:55:28.920 | - Yeah, so if you hit a whole bunch

00:55:30.120 | of networks simultaneously, you're just gonna change

00:55:32.220 | the way that information processing and perception occurs,

00:55:35.600 | and I think as a consequence of that,

00:55:37.820 | that's what produces the intoxicating state,

00:55:39.600 | not that THC is like a super-duper version

00:55:44.320 | of an endocannabinoid or that it's boosting endocannabinoids.

00:55:46.980 | It's kind of like just indiscriminately activating

00:55:50.760 | all the receptors as opposed to a system

00:55:52.600 | that's very finely tuned to do very specific things

00:55:55.120 | at very specific times.

00:55:56.360 | - That's very helpful.

00:55:57.480 | So the analogy that I was considering using coming in here,

00:56:00.560 | like the difference between endogenous testosterone

00:56:03.000 | or estrogen versus pharmacologic testosterone or estrogen

00:56:07.240 | given as a therapy is very different

00:56:09.280 | because that's a levels issue.

00:56:11.880 | This is a levels and an extent issue.

00:56:14.040 | - Yeah, this is a lot more to do with just, yeah,

00:56:16.160 | the nature of how it hits everything,

00:56:17.880 | because like, so for example, if we talk about feeding,

00:56:20.920 | we know it's been established at this point that,

00:56:23.520 | for example, if an organism doesn't eat for like a day,

00:56:25.800 | so you fasted, at that point in those feeding circuits

00:56:30.640 | in your brain, like the arcuate area

00:56:31.960 | where these AGRP neurons and stuff are,

00:56:33.960 | you'll start seeing elevations in endocannabinoids.

00:56:36.640 | So endocannabinoid levels start kind of going up and up

00:56:40.000 | following kind of fasting periods.

00:56:42.000 | And part of this is because they're trying to engage

00:56:44.380 | that feeding circuitry now and they're shifting

00:56:46.560 | the activity of those neurons

00:56:48.280 | to promote food-seeking behavior

00:56:50.040 | because an organism is basically like energy-detecting

00:56:53.060 | its periphery and saying, oh, you know,

00:56:54.480 | we might be burning through our energy reserves,

00:56:56.560 | we should probably eat more.

00:56:57.920 | And so there are obviously a few mechanisms that do this.

00:57:00.680 | NPY is another one and ghrelin and things like that.

00:57:04.120 | So there's a lot of redundancy in these systems,

00:57:05.960 | but endocannabinoids are just one of the molecules

00:57:07.720 | that seem to fine-tune like the feeding circuitry.

00:57:10.380 | And so in states of fasting,

00:57:12.080 | endocannabinoids go up explicitly in that circuit.

00:57:14.660 | And there's some evidence they also go up

00:57:16.560 | in like the nucleus accumbens

00:57:17.760 | and affect some of the reward circuitry.

00:57:19.200 | So they're probably driving food-seeking behavior

00:57:21.400 | and enhancing the rewarding aspects of food

00:57:23.280 | at the same time.

00:57:24.320 | And so that's like a natural endogenous mechanism

00:57:27.200 | to regulate feeding based on nutritional state.

00:57:30.280 | THC, on the other hand, you know, it hits the brain.

00:57:32.940 | Yeah, some of it's gonna be the intoxication,

00:57:34.680 | but in tandem, you're gonna hit the CB1 receptors

00:57:37.040 | that are in those feeding circuits as well.

00:57:38.540 | And the consequence of that is gonna be,

00:57:41.960 | I mean, the way I kind of analogize it to people,

00:57:43.880 | as I say, it's almost like tricking the brain

00:57:45.640 | into thinking that you've been fasting

00:57:47.760 | because you're now activating receptors

00:57:49.200 | that are normally activated

00:57:50.400 | following kind of a fasting state.

00:57:52.220 | And as a consequence of that,

00:57:54.080 | it pushes someone or an organism or human or whatever

00:57:57.400 | into a state of food-seeking behavior

00:57:59.280 | because now food also has high reward value

00:58:01.200 | and they're kind of,

00:58:02.480 | the way that their food circuitry is responding,

00:58:04.460 | in the brain at least,

00:58:05.400 | seems to be similar to what would happen

00:58:07.240 | if they'd been fasted.

00:58:08.280 | And the thought is that's why when people,

00:58:10.820 | you know, when someone gets stoned,

00:58:12.960 | they're not like going to eat lettuce.

00:58:14.480 | They want high calorie food.

00:58:16.380 | They tend to like things that are high carb, high fat.

00:58:19.360 | That combo seems to be what people like

00:58:21.240 | when they're intoxicated with cannabis.

00:58:23.120 | And that comes with a lot of calories.

00:58:24.800 | And the point of that would be

00:58:26.080 | you're trying to replenish lost energy stores.

00:58:28.560 | And so this at least is the kind of the theory that I have

00:58:31.600 | about what it is that it's doing is, you know,

00:58:34.120 | and I think you can make this analogy

00:58:35.400 | for multiple different things.

00:58:36.640 | You know, if we talk about pain or stress,

00:58:38.020 | we can say similar kinds of things are going on,

00:58:40.480 | is that endocannabinoids normally do one thing,

00:58:43.280 | but when THC hits the brain,

00:58:45.240 | it's still activating these circuits

00:58:46.660 | in addition to everything else that hits.

00:58:48.700 | So you still drive that response

00:58:50.420 | that the endocannabinoid system

00:58:51.440 | normally physiologically controls,

00:58:53.460 | but you're almost like tricking the brain

00:58:55.260 | into thinking you're in that state now.

00:58:57.140 | And so then you, then yeah,

00:58:58.660 | you go into food seeking behavior mode.

00:59:00.760 | - Super interesting.

00:59:02.020 | Well, I have to imagine that there are many people

00:59:04.140 | who use cannabis not to stimulate appetite,

00:59:07.260 | but for other reasons.

00:59:08.380 | They either like the euphoria or to adjust their anxiety.

00:59:13.840 | What are some other known mechanisms

00:59:16.380 | by which cannabis can change people's psychology?

00:59:20.940 | Let me focus in on one particular aspect

00:59:24.480 | of subjective experience, which is focus.

00:59:27.220 | Do you think that some people use cannabis

00:59:29.080 | because it allows them to focus better?

00:59:31.620 | And I raise this specifically because I think that

00:59:34.660 | in the past, cannabis has had a bit of a reputation

00:59:38.420 | for making people spacey.

00:59:40.140 | Now you use the word stoned, kind of out of it.

00:59:43.140 | And yet I've heard of some potential uses

00:59:45.380 | for enhancing focus.

00:59:47.040 | - I mean, honestly,

00:59:47.880 | this is a bit of a tricky one to speak to

00:59:49.260 | because I just don't think there's good evidence for it.

00:59:52.620 | - Either way or?

00:59:54.340 | - I just don't.

00:59:55.180 | I mean, as far as I'm aware,

00:59:56.140 | it hasn't been studied in a lot of depth.

00:59:58.460 | I mean, there's some things,

00:59:59.860 | a lot of the stuff that's been done

01:00:00.900 | is usually more like kind of acute memory tasks,

01:00:03.480 | like a working memory or recall or something like this,

01:00:06.420 | as opposed to explicitly studying focus.

01:00:09.020 | Anecdotally, there is certainly a lot of people

01:00:11.340 | that report that.

01:00:12.180 | - My understanding is that people who use cannabis

01:00:15.140 | have poor, certain forms of memory,

01:00:18.240 | but not necessarily poor memory across the board.

01:00:20.500 | Is that correct?

01:00:21.460 | - I don't think I would say that.

01:00:22.460 | I don't think you could lump anything in that context.

01:00:24.660 | I mean, I would say the only thing you can say confidently

01:00:27.900 | that I would be comfortable saying is that

01:00:30.200 | acutely while someone's intoxicated on cannabis,

01:00:32.720 | there is definitely short-term effects on memory processing.

01:00:35.660 | So people tend to-

01:00:36.880 | - Negative effects or enhancements or decrements?

01:00:40.140 | - I would say most of it has to do

01:00:41.740 | with recall or consolidation.

01:00:43.360 | So there does seem to be some,

01:00:45.100 | I mean, certainly the animal evidence

01:00:46.380 | is very compelling there, but again,

01:00:48.100 | we can talk to what some of the limitations of that are.

01:00:50.860 | But in humans, I would say most of the work

01:00:52.940 | that's been done would suggest

01:00:54.220 | there is some short-term memory deficits

01:00:57.400 | that are present during the intoxicated state.

01:01:00.600 | I have not seen very much compelling evidence

01:01:03.660 | of long-term effects that emerge,

01:01:05.840 | like when someone's not intoxicated,

01:01:07.580 | but they use cannabis somewhat regularly.

01:01:09.620 | I don't think there's anything compelling for that.

01:01:12.180 | And even in that case, like Carrie Cutler,

01:01:15.140 | who's at Washington State,

01:01:16.180 | she's done a lot of this stuff looking at

01:01:18.620 | cognitive processing and different kinds of memory tasks

01:01:21.180 | in users while they're stoned often.

01:01:24.820 | And within a person,

01:01:27.060 | either they have adapted to using it as much as they do,

01:01:31.100 | or they've developed some form of tolerance to it.

01:01:33.240 | But even in regular users,

01:01:35.240 | the impact on memory processing

01:01:37.080 | is usually not super robust.

01:01:39.960 | It's still there.

01:01:40.800 | I mean, I think the effects that are more often seen

01:01:43.520 | in kind of, let's say, smaller laboratory studies

01:01:47.080 | where they're using people who've used cannabis,

01:01:48.480 | but aren't regular users,

01:01:49.720 | might be a little bit more profound

01:01:51.520 | because they may not be used to that state, let's say.

01:01:55.720 | I mean, there's certainly something

01:01:57.080 | we call state-dependent learning,

01:01:58.160 | which I'm sure you're familiar with.

01:01:59.640 | And this is something people,

01:02:01.360 | I mean, I remember learning about this

01:02:02.560 | in undergrad through alcohol.

01:02:03.960 | So like, you know, someone,

01:02:05.920 | first time they get drunk, tries doing something,

01:02:07.720 | they're very bad at the task.

01:02:08.920 | But if every time they're drunk, they do that task,

01:02:11.260 | they become better at doing it under the influence.

01:02:13.560 | And so then all of a sudden, you know,

01:02:16.200 | they regularly do this task while they're drunk

01:02:18.040 | and someone tests them,

01:02:18.880 | and they don't look like they're impaired at all

01:02:20.320 | because they've done it so much.

01:02:21.440 | And so-

01:02:22.280 | - I should just say this point has often been confused

01:02:24.400 | by undergraduates and others to assume that

01:02:28.920 | just because one can gain proficiency at a task

01:02:31.440 | while under the influence of a substance

01:02:33.480 | does not mean that you have higher proficiency

01:02:35.860 | at that particular task while under the influence.

01:02:38.600 | In fact, the way it was presented to me

01:02:40.040 | when I was an undergraduate was incorrect.

01:02:44.240 | I remember the lecturer said and later corrected himself.

01:02:48.280 | I won't call him out here 'cause that's unfair.

01:02:50.200 | He's not here to defend himself,

01:02:51.360 | but it happens in lectures that people who studied drunk

01:02:56.120 | would be better off coming to the exam drunk.

01:02:58.120 | That is not true from what I understand.

01:03:00.120 | - I don't think better off, no.

01:03:01.740 | - But they would probably score better than someone

01:03:03.980 | who had never studied drunk and came to the test drunk.

01:03:07.000 | - Correct.

01:03:07.840 | - Just because they had had some state-dependent learning.

01:03:10.000 | And so I think when we're talking about,

01:03:11.800 | if you're talking about someone who's a chronic cannabis user

01:03:14.080 | they're going to have done a lot of cognitive tasks

01:03:16.760 | while they're under the influence.

01:03:18.120 | And so if you acutely test them,

01:03:20.680 | the impairment you might see in them is probably less

01:03:23.520 | than you would see in someone who's relatively naive

01:03:25.520 | or a much less experienced user.

01:03:27.520 | That being said, I think it's relatively well-established.

01:03:30.280 | Most people would agree that acutely intoxication

01:03:33.100 | with cannabis does impair memory processes in some capacity.

01:03:36.420 | What explicit form of memory?

01:03:38.100 | I don't think I could speak to comfortably

01:03:40.380 | just 'cause I'm not a memory researcher

01:03:42.020 | and I know there's very specific things

01:03:43.340 | of like episodic and declarative and whatnot.

01:03:45.340 | So I can't say that, but I'd say it's kind of generally,

01:03:49.300 | and I mean, again, you can replicate this in animals

01:03:51.140 | where if you train them on a task

01:03:53.020 | while they're under the influence,

01:03:54.060 | they don't seem to have consolidated

01:03:55.780 | that information as well.

01:03:58.380 | But again, I don't really think

01:04:00.200 | there's super compelling evidence

01:04:01.680 | that there's kind of long-term permanent effects

01:04:03.960 | on cognitive function in individuals who use cannabis.

01:04:07.120 | At least I've never seen anything that's replicable

01:04:09.640 | or reliable or stable in any way, so yeah.

01:04:13.160 | - Thanks for clarifying that.

01:04:14.200 | And also thank you for clarifying the discrepancy

01:04:18.160 | between endogenous cannabinoid binding

01:04:20.640 | and affinity for CB1 versus THC.

01:04:23.200 | I really appreciate that because that's something

01:04:24.720 | that you and I discussed in light of the solo episode

01:04:27.440 | I did about cannabis, and now you've made it clear

01:04:31.060 | that THC does not bind with much higher affinity.

01:04:33.820 | It's just, as I think your words were,

01:04:35.900 | assuming high THC levels in the cannabis carpet bombs

01:04:39.740 | all the networks as opposed to binding more

01:04:42.580 | with higher affinity at particular receptors.

01:04:44.660 | - Yeah, I mean, I don't actually even think it matters

01:04:46.380 | if it's high THC in the cannabis.

01:04:47.720 | I think like some people can get very intoxicated

01:04:49.800 | off of very, very low doses of cannabis.

01:04:51.860 | - Is that right?

01:04:52.700 | - I mean, you look at edibles, for example.

01:04:55.140 | I mean, this may be an interesting segue

01:04:57.340 | into root of administration stuff,

01:04:58.580 | 'cause I think it's an important point

01:04:59.580 | that a lot of people don't recognize,

01:05:01.180 | is the difference between someone inhaling cannabis

01:05:04.940 | versus someone orally consuming cannabis

01:05:06.680 | is like a different game.

01:05:08.720 | - Yeah, let's talk about this, 'cause I know that you

01:05:11.420 | and I arrived at different understanding

01:05:13.640 | of the fastest, typical, and slowest routes of entry

01:05:18.640 | for THC into the system, to arrive at the brain, right?

01:05:26.820 | The numbers I gave in the previous discussion about this

01:05:28.980 | were related to how quickly inhaled smoke moves

01:05:31.620 | from the lungs to the bloodstream

01:05:33.060 | and crosses the blood brain barrier.

01:05:34.700 | - Which is very fast.

01:05:35.620 | - Right, which is very fast.

01:05:37.660 | - I don't know if it's different than nicotine.

01:05:39.260 | I'm not sure.

01:05:40.500 | Again, I don't know if I would say that,

01:05:41.860 | but yeah, it's very fast.

01:05:43.380 | - Okay, so it may be that it is the same as nicotine.

01:05:48.380 | It may be that it's faster,

01:05:50.180 | but importantly, it can be fast.

01:05:53.780 | But typically, how fast is the onset

01:05:56.020 | of the subjective experience of,

01:05:58.120 | okay, somebody takes a hit off a joint or a bong hit

01:06:03.120 | and they start to experience the subjective effects

01:06:07.180 | of euphoria, et cetera, how quickly after?

01:06:09.980 | - Two to five minutes, I would say.

01:06:11.340 | It's pretty fast.

01:06:12.180 | I mean, so this is one of the things with cannabis is,

01:06:15.020 | and again, this will kind of go into this idea

01:06:18.900 | of the change in potency of the plant as well.

01:06:23.180 | It's pretty quick and people titrate cannabis pretty well,

01:06:26.300 | like at least people who've used it a couple of times

01:06:28.660 | and understand this.

01:06:29.500 | - I've seen some people not titrate it very well.

01:06:31.700 | - Depending again on how you're, so again, this can vary.

01:06:34.220 | So like, you know, cannabis from the '70s was like,

01:06:38.340 | I don't know, 5% THC, let's say.

01:06:40.260 | It was pretty low.

01:06:41.500 | And nowadays, cannabis is,

01:06:43.540 | a lot of the commercial stuff is between 20 and 30,

01:06:45.680 | although whether those are super accurate numbers,

01:06:48.140 | not entirely clear, but so it's gone up a fair amount.

01:06:50.980 | - Yeah, I mean, that's not just a fair amount.

01:06:54.340 | I mean, if we were talking about alcohol concentration.

01:06:56.660 | - It's beer to vodka.

01:06:57.900 | Yeah, basically you're talking about a beer

01:06:59.940 | or a wine to a spirit.

01:07:01.020 | - And there are aquavit varieties, so to speak.

01:07:04.400 | By the way, I think when people hear me talk about

01:07:07.720 | any kind of a drug that can be used recreationally

01:07:10.380 | or alcohol, I think some people assume that,

01:07:12.180 | you know, I'm ultra anti all these things.

01:07:14.660 | I'm actually not, right?

01:07:15.820 | I'm not an alcoholic, so I can drink a little bit

01:07:18.660 | and I have, I just don't tend to.

01:07:20.760 | And we could discuss cannabis in a different venue.

01:07:23.820 | But the point here is we're not trying to frame this

01:07:27.740 | as what people should or shouldn't do.

01:07:29.020 | We're just trying to inform people.

01:07:30.340 | I want to be very, very clear about that.

01:07:32.060 | So, but when I hear about, you know,

01:07:35.020 | 20 to 30% concentration, as opposed to 5% concentration,

01:07:40.020 | that's significant.

01:07:41.500 | - So I would say this is what's super interesting.

01:07:44.620 | And this was something that came out of the way

01:07:47.620 | that cannabis research is done, certainly in the States.

01:07:50.380 | And Canada has been quite behind on this,

01:07:52.660 | even with legalization, we haven't caught up.

01:07:55.140 | But they have been doing lab-based studies of cannabis.

01:07:58.380 | You know, Meg Haney, Harriet DeWitt,

01:08:00.380 | this cluster of researchers around the country,

01:08:01.980 | Ziva Cooper at UCLA here, have all done this where,

01:08:04.960 | you know, you have people come into the lab,

01:08:06.420 | you give them cannabis, you measure subjective outcomes

01:08:09.400 | or neuroimaging outcomes or whatnot.

01:08:11.500 | So to do this, you can't use commercial cannabis.

01:08:15.760 | And even like the state by state legalizations

01:08:19.140 | hasn't changed this.

01:08:19.980 | So if you are doing cannabis research in humans

01:08:22.660 | and you're funded by like NIDA,

01:08:23.820 | which is National Institute of Drug Abuse,

01:08:26.620 | you get all your cannabis sourced.

01:08:28.980 | I mean, this may be changing.

01:08:30.340 | I think there are some shifts that are happening,

01:08:31.820 | but historically in all the literature

01:08:33.500 | that we would talk about,

01:08:34.380 | that's kind of pre the last couple of years,

01:08:36.580 | all that cannabis came from one source,

01:08:38.780 | which was, I believe a farm in like Mississippi

01:08:41.340 | that was essentially funded by NIDA to produce cannabis.

01:08:44.300 | - Lucky farm.

01:08:45.120 | - And well, the cannabis that came out of it though,

01:08:47.740 | and this is one of the reasons a lot of the clinical stuff,

01:08:50.140 | people have kind of been like,

01:08:51.260 | "Oh, I don't know how representative this is."

01:08:52.900 | 'Cause it reflects cannabis that I would say is more

01:08:55.620 | from like the seventies or eighties.

01:08:56.820 | So it would be like five to 9% kind of THC cannabis.

01:09:01.300 | Now, when you put someone in a lab setting

01:09:04.400 | and you get them to smoke to level of intoxication,

01:09:08.340 | people would take, you know, whatever, eight tokes,

01:09:11.060 | let's say, something like that.

01:09:12.740 | And that's where they would stop.

01:09:14.260 | And so, you know, a lot of the labs that use this

01:09:17.020 | have always been like,

01:09:18.140 | "Our people who are regular cannabis users

01:09:19.940 | are getting high off of it.

01:09:20.860 | It's not as potent as the stuff that's on the street,

01:09:23.240 | but they're clearly getting intoxicated from it

01:09:25.060 | and it's giving us reliable data."

01:09:27.820 | So when they started looking at the blood levels of THC

01:09:29.980 | that you achieve,

01:09:31.100 | it was around a hundred nanograms per mil of THC,

01:09:34.220 | give or take.

01:09:35.220 | That seemed to be where it was.

01:09:36.980 | Now, because of the way that the,

01:09:40.820 | you can legally study cannabis in the States,

01:09:43.820 | you couldn't just go down to a dispensary

01:09:46.540 | and buy the products that everyone on the street are using,

01:09:48.460 | which is kind of like,

01:09:49.360 | it's been a weird thing for a lot of people

01:09:50.780 | 'cause they're like,

01:09:51.620 | "Why wouldn't you study what we're using?"

01:09:53.020 | But because of the legal aspects of this,

01:09:55.180 | you couldn't bring those products into the lab.

01:09:56.740 | They'd never been standardized.

01:09:58.480 | No one knew exactly what was in them,

01:10:00.360 | pesticides, all this other stuff that could influence it.

01:10:02.560 | So from a safety perspective,

01:10:04.260 | it was always like,

01:10:05.100 | "No, you use the cannabis that's sourced from NIDA."

01:10:08.800 | So there's a group in Colorado,

01:10:12.500 | so Kent Hutchinson and Angela Bryan and Cinnamon Bidwell

01:10:15.140 | have kind of, I would say,

01:10:17.060 | became very creative actually

01:10:18.740 | to figure out how to study cannabis

01:10:21.580 | that's being used, I call it, in the wild,

01:10:23.980 | in kind of an ecological setting, let's say.

01:10:26.100 | And so they created what was called the Canavan.

01:10:29.380 | And the Canavan was a way to study people

01:10:32.580 | using products on the street,

01:10:34.340 | but not have them come into a laboratory setting

01:10:36.540 | where it was complicated.

01:10:37.580 | And so what they would do

01:10:39.140 | is they would drive the Canavan to someone's house,

01:10:42.500 | but they'd be parked on the street,

01:10:44.100 | and someone would use the product,

01:10:46.140 | whatever it was, in their own property, in their own time,

01:10:49.980 | and then come into the Canavan to have blood taken,

01:10:53.020 | to look at what their THC levels are,

01:10:54.380 | and to undergo testing.

01:10:56.140 | And so it was actually like,

01:10:57.340 | I think this was a great advance in the field

01:10:59.740 | 'cause it was this huge innovative approach

01:11:01.620 | that allowed us to start comparing

01:11:03.280 | what we've learned from lab-based settings

01:11:05.460 | with this kind of old school weed

01:11:07.740 | that was coming from NIDA

01:11:08.740 | with what is being used on the street.

01:11:10.620 | - I love this.

01:11:11.460 | I mean, as somebody whose lab has done

01:11:12.700 | a in-laboratory VR-based experiment

01:11:15.400 | on human anxiety and fear,

01:11:17.740 | and then compared that to a clinical study

01:11:22.100 | that we did sort of in mass,

01:11:25.000 | where people were at home

01:11:26.160 | doing specific respiration practices.

01:11:28.140 | You have many more subjects,

01:11:29.200 | but of course they're reporting back their effects.

01:11:32.020 | Well, you can monitor them by device,

01:11:34.380 | look at HRV, look at heart rate, et cetera.

01:11:37.340 | I think having the ability to compare and contrast

01:11:39.780 | in-laboratory and ex-laboratory data is extremely valuable.

01:11:43.600 | - Yeah, and I mean, my view is you need both

01:11:45.380 | because you need the in-laboratory for the control

01:11:47.460 | because we all need control over various things,

01:11:49.980 | but you also need the ecological validity

01:11:52.580 | to see how it shakes out and make sure it looks the same.

01:11:55.060 | - Yeah, for people that have never been to a laboratory

01:11:57.500 | or tried to find a parking spot at a university,

01:11:59.820 | that's an anxiety-inducing experience in and of itself.

01:12:02.780 | - A novel experience while someone's intoxicated

01:12:04.780 | with cannabis can also create

01:12:06.340 | a very different altered state.

01:12:07.540 | - I would wanna be stoned in a laboratory.

01:12:09.140 | I'll tell you that much.

01:12:09.980 | - I feel like there's pluses and minuses to both sides,

01:12:12.540 | but I think the data together is very compelling

01:12:14.800 | and that's where we get a lot of advance in the field.

01:12:16.860 | So what Kent and Angela and Cinnamon did with the Canavan

01:12:20.100 | was kind of create the situation

01:12:21.600 | that allowed this research to occur.

01:12:24.180 | And what we found fascinating,

01:12:26.060 | I remember talking to Meg Haney about this

01:12:27.340 | because all the people in her lab studies

01:12:29.700 | tended to always hit around 100 nanograms per mil

01:12:31.660 | using this relatively lower potency cannabis.

01:12:34.860 | When Kent and Angela and Cinnamon

01:12:36.500 | started studying this in the people and taking blood,

01:12:39.540 | despite the fact that these people

01:12:40.740 | are now using cannabis that's 20 to 30%,

01:12:43.340 | their blood levels are the same.

01:12:44.980 | So they're still coming in around 100 nanograms per mil

01:12:47.560 | because people are really good at self-titrating.

01:12:50.700 | Now, where things fall apart is with the concentrates.

01:12:54.300 | So then you go into things like dabs

01:12:56.980 | or these high-potency products that are now like,

01:12:59.940 | 'cause cannabis itself, realistically,

01:13:02.980 | from what I understand from the botanists

01:13:04.460 | that I've talked to, you can't really grow a plant

01:13:06.820 | that's gonna exceed more than 25 to 30% THC

01:13:09.260 | just by sheer biology.

01:13:10.940 | So it taps out there.

01:13:12.220 | That's about as high as it's gonna go.

01:13:14.100 | Concentrates can go up to like 90, 98%.

01:13:16.660 | So you can get really, really-

01:13:18.020 | These are tinctures?

01:13:19.780 | Distillates, like, yeah, various just in oil-based forms

01:13:23.500 | that are very, very high-potency products.

01:13:26.660 | Those are incredibly challenging to titrate.

01:13:29.380 | Like, they cannot be titrated

01:13:30.780 | because the sheer volume of THC that hits the system,

01:13:33.260 | even from a single hit, is so overwhelming.

01:13:35.820 | And so when the Colorado group looked at those,

01:13:38.780 | their blood levels were closer

01:13:40.140 | to 200 to 300 nanograms per mil.

01:13:41.980 | So with cannabis plant,

01:13:44.620 | there does seem to be this ability

01:13:47.020 | for people to relatively self-titrate.

01:13:49.260 | And then my buddy Ryan McLaughlin,

01:13:51.260 | who's also at Washington State,

01:13:52.540 | he was really one of the ones

01:13:53.580 | that pioneered these vape chambers in rats

01:13:55.540 | and created this really cool model of self-administration,

01:13:59.340 | which was a very important thing to actually establish

01:14:02.220 | because it was very challenging

01:14:03.540 | to get rodents to self-administer cannabis

01:14:05.820 | if you're doing, like, an IV approach or something else

01:14:07.780 | 'cause they found it quite aversive.

01:14:09.140 | But when you let rodents actually titer

01:14:12.020 | their ability to get vape hits,

01:14:13.460 | they will, like, work for this,

01:14:15.500 | the same way they will other reinforcing drugs.

01:14:18.020 | So it was a really important finding that you could do this.

01:14:20.740 | And what Ryan found was he actually did one study

01:14:23.500 | where he gave them access to a low-potency product,

01:14:27.220 | and we'll call it medium, and then a high.

01:14:30.460 | And what you ended up, if you look at the data,

01:14:32.100 | is the one the rats liked the best

01:14:33.540 | was the medium-potency product.

01:14:35.180 | Interesting.

01:14:36.020 | And if you gave them the high-potency product,

01:14:37.540 | they would actually take less vape hits off of that

01:14:39.740 | than they would off the lower ones.

01:14:41.020 | And again, all their blood levels

01:14:42.900 | tended to cluster in the same range

01:14:44.540 | because they titrated.

01:14:47.460 | Like, even at the rodent level,

01:14:48.940 | they're able to titrate

01:14:49.980 | because of the lag between inhalation

01:14:52.420 | and feeling the effects is only

01:14:54.220 | on the order of a couple of minutes.

01:14:56.260 | People can titrate better.

01:14:58.740 | I mean, not just people.

01:14:59.780 | It seems like the rodents can as well.

01:15:01.020 | So the higher-potency cannabis,

01:15:03.620 | where it becomes a problem

01:15:04.660 | is if someone's highly inexperienced

01:15:06.220 | and they consume a whole bunch of it

01:15:07.540 | without allowing that time lag to occur.

01:15:10.100 | And then they can probably exceed the levels

01:15:12.300 | they intended to and consume too much

01:15:13.940 | and then have probably an adverse response.

01:15:16.500 | So does that mean that cannabis use

01:15:18.100 | rarely leads to tolerance of cannabis use?

01:15:20.720 | I wouldn't say that.

01:15:22.720 | There's definitely some degree of tolerance.

01:15:24.740 | The tolerance is definitely more prominent

01:15:26.780 | when people start using concentrates.

01:15:28.220 | There's no question about that.

01:15:29.180 | I mean, we can talk about the concentrates,

01:15:30.660 | I guess, separately after.

01:15:31.940 | 'Cause I would say,

01:15:32.780 | if we're talking about a harm reduction thing,

01:15:34.560 | that's more where we need to focus a lot more

01:15:37.220 | is this idea of these high-potency products.

01:15:39.020 | - Yeah, it sounds like those are precarious.

01:15:41.540 | That somebody who thinks they have a lot of experience

01:15:43.540 | or God forbid, no experience,

01:15:45.660 | takes a concentrate and is, what,

01:15:47.900 | no longer getting the euphoric experience

01:15:50.620 | that they anticipated,

01:15:52.480 | but instead are getting, what, a paranoid anxiety attack.

01:15:55.620 | - I think you're far more likely to go overboard

01:15:58.340 | and have an adverse response.

01:15:59.360 | But also, I think the problem is,

01:16:00.940 | if you're using a product of that potency

01:16:04.120 | and that much THC floods your system on a regular basis,

01:16:07.600 | the biological changes from that

01:16:09.160 | are going to be very different

01:16:10.480 | than what you get if, again,

01:16:12.160 | you're titrating your THC from inhaling plant

01:16:16.520 | at roughly the same level,

01:16:17.680 | whether that's a 10%, 5%, or 25%,

01:16:21.480 | people generally tend to scale.

01:16:23.560 | - This is a very important point,

01:16:24.880 | and I'm going to highlight it

01:16:25.760 | because I think it's very, very, very important.

01:16:29.160 | Although you're making it very clearly already,

01:16:31.180 | which is, these days we hear a lot

01:16:33.000 | about the "problems" with high THC containing cannabis

01:16:38.000 | as relative to what was present in the '70s and '80s,

01:16:41.960 | and presumably '90s as well.

01:16:43.620 | I was a teen in the '90s,

01:16:45.920 | so maybe I'm alluding to something there.

01:16:48.240 | But what you're saying is that

01:16:49.480 | unless one is talking about concentrates,

01:16:52.340 | that people, and animals in the laboratory,

01:16:55.160 | will self-regulate the amount of intake

01:16:58.060 | in a way that leads to

01:16:59.480 | approximately the same blood levels of THC.

01:17:03.120 | So it may not be as much of a concern,

01:17:05.280 | at least in light of the concerns about,

01:17:08.280 | oh, these levels are so high

01:17:09.980 | that people are overwhelming their system with THC.

01:17:12.740 | Basically, this could be stated in real-world terms

01:17:15.480 | as people are taking fewer tokes

01:17:17.840 | of the higher concentration stuff

01:17:21.100 | that allow them to match blood levels

01:17:22.620 | that were present in the person

01:17:24.680 | taking many more tokes in the '70s.

01:17:26.660 | So the joke I always make to people is I say,

01:17:28.520 | go watch a Cheech and Chong movie from the late '70s.

01:17:30.880 | Look at the size of the joints that they smoke

01:17:33.360 | in movies like that,

01:17:34.320 | relative to what you would see

01:17:35.520 | someone on the street consuming nowadays.

01:17:37.560 | So the advantage that existed from a titration perspective

01:17:42.840 | was with '70s weed, there's a large window to titrate.

01:17:46.360 | So people could take small amounts

01:17:49.000 | and not over-consume, let's say,

01:17:50.880 | because there was a much lower concentration

01:17:53.120 | of THC in the plant.

01:17:54.040 | So they're able to consume,

01:17:55.400 | even if they were doing it relatively fast,

01:17:59.200 | because of how little THC was coming into the system,

01:18:01.280 | it was a little easier to scale that.

01:18:03.160 | So there certainly is the propensity

01:18:05.040 | for people to over-consume higher-potency cannabis,

01:18:07.960 | even independent of concentrates,

01:18:10.040 | if they're not allowing that titration to occur.

01:18:12.280 | Also, if you have someone who is just

01:18:14.200 | exquisitely sensitive to THC for various reasons,

01:18:18.020 | even one or two tokes could be too much for them

01:18:20.360 | because at the higher potency,

01:18:22.440 | they may not have that ability to titrate quite as well.

01:18:25.280 | And so a lot of people,

01:18:27.080 | anecdotally, you talk to people about cannabis,

01:18:29.620 | and a lot of people who don't like cannabis have said,

01:18:31.560 | oh, you know, I've tried, the new stuff's too strong.

01:18:33.560 | And if there's someone who's kind of more in our age range

01:18:36.480 | who grew up in an earlier decade

01:18:38.520 | where things were a bit different,

01:18:40.020 | they may be referencing their own experience

01:18:41.640 | from when they were younger

01:18:42.480 | and what they were able to consume,

01:18:43.480 | and now they try doing the same

01:18:44.620 | and it hits them like a sledgehammer.

01:18:45.880 | - Got it.

01:18:46.720 | - So it's a little different in that sense,

01:18:48.100 | but, you know, and I don't think it's to say

01:18:51.000 | it's like not concerning

01:18:52.640 | that cannabis is as high as THC as it is.

01:18:54.800 | I just think if I'm gonna put my efforts

01:18:57.000 | into kind of like, you know,

01:18:59.040 | public health perspectives of this,

01:19:01.160 | I would be digging my feet in much more

01:19:03.000 | about the access to concentrates

01:19:04.800 | and the issues and the potential harms

01:19:06.760 | that are gonna come with them

01:19:07.720 | than I would about the cannabis flower myself.

01:19:10.280 | That's just my opinion based on what I see

01:19:12.680 | with the concerns and what we've seen

01:19:14.880 | from the data in humans.

01:19:15.960 | And I think the real world ecological studies

01:19:19.160 | that the Colorado group have done

01:19:20.220 | have been very informative in the sense,

01:19:21.560 | because yeah, if the blood levels of THC

01:19:24.200 | you achieve from concentrates are double to triple

01:19:26.560 | of what you get even from higher potency flower,

01:19:29.040 | that's a concern.

01:19:29.920 | Like, I think that's where problems start arising

01:19:31.720 | because then you're gonna start seeing

01:19:33.780 | a lot higher degree of tolerance.

01:19:35.340 | I mean, there used to be more of a debate in the field

01:19:37.400 | as to whether people develop tolerance,

01:19:39.200 | because one of the things with cannabis

01:19:41.200 | that I do find very interesting

01:19:42.400 | is with a lot of chronic users,

01:19:44.680 | they don't escalate the way you would see

01:19:46.320 | with cocaine or alcohol,

01:19:47.460 | where there's very profound tolerance that develops.

01:19:49.780 | And so, I mean, people definitely see this in cocaine

01:19:53.000 | where people can become tolerant almost immediately.

01:19:55.960 | And so, dosing starts scaling up very fast.

01:19:58.440 | - Yeah, usually it's the life destruction

01:20:00.280 | that thwarts their progressive increase.

01:20:03.480 | Seriously. - Or the cost.

01:20:04.760 | I mean, the sheer cost.

01:20:05.600 | - Another form of life deterioration.

01:20:08.320 | - Yeah, that is required to be able to maintain that.

01:20:10.480 | But with cannabis,

01:20:11.560 | it seems like there is some degree of tolerance

01:20:15.160 | that people exhibit.

01:20:16.120 | It varies from person to person,

01:20:17.520 | but as Meg has said to me many times,

01:20:21.700 | the guys that come in her studies,

01:20:23.300 | these are very heavy users,

01:20:24.880 | and then they will use this relatively low potency product

01:20:28.440 | and still get high off of it.

01:20:29.880 | And so, it's not to say that there's no tolerance.

01:20:32.120 | It's just, it's not as profound

01:20:33.740 | as I think we see with a lot of other drugs.

01:20:35.840 | And this is probably due to the fact of just like,

01:20:39.280 | we definitely see,

01:20:41.420 | like if we look at some pet imaging studies,

01:20:43.540 | chronic cannabis users do have some down--

01:20:45.460 | - Sorry, I have to interrupt.

01:20:46.300 | - Pet, positron emission tomography, not pets.

01:20:49.420 | Although people get their pets high

01:20:50.880 | and we don't know what those pets think about that.

01:20:53.320 | - Not good, don't get dogs high.

01:20:54.880 | - If also high, one can assume a lot of things

01:20:57.000 | about what your pet is thinking while also high.

01:20:59.880 | Sort of half joke there.

01:21:01.560 | But yes, positron emission tomography

01:21:03.080 | is one way to assess the binding of drugs within the brain

01:21:08.080 | as well as activity of endogenous neurotransmitters,

01:21:12.720 | neuromodulators, such as anandamide, dopamine, et cetera.

01:21:17.340 | - Yeah, so a typical pet study and a human looking at this,

01:21:21.060 | they'd give a molecule that's radiolabeled

01:21:23.140 | that will bind to CB1 receptors.

01:21:25.340 | You can scan them and then look at the emission rates

01:21:28.460 | of the radiation to get an idea of the density of receptors

01:21:30.780 | that are in the brain.

01:21:31.780 | Chronic cannabis users tend to have less.

01:21:33.980 | What that means in terms of the functional outcome

01:21:40.140 | is unclear.

01:21:41.140 | I mean, there could be some,

01:21:43.000 | I think there's a lot of evidence

01:21:44.920 | that there's some degree of a reservoir of CB1 receptors

01:21:47.560 | that there might be a lot more receptors there

01:21:49.660 | than we necessarily always need

01:21:51.040 | or are always using, let's say.

01:21:52.880 | So we might be downregulating a component of this,

01:21:55.560 | but maybe not all of the ones that are required

01:21:57.560 | to produce the psychoactive effects

01:21:59.040 | 'cause there's clearly some maintenance of the system

01:22:01.480 | that allows someone to continue to get intoxicated.

01:22:04.600 | And so with cannabis users, we do see that.

01:22:07.020 | But you do see much more profound tolerance

01:22:09.680 | with people using high potency extracts and concentrates

01:22:12.660 | and things like this.

01:22:13.500 | And again, surely I think as a response to the biology

01:22:16.860 | of hitting the system that heavily

01:22:19.380 | with that much THC as it comes in

01:22:22.460 | 'cause they can't titrate it the same way.

01:22:24.100 | - It makes sense.

01:22:24.940 | Yeah, these concentrates sound like something

01:22:27.620 | to at least pay attention to as a potential problem.

01:22:31.100 | I'd like to take a quick break

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01:23:41.860 | Along the lines of use, tolerance, et cetera,

01:23:45.600 | is cannabis addictive and/or habit-forming?

01:23:50.300 | And I think it's probably important

01:23:51.460 | that we distinguish between the two.

01:23:52.720 | I may have made this joke in the previous episode

01:23:55.740 | I did on cannabis.

01:23:57.620 | I've known a lot of chronic cannabis users

01:24:00.700 | and none of them admit to being addicted.

01:24:04.980 | It's not my place to challenge them on that,

01:24:08.180 | but they do seem, in my experience,

01:24:10.820 | this is not an experiment,

01:24:12.260 | but in my experience, more irritable

01:24:14.100 | when they don't have access to what they call

01:24:17.380 | their "medicine."

01:24:19.300 | So that speaks to a dependence or something,

01:24:24.300 | but then we need to be careful

01:24:25.860 | because in the classic sense, addiction,

01:24:29.060 | I've defined and others in the field of addiction

01:24:32.220 | have defined it as a progressive narrowing

01:24:34.180 | of the things that bring you pleasure,

01:24:35.460 | such that it causes disruption to other areas of life.

01:24:40.180 | Your life becomes maladaptive.

01:24:42.420 | - Yeah, I mean, I'm not going to play

01:24:44.140 | with the definition of addiction.

01:24:45.300 | I feel like I have enough friends in the addiction space

01:24:48.940 | that it's a very contentious field.

01:24:50.860 | So, I mean, I will try and not use that word,

01:24:53.620 | although I understand talking to the general public,

01:24:56.460 | that's kind of, you know,

01:24:57.340 | if you say someone has a use disorder versus an addiction,

01:25:00.020 | that may not make sense to them.

01:25:01.460 | - But that's the nomenclature now

01:25:02.620 | that people are using, alcohol use disorder,

01:25:04.820 | cannabis use disorder.

01:25:06.860 | This is what you start to see now

01:25:08.300 | instead of saying being addicted to pot

01:25:09.860 | or being addicted to alcohol.

01:25:10.780 | - And so, I mean, an addiction is obviously

01:25:13.380 | a very complex thing that, again, I don't want to touch it

01:25:17.860 | simply because it's not my space.

01:25:20.300 | But that being said, there's no question

01:25:23.100 | that people can develop cannabis use disorder.

01:25:24.700 | I mean, it's definitely a thing.

01:25:27.020 | So if we say, is cannabis addictive

01:25:28.620 | in kind of a, you know, normal lay speak,

01:25:31.180 | I would say, yes, it is addictive.

01:25:32.860 | What does that look like?

01:25:34.100 | How does that relate to other substances of abuse?

01:25:37.020 | I mean, certainly the outcomes associated with it

01:25:42.020 | are gonna be slightly different than someone,

01:25:43.780 | something like opiates or alcohol,

01:25:45.780 | because that's a totally different beast,

01:25:47.740 | because you have a fatality potential.

01:25:50.220 | There's a whole bunch of other health consequences.

01:25:52.140 | But if we look at how we would define a use disorder,

01:25:55.300 | the criteria for someone hitting cannabis use disorder

01:25:57.940 | is really no different

01:25:58.980 | than how someone would hit alcohol use disorder

01:26:00.860 | or opiate use disorder in the sense

01:26:02.140 | that it can consume their life.

01:26:04.020 | It can shift the way that they behave.

01:26:06.100 | They can put themselves in risky positions

01:26:07.860 | to get access to a drug.

01:26:08.980 | It can consume their time and their energy to have it.

01:26:12.780 | Like you said, if they don't have access to it,

01:26:14.740 | it can trigger, you know, an assembly of behaviors

01:26:17.580 | that looks like irritability, anger, frustration,

01:26:20.060 | things like that.

01:26:21.420 | So, I mean, the numbers in terms of the conversion rate

01:26:26.420 | of use to developing use disorder,

01:26:28.820 | I would say are not entirely clear.

01:26:30.780 | The kind of old numbers that used to get tossed around

01:26:32.940 | were like nine to 11% of people

01:26:35.180 | that would start initiating cannabis use

01:26:37.420 | would probably transition to develop use disorder.

01:26:40.780 | The more modern numbers, I would say, you know,

01:26:43.220 | if we're looking at people who are already using weekly,

01:26:45.420 | we're talking probably closer to 30%.

01:26:47.420 | Like, so it's a much higher,

01:26:48.700 | I mean, when you're using that frequently,

01:26:50.260 | then the rates of people who would qualify

01:26:52.020 | as having cannabis use disorder probably go higher.

01:26:54.100 | - So, I just wanna make sure I'm understanding clearly.

01:26:55.900 | For people that use cannabis weekly,

01:26:59.420 | the propensity for developing cannabis use disorder

01:27:03.900 | is on the order of about 30%.

01:27:05.900 | - Yeah, I'd say in that neighborhood,

01:27:07.500 | they would probably qualify as meeting criteria

01:27:10.020 | for cannabis use disorder.

01:27:11.260 | - 'Cause weekly doesn't seem like that often.

01:27:13.300 | - No, I mean, it depends again on how you vary this.

01:27:16.380 | Like, I've had a lot of conversations with the public,

01:27:18.540 | and I think depending on someone's experience

01:27:21.500 | in their own or in their own inner circles,

01:27:23.700 | life with cannabis,

01:27:24.540 | the way they would view it is very differently.

01:27:26.060 | 'Cause I think a lot of people, you know,

01:27:28.820 | again, regardless of anyone's opinion of alcohol,

01:27:31.060 | if someone told you they had a glass of wine with dinner

01:27:33.380 | every night, I don't think people would say

01:27:35.100 | you have an alcohol use disorder.

01:27:37.260 | I think that's not uncommon.

01:27:38.540 | - I don't think they would.

01:27:39.580 | - Similarly, if someone had a brandy at the end of the night

01:27:42.580 | or like, you know, a nightcap to go to bed,

01:27:45.180 | and they did that on a nightly basis,

01:27:46.460 | I don't think anyone would say

01:27:47.980 | that they have a use disorder.

01:27:49.140 | And I think with cannabis,

01:27:51.100 | there are a lot of people that kind of fall

01:27:53.020 | into that bracket that would use it, you know, even daily,

01:27:56.140 | but relatively infrequently,

01:27:57.820 | and kind of as an end of the day thing.

01:28:00.420 | I think some of them certainly would fall

01:28:02.900 | into the criteria of cannabis use disorder.

01:28:04.780 | 'Cause if you start looking and say, well, you know,

01:28:06.820 | if you travel to like Egypt,

01:28:09.420 | are you gonna go put yourself at risk of going to jail

01:28:11.580 | to get access to cannabis?

01:28:12.620 | 'Cause you can't function without it.

01:28:14.100 | If you do, then yeah, you know,

01:28:15.740 | you've got cannabis use disorder.

01:28:17.460 | You know, are you going to burn relationships?

01:28:19.940 | Are you gonna start failing at meeting responsibilities

01:28:22.860 | or getting things done on time

01:28:24.260 | because you're preoccupied with cannabis?

01:28:26.860 | Yes, you're gonna hit the criteria

01:28:28.660 | for cannabis use disorder.

01:28:30.220 | If it's someone who's kind of just intermittently using it,

01:28:33.300 | the same way that a lot of people casually use alcohol,

01:28:36.220 | I would say a lot of them probably wouldn't hit criteria.

01:28:39.780 | But I think to someone who has never had cannabis

01:28:42.820 | in their inner circle or in their life,

01:28:44.860 | they look at it like a drug like cocaine,

01:28:47.420 | whereas they're like, wow,

01:28:49.020 | if you were using cocaine on a daily basis,

01:28:50.780 | we'd be super concerned about you.

01:28:52.700 | And so I think that's this, like,

01:28:55.500 | it's just as you go, I mean,

01:28:57.020 | cannabis is in this really weird transitionary period,

01:29:00.580 | I would say, of going from illicit to not,

01:29:03.060 | just because of the changes

01:29:04.140 | in the legal regulatory framework.

01:29:05.700 | I mean, in Canada now,

01:29:07.140 | we're like five and a half years into legalization.

01:29:09.380 | So in many ways, I would say the transition has happened

01:29:12.740 | where a lot of people view cannabis

01:29:14.100 | very similarly to alcohol,

01:29:15.340 | whereas you go to some states

01:29:17.300 | and the perspective is still very different.

01:29:18.860 | And certainly if you're still in one of the states

01:29:20.020 | where there's no legal access,

01:29:21.420 | people still look at cannabis the same way

01:29:23.460 | they look at a lot of other illicit drugs

01:29:26.300 | like cocaine or amphetamines or things.

01:29:27.740 | - That's interesting.

01:29:28.580 | I was under the impression this has really changed

01:29:30.980 | over the last, you know, five, 10 years.

01:29:33.340 | You know, growing up, it was,

01:29:34.860 | I mean, I think there are still people in jail now

01:29:38.300 | because of possession and sale of cannabis.

01:29:41.900 | And then of course there are stores not far from here

01:29:45.260 | where people are selling cannabis.

01:29:46.220 | - Ironic, yeah, sadly.

01:29:48.580 | I mean, obviously a big push for legalization

01:29:51.900 | is not endorsement of the safety of cannabis.

01:29:55.140 | It's more the harms associated with prohibition

01:29:58.380 | outweigh the harms associated with legalization.

01:30:00.500 | I think that's generally the public health perspective.

01:30:02.940 | That's certainly what motivated it in Canada.

01:30:05.180 | And there was, you know, some attempts, let's say,

01:30:07.740 | at restorative justice

01:30:08.660 | in terms of removing criminal records and things.

01:30:11.260 | May not have been entirely as successful

01:30:12.740 | as people had hoped it would be,

01:30:14.100 | but it certainly has changed things.

01:30:15.620 | I mean, we can look at our federal data

01:30:17.500 | and see that arrest rates related to cannabis

01:30:19.420 | are obviously very low compared to what they were.

01:30:22.900 | That obviously becomes very important

01:30:24.140 | because there are clearly minoritized communities.

01:30:26.180 | They get hit more with this than other communities.

01:30:29.220 | And so the kind of perpetual disenfranchisement

01:30:32.860 | that happens with a prohibition model

01:30:35.660 | in communities that are already suffering

01:30:37.580 | from various other things that affect them

01:30:40.420 | just potentiates all that.

01:30:41.940 | So I can understand the legal framework

01:30:44.380 | behind why there'd be a move to a legalization state

01:30:46.900 | over a prohibition state,

01:30:48.420 | which again, a lot of people confuse legality with safety,

01:30:52.140 | which is a weird,

01:30:53.780 | I mean, alcohol is the perfect example of this.

01:30:55.620 | I mean, you look at the scale of harms

01:30:58.100 | on a public health level.

01:30:59.300 | I mean, alcohol stacks at the top.

01:31:01.740 | Across the board in terms of harms to the individual,

01:31:03.820 | harms to society, it's a lot.

01:31:06.180 | Cannabis has harms, there's no question on that.

01:31:08.700 | It just would fall lower than alcohol.

01:31:11.260 | But the way that people view it,

01:31:12.820 | a lot of people are like alcohol is legal,

01:31:14.340 | therefore it's safe,

01:31:15.180 | and it's not something to judge people on.

01:31:17.260 | Cannabis at least historically was illegal

01:31:19.500 | and in some states still is.

01:31:20.780 | So people view it very differently.

01:31:22.060 | And I think it's an interesting thing

01:31:25.300 | because I feel like,

01:31:27.860 | despite the fact that some people hate the government

01:31:29.540 | and hate the way that it regulates their life,

01:31:31.440 | there's this weird passive belief that like,

01:31:33.480 | if the government dictates something as legal,

01:31:34.900 | that means it's safe.

01:31:36.540 | - Is the legalization of cannabis

01:31:39.660 | leading to more cannabis users or fewer

01:31:43.500 | and/or incidents of people going into the emergency room,

01:31:48.500 | suffering from cannabis-induced psychosis,

01:31:51.620 | something that I hope we can also talk about.

01:31:53.100 | - Yeah.

01:31:53.940 | So it depends on how you break this down.

01:31:57.500 | So what we've seen in Canada is,

01:31:59.780 | I would say there's like demographic differences.

01:32:02.620 | Proportionately, when we look at the biggest change in use,

01:32:06.060 | it's actually elderly communities.

01:32:07.800 | It's like 55 plus, especially women over 55 tend to be-

01:32:11.700 | - More cannabis use.

01:32:12.540 | - More cannabis use.

01:32:13.360 | Now granted, their baseline was quite low pre-legalization.

01:32:16.700 | So if you look at a fold change,

01:32:18.860 | it looks like a very dramatic increase.

01:32:21.660 | Raw numbers, it's probably not that high,

01:32:24.500 | but I mean, it was like one to 2% or something before,

01:32:27.060 | and now it's gone up to like 8% or something.

01:32:28.900 | So it's a fourfold increase kind of thing.

01:32:30.980 | So we do see the magnitude of that seems to be the biggest

01:32:34.020 | in terms of where the use has come from.

01:32:36.140 | Definitely the young adult population, like 20, 24,

01:32:39.780 | that group has definitely seen increased use as well.

01:32:43.520 | - Does it split male, female?

01:32:45.240 | - Historically, cannabis tended to be more male biased.

01:32:48.000 | I'd say the gender separation there

01:32:51.000 | has kind of narrowed quite a bit,

01:32:53.600 | where you do see a lot more females used

01:32:56.680 | than historically had.

01:32:58.760 | There is a little bit of difference.

01:32:59.840 | Females tend to prefer edibles over males.

01:33:02.040 | So males tend to like inhalation over females.

01:33:05.080 | So like roots of administration vary a little bit

01:33:07.400 | based on who someone is.

01:33:10.260 | But yeah, interestingly, we don't have a lot

01:33:14.500 | of actual indication that teenagers have used more.

01:33:17.660 | So like, you know, you look at 14 to 18 year olds,

01:33:20.740 | that has been, now granted our baseline going in

01:33:23.540 | was pretty high as is down here in the States.

01:33:25.780 | I mean, Canada and the States both hover,

01:33:27.580 | you look at like grade 12ers and you know,

01:33:29.880 | it's somewhere between 35 and 40% of them

01:33:31.700 | have used cannabis.

01:33:32.780 | Now, I mean, you even have some that are like,

01:33:35.660 | probably around 5% are probably almost daily users.

01:33:38.240 | So like you do have a pretty high baseline

01:33:40.600 | to begin with in that group,

01:33:41.680 | but that has remained relatively unchanged.

01:33:44.920 | If anything, some of the States when they legalized

01:33:46.880 | saw slight dips in teenage use of cannabis.

01:33:49.580 | So I think like that's obviously an important demographic

01:33:53.520 | to have tracked.

01:33:54.480 | This was one of the concerns with legalization

01:33:57.080 | was you'd prove, you know, increase access.

01:33:59.160 | Teenagers would get it from their parents and whatnot,

01:34:01.460 | or had just, you know, other siblings and stuff.

01:34:03.440 | And so you'd get this big boost in consumption,

01:34:06.760 | but we don't seem to see that in terms of raw numbers

01:34:08.920 | of teenagers who are using cannabis.

01:34:10.320 | So that's good.

01:34:11.720 | ER visits.

01:34:12.820 | So we did an interesting rollout in Canada.

01:34:16.660 | We legalized flour for a year before edibles came online.

01:34:20.380 | So we have kind of a before and after.

01:34:22.500 | Once edibles became available,

01:34:26.320 | there was a notable increase

01:34:28.680 | in unintentional pediatric consumption

01:34:33.240 | that resulted in ER visits because kids would, you know,

01:34:36.080 | a lot of these look like gummies and candies.

01:34:38.200 | People are buying them, not, you know,

01:34:40.040 | storing them properly.

01:34:41.600 | Kids would find them and eat them

01:34:43.120 | and like become very intoxicated.

01:34:46.440 | - I want to make mention of something along those lines.

01:34:49.520 | I actually know somebody whose child

01:34:52.520 | accidentally ate THC containing gummies.

01:34:58.200 | Fortunately, the child was fine,

01:35:01.120 | but there are actually pretty serious

01:35:02.560 | ramifications for this.

01:35:03.940 | The parents actually are quite susceptible

01:35:07.680 | to legal action if this happens, right?

01:35:11.520 | So this is something to like really keep in mind.

01:35:13.680 | I mean, there are a million other health-related reasons

01:35:16.160 | why this is probably-

01:35:17.560 | - I don't know if that's true in Canada the same way,

01:35:19.440 | but in the States, yeah.

01:35:20.320 | - Yeah, like if your kid gets into a stash

01:35:24.000 | of THC containing gummies and ends up in the emergency room,

01:35:26.960 | there will also be, most likely,

01:35:29.240 | there'll be a police visit to that emergency room also,

01:35:32.080 | and it doesn't bode well for the parents.

01:35:34.560 | It's a very serious issue.

01:35:35.880 | And again, this was highlighted to me

01:35:37.380 | by someone that I know who didn't anticipate any of this,

01:35:41.000 | but, you know, kids are good at finding candy.

01:35:43.320 | And if that candy contains THC

01:35:44.880 | and they end up in the emergency room, serious issues.

01:35:47.280 | Nonetheless, if your kid is acting strange

01:35:49.080 | 'cause you think they ingested THC containing anything,

01:35:51.520 | take them to the emergency room anyway.

01:35:53.120 | - Well, so this was one of the things

01:35:54.440 | that also was influenced by legalization is in Canada,

01:35:58.440 | like some of the increase in the ER visits

01:36:01.640 | was because of the shift in legalization

01:36:04.760 | and the change in policy.

01:36:06.280 | And so, you know, if your kid ends up drunk underage,

01:36:10.740 | it's not the same ramifications

01:36:12.280 | as if your kid used an illegal substance underage.

01:36:14.720 | And so people are, once cannabis was legal,

01:36:17.640 | people were more likely to actually go into the ER

01:36:21.220 | because the consequences were different.

01:36:23.580 | - I see.

01:36:24.420 | - And so, sure, some of this is availability,

01:36:27.000 | and some of it is just like, okay,

01:36:28.920 | I'm not as concerned now about something happening

01:36:32.000 | because I've taken my kid in.

01:36:33.220 | Like, I'm not gonna have my kid

01:36:34.060 | taken away from me or whatnot.

01:36:35.320 | So there is, I mean, both those factors,

01:36:37.600 | I think, have contributed to it,

01:36:38.560 | but we definitely see the majority,

01:36:41.200 | at least, of kids ending up in the ER

01:36:42.920 | is almost all based on edibles.

01:36:44.240 | That's, I can't imagine a situation

01:36:48.360 | where that would happen from inhalation.

01:36:50.040 | It would be very rare if it would.

01:36:51.440 | It's almost always edibles 'cause kids find them.

01:36:53.840 | - So as long as we're talking about edibles,

01:36:56.720 | is there any fundamental difference

01:36:58.280 | between the dose regulation that you talked about earlier

01:37:02.320 | of inhalants versus, excuse me, versus edibles?

01:37:06.000 | Meaning earlier you said that even if it's high THC

01:37:09.000 | containing cannabis, people will self-regulate

01:37:11.660 | to achieve the same,

01:37:12.500 | approximately the same blood concentrations.

01:37:14.640 | But with edibles, I imagine you eat half a cookie,

01:37:17.280 | a quarter of a cookie,

01:37:18.160 | and you can end up in a vastly different place

01:37:20.680 | than you expected.

01:37:21.520 | - So edibles, so this throws a wrench in the whole system.

01:37:25.680 | And I'll say this in the context of blood levels

01:37:28.760 | and then what that means from a regulatory capacity as well

01:37:30.960 | because of the impact this has.

01:37:32.240 | So edibles are very low doses for the most part.

01:37:37.240 | I mean, in Canada, at least,

01:37:38.960 | you cannot buy a pack of edibles.

01:37:40.840 | And I think this law might be changing,

01:37:42.140 | at least when they first brought it in,

01:37:43.760 | no pack could have more than 10 milligrams of THC in it.

01:37:46.200 | So that either meant one 10 mg gummy or two 5 mg gummies

01:37:49.520 | or four 2.5 mg gummies, you get it.

01:37:52.600 | So you couldn't, in one package,

01:37:54.160 | have more than 10 milligrams of THC.

01:37:55.760 | Now for people who are, I would say,

01:37:59.960 | relatively naive to cannabis or THC,

01:38:02.200 | even people who might use it intermittently,

01:38:04.540 | most people will feel five milligrams.

01:38:07.640 | Like they'll feel some form of intoxication.

01:38:10.880 | Some will even feel it at 2.5 mg.

01:38:13.280 | Most people will feel it at five.

01:38:15.120 | Virtually everyone will feel it at 10.

01:38:17.520 | Now, if you look at the blood levels these produce,

01:38:20.640 | we're now talking blood levels

01:38:22.160 | of two to five nanograms per mil.

01:38:24.000 | So folds lower than what you get from inhalation.

01:38:27.200 | - Right, before you said 100.

01:38:28.040 | - Yeah, so this is dramatically lower.

01:38:30.680 | And so also the time course of this

01:38:34.520 | is fundamentally different.

01:38:35.640 | So in oral consumption, you're looking at a minimum

01:38:40.560 | of 30 to 45 minutes for onset of intoxication.

01:38:44.280 | For some people, up to 90 minutes after they've eaten.

01:38:46.840 | Now, this is also the reason why

01:38:49.720 | the majority of adverse events that happen with cannabis

01:38:52.000 | happen with edibles, because people don't understand this.

01:38:54.240 | And so they eat a cookie or a gummy.

01:38:56.880 | They wait half an hour, like I'm not feeling anything.

01:38:58.640 | I clearly didn't take enough.

01:38:59.800 | And then they'll double their dose.

01:39:01.480 | And then like 15 minutes later, it starts hitting them.

01:39:03.760 | And then like once it fully kicks in,

01:39:05.480 | it's just like a steamroller.

01:39:07.320 | - I've heard of this happening.

01:39:08.160 | - Yeah, I mean, there was that New York,

01:39:09.680 | I think it was Maureen Dowder,

01:39:10.680 | someone went down to Colorado and she ate like

01:39:13.560 | an insane amount of THC in a chocolate bar,

01:39:16.160 | something like 50 or 100 milligrams,

01:39:17.960 | and spent like the weekend on the floor of a hotel room

01:39:21.020 | being like, this was the most aversive experience.

01:39:22.880 | Why would anyone do this?

01:39:24.480 | And again, I think people just don't understand

01:39:26.600 | the dosing around this.

01:39:27.520 | And so this is one of the things we're trying to do

01:39:29.080 | in Canada, and that was create this idea

01:39:30.400 | of standardized dosing units, so that people have an,

01:39:32.640 | like we do with alcohol, where we say,

01:39:34.520 | one beer is the equivalent to one glass of wine

01:39:36.480 | versus like a shot of tequila or something,

01:39:38.560 | so that there's some comparator that people understand

01:39:41.620 | how many drinks are, you say two drinks you do,

01:39:44.480 | you're going to hit legal limit kind of thing.

01:39:45.320 | - Yeah, it seems very important.

01:39:46.640 | - Yeah, and so this is very difficult to do with cannabis

01:39:49.320 | because the dosing with oral consumption

01:39:51.940 | is just a different ball game than it is with inhalation.

01:39:55.100 | But what happens with oral consumption is like,

01:39:57.620 | it kind of very slowly leaks out of the GI tract.

01:40:00.900 | And it also goes through first pass metabolism in the liver.

01:40:03.580 | And what happens there is you get a metabolite

01:40:05.700 | called 11-hydroxy-THC, which seems to be a bit more potent

01:40:10.700 | than THC is in terms of its ability

01:40:12.840 | to activate the receptor.

01:40:13.820 | So, and its efficacy at least at driving a response

01:40:17.980 | through CB1 receptors seems to be higher

01:40:20.080 | than what you would get with just the parent molecule

01:40:22.720 | of THC itself.

01:40:24.000 | And so, and it seems to accumulate a lot more as well.

01:40:29.600 | So at any given time, you know, you've got THC

01:40:33.320 | kind of leaking out of the gut, going through the liver,

01:40:35.040 | making 11-hydroxy, and it progressively accumulates

01:40:38.540 | in the brain.

01:40:39.380 | And that's one of the reasons why it takes, you know,

01:40:41.400 | 45 to 90 minutes to kick in.

01:40:43.240 | But then the high itself also lasts like six hours,

01:40:46.200 | four to six, sometimes eight, depending on the person,

01:40:48.500 | what they've eaten.

01:40:49.620 | Versus inhalation is just this like spike.

01:40:52.840 | So you get this very rapid,

01:40:54.300 | 'cause it goes right through the lungs into the blood,

01:40:56.220 | goes into the brain, but it also clears out.

01:40:58.100 | And so, yeah, people will start feeling intoxicated

01:41:00.980 | two to five minutes.

01:41:02.420 | The peak high is like 15 to 30 minutes

01:41:05.460 | maybe from consumption,

01:41:06.660 | and then they'll start to come back down.

01:41:08.300 | And you will still see some indications of intoxication

01:41:11.400 | that can go on for three to four hours,

01:41:13.300 | but the bulk of the intoxication from inhalation

01:41:15.900 | is done by two hours for the most part.

01:41:18.720 | - As long as we're on the topic of time course,

01:41:21.560 | you know, based on what I was able to find,

01:41:23.720 | I believed, and tell me if I was wrong,

01:41:28.280 | that cannabis can stay in one system

01:41:30.160 | for as long as 80 days.

01:41:31.480 | The reason I brought this up previously

01:41:34.000 | was there are a number of people who have used cannabis

01:41:36.640 | are going to take a drug test

01:41:38.240 | and want to know how fast it can clear from their system.

01:41:41.040 | But based on conversations we had offline,

01:41:45.600 | sounds like that 80 days might be a bit too long.

01:41:48.900 | - I mean, you could still fail a drug test at 80 days.

01:41:51.380 | I would say, I feel like,

01:41:53.100 | I think the way it was worded more was like that,

01:41:54.980 | you made it sound like that was the standard.

01:41:56.360 | I wouldn't say that was the standard at all.

01:41:58.100 | I would say for the majority of people,

01:42:01.700 | 30 days probably after that, they would not pass

01:42:05.700 | or they would be able to pass a drug test.

01:42:07.340 | - So abstinence for 30 days.

01:42:08.660 | - Yeah, after abstaining for 30 days.

01:42:10.460 | And it's going to be highly variable

01:42:12.060 | depending on how much you consume.

01:42:13.940 | I mean, if you're talking about someone

01:42:15.180 | who's used it once,

01:42:16.460 | I don't imagine it would be in your system that long.

01:42:18.640 | That'd be surprising.

01:42:19.900 | The thing is THC is a lipophilic molecule.

01:42:23.660 | - It's fat soluble.

01:42:24.500 | - Yeah, so it's fat soluble.

01:42:25.340 | It likes to store, it doesn't like the blood.

01:42:27.540 | The blood is aqueous and watery.

01:42:29.220 | It likes fat.

01:42:30.060 | So it goes into the brain, it goes into the fat

01:42:32.420 | and it kind of resides there.

01:42:33.860 | And it can essentially kind of slowly leak back as it,

01:42:38.860 | as THC concentrations in the blood would reduce,

01:42:44.020 | THC that's in the fat will start kind of leaking back

01:42:46.440 | into the blood still.

01:42:47.620 | So detectably you will still have THC for quite some time.

01:42:51.760 | I mean, some of this, again,

01:42:52.660 | it's gonna be dependent on how much cannabis someone's used,

01:42:54.580 | how much THC they've consumed,

01:42:56.380 | how long it's been in their system for.

01:42:58.500 | I would have thought this was gonna be somewhat reflective

01:43:01.220 | of people's body fat content.

01:43:03.040 | Although talking to colleagues who do this,

01:43:04.540 | they say not always.

01:43:06.580 | But we do know, you know,

01:43:10.140 | certain things like exercise, for example,

01:43:12.840 | anything that's gonna trigger adrenaline,

01:43:14.180 | 'cause adrenaline is lipolytic.

01:43:15.620 | So adrenaline causes fat to metabolize

01:43:19.020 | and release stuff that's inside it.

01:43:20.220 | So there are plenty of cases I've heard from people

01:43:22.820 | where they were testing themselves and were negative

01:43:25.580 | and then went for a run or went to the gym

01:43:27.860 | and then tested positive.

01:43:29.620 | - Or lost weight.

01:43:30.820 | - Yeah, or they've lost weight.

01:43:32.040 | And anything that's gonna cause the lipolysis to occur

01:43:36.940 | so that it releases that THC,

01:43:40.300 | you can certainly all of a sudden test positive again

01:43:42.880 | when someone had tested negative previously,

01:43:44.980 | just because of the fact

01:43:46.040 | that there still is some in the fat.

01:43:47.880 | And so this is where something like,

01:43:49.360 | and this is what I mean by standardization

01:43:50.960 | of regulatory issues become very complicated,

01:43:52.760 | was I remember right when legalization happened in Canada,

01:43:55.600 | all these kind of chemists were like talking to me

01:43:58.220 | about they're gonna create like a breathalyzer for cannabis

01:44:00.620 | because this way they'll be able to do roadside detection

01:44:02.920 | the same way they could do with alcohol.

01:44:05.240 | And I kept trying to say to them, I'm like,

01:44:07.100 | the rate limiting step here is not the science

01:44:10.520 | of detection thresholds.

01:44:12.760 | It's the biology of how the body processes cannabis.

01:44:15.960 | And you're never gonna get a test that works

01:44:18.000 | because you can take someone who has eaten an edible

01:44:21.520 | and is profoundly intoxicated

01:44:23.600 | and they will have possibly under five nanograms per mil

01:44:27.320 | of THC in their blood.

01:44:28.920 | - But you're talking about this metabolite

01:44:31.100 | that can come from the edibles

01:44:33.220 | that doesn't come from inhalants

01:44:34.440 | that can have a much more potent effect.

01:44:35.280 | - You get a bit of it from inhalant,

01:44:36.160 | but not nearly as much as you get from edibles.

01:44:38.340 | - So it's a different,

01:44:39.180 | it's sort of a different situation altogether.

01:44:40.980 | - It is, but it's also the timeline

01:44:42.500 | because of the fact that with inhalation,

01:44:44.580 | it's like a bolus that hits you at once.

01:44:47.420 | You get a high blood level.

01:44:48.920 | With edibles, it's like the time course.

01:44:52.380 | So, I mean, it's gonna be like five nanograms per mil,

01:44:54.900 | let's say, but it would be like that for a long time.

01:44:57.660 | Whereas the a hundred nanogram per mil from smoking

01:44:59.580 | is like for 20 minutes and then it starts dropping.

01:45:02.180 | So, but the problem is with the way that you detect it

01:45:06.160 | is you can take someone who's a chronic cannabis user

01:45:09.320 | and is completely sober and hasn't consumed in a day or two,

01:45:12.680 | and their basal levels of THC in their blood

01:45:15.400 | may be higher than someone

01:45:16.880 | who's profoundly intoxicated by an edible.

01:45:19.040 | Just by the sheer nature of the fact

01:45:20.680 | that it would reside in their fat tissue or their brain,

01:45:23.200 | it would leak back into the blood.

01:45:24.560 | And so you have this issue where,

01:45:28.720 | let's say your cutoff was five nanograms per mil,

01:45:30.760 | which is for some of the stuff detection thresholds

01:45:32.900 | would hover around that area.

01:45:34.380 | So you can have someone who's dead sober that tests positive

01:45:37.820 | and someone who's profoundly intoxicated who tests negative.

01:45:40.660 | So it's like, what's the value in this?

01:45:42.700 | It's not telling us anything.

01:45:44.220 | - Well, I guess it sounds like the drug tests

01:45:46.180 | either have to be revised or discarded.

01:45:48.300 | And it also sounds like if somebody is going to take

01:45:50.620 | a drug test for cannabis and they have used cannabis

01:45:53.580 | in any form in the previous 90 days, let's say,

01:45:57.540 | going for a run right before your test

01:46:00.220 | is going to liberate whatever the THC resides

01:46:03.800 | in the fat stores.

01:46:04.640 | - Potentially, yeah.

01:46:05.460 | So I mean, it is complicated.

01:46:06.300 | - A lot of people are writing this down.

01:46:08.260 | Along the lines of what's known and not known,

01:46:11.980 | I'm curious what is known and not known

01:46:14.180 | about the effects of cannabis THC in particular on hormones.

01:46:19.180 | I've seen studies that cite increases in testosterone

01:46:24.600 | from cannabis use.

01:46:25.720 | I've seen studies that cite increases in estrogen

01:46:29.040 | from cannabis use, and they argue for increased

01:46:31.920 | aromatization of testosterone into estrogen

01:46:34.440 | as the mechanism.

01:46:35.840 | I've also seen studies that say the exact opposite.

01:46:39.640 | So is there any global takeaway message yet,

01:46:43.680 | or is it just highly variable or depends too much on dose

01:46:46.840 | and individual age, et cetera, that we just really can't-

01:46:49.160 | - I would say there's nothing that's super clean cut.

01:46:54.160 | I mean, I know in the previous podcast,

01:46:55.680 | you talked about a prolactin thing.

01:46:57.480 | - Right, well, there's, and this is where I think

01:46:59.640 | it's important that people understand that,

01:47:02.360 | on this podcast, we cover science and studies,

01:47:05.040 | but we also pull from common experience

01:47:07.560 | that people want explained if we can.

01:47:10.320 | And one of the experiences that is talked about a lot

01:47:13.280 | in certain, let's just say online communities,

01:47:15.840 | is the experience of people who had no preexisting

01:47:18.880 | gynecomastia, male breast development,

01:47:21.360 | will smoke marijuana, do we call it marijuana these days?

01:47:25.280 | - We'll go with cannabis.

01:47:26.620 | I actually got someone, I got a lot of comments

01:47:29.920 | that said marijuana is an inappropriate term.

01:47:31.880 | Okay, smoke, we'll go back to that.

01:47:34.560 | That was new to me, I didn't know,

01:47:35.560 | so forgive me if I didn't know.

01:47:36.400 | - No, no, no, I mean, I understand it,

01:47:37.680 | but yeah, a lot of people don't know that.

01:47:38.680 | - Okay, so will smoke cannabis and experience gynecomastia,

01:47:42.520 | or in females, so males and females both have breast tissue,

01:47:45.880 | but in males, it's typically, it's not hypertrophied,

01:47:50.380 | but they'll smoke cannabis and get gynecomastia,

01:47:53.400 | growth of the male breast tissue.

01:47:55.620 | That's sometimes reversible, sometimes not,

01:47:57.260 | presumably through the aromatization of testosterone

01:47:59.300 | into estrogen, which then acts on the tissue,

01:48:01.280 | makes it grow, as well as reports of breast tissue

01:48:05.280 | tenderness after cannabis use in females.

01:48:08.680 | So that was sort of the origin of that discussion

01:48:11.960 | around does cannabis impact aromatization

01:48:16.620 | of testosterone into estrogen,

01:48:17.960 | and you can find a little bit of evidence for that,

01:48:19.760 | but you can also find evidence to the contrary

01:48:21.520 | in the scientific literature.

01:48:22.720 | So I'm just curious your thoughts on this.

01:48:23.560 | - It's super mixed, so I mean,

01:48:24.600 | you're talking about something like prolactin, for example,

01:48:26.920 | that is another one that's obviously involved

01:48:28.840 | in this whole cascade stuff.

01:48:31.320 | Generally, I would say the bulk of the literature

01:48:34.080 | actually says that cannabis would suppress prolactin,

01:48:36.700 | not increase it.

01:48:37.540 | That's the majority of the literature that's out there.

01:48:39.000 | - Interesting, because dopamine is one of the main ways

01:48:40.920 | that prolactin is suppressed, they're kind of in a seesaw,

01:48:43.840 | they work in somewhat seesaw fashion.

01:48:46.120 | - And it probably, I mean, the rodent work would suggest

01:48:48.120 | it's through dopamine that's turning off prolactin,

01:48:50.160 | because you can reverse some of these effects

01:48:52.160 | by playing with dopamine signaling.

01:48:53.560 | So I don't doubt that's the mechanism.

01:48:55.880 | So typically, I would say more often,

01:48:58.440 | I mean, there's studies with inhalation and IV

01:49:00.720 | that have generally found reduced prolactin,

01:49:03.840 | and in chronic cannabis users,

01:49:05.420 | they find somewhat lower resting states of prolactin.

01:49:08.360 | That's been found in one study that came out of Yale.

01:49:10.600 | - Interesting.

01:49:11.680 | - Testosterone gets a little bit more complicated,

01:49:14.040 | because there are a lot of studies that find,

01:49:17.920 | A, to begin with, cannabis users may have higher levels

01:49:21.720 | of testosterone just at rest.

01:49:24.000 | Now, whether that's a pre-existing thing--

01:49:25.160 | - Is there any reason to think that would be the case?

01:49:26.840 | - I don't know.

01:49:29.000 | Yeah, I mean, that being said, a lot of the stuff,

01:49:31.960 | now, granted, this was mostly done in the '70s,

01:49:34.320 | and this is from my previous life,

01:49:37.820 | because my undergrad and graduate supervisor,

01:49:39.920 | he was a neuroendocrinologist who focused much more

01:49:42.400 | on sex hormones and reproductive hormones.

01:49:44.400 | So we've written a few reviews,

01:49:45.800 | so I've done reviews on this area,

01:49:48.240 | and I know the literature somewhat.

01:49:50.520 | It's mixed, but generally, from the '70s studies,

01:49:53.040 | what they would often see is that if they

01:49:55.800 | would serially look at testosterone after someone consumed,

01:50:00.400 | they would have little dips.

01:50:01.680 | Like, that wasn't uncommon for them to find it.

01:50:03.720 | Not every study found it.

01:50:05.120 | That being said, the kind of range that testosterone stayed

01:50:09.880 | in was always the normative range.

01:50:11.680 | Like, it was never that it went so low

01:50:13.740 | that someone would have classified as being hypogonadal

01:50:15.840 | or would lead to something like gynecomastia,

01:50:18.880 | at least from a testosterone deficiency side

01:50:20.800 | in terms of the balance between testosterone and estradiol.

01:50:23.660 | I don't know as much about the aromatization side of it.

01:50:28.080 | Again, I'd say it's pretty mixed.

01:50:29.920 | I mean, I don't think the gynecomastia stuff is,

01:50:33.760 | I mean, certainly people online might be talking about it,

01:50:36.240 | and there might be some other components to this.

01:50:37.680 | I've also heard, and again, this isn't like science.

01:50:40.680 | This is just the same kind of stuff you see

01:50:42.600 | on random internet communities, people talking about,

01:50:44.800 | oh, well, you know, it has plant estrogens,

01:50:46.480 | so maybe they're subbing in

01:50:47.680 | and having estrogenic effects.

01:50:49.080 | I don't know how valid any of this is.

01:50:50.840 | - Yeah, it seems a bit, I mean,

01:50:52.120 | there are phytoestrogens in tons of different plants.

01:50:54.720 | The sort of attacks on soy and the attacks on,

01:50:58.200 | this I think grew out of the kind of the soy

01:51:00.840 | versus meat communities and plant-based versus carnivore.

01:51:04.180 | This podcast has always been agnostic

01:51:06.280 | with respect to nutrition and is really,

01:51:09.000 | if we encourage anything, it's that people consume

01:51:12.200 | unprocessed and minimally processed foods.

01:51:15.160 | As the bulk of their food intake,

01:51:16.600 | there seems to be enough data on that,

01:51:17.920 | but whether or not people choose to be vegan

01:51:19.560 | and eat a lot of plants or carnivore and eat just meat,

01:51:23.240 | we've essentially stepped out of that debate

01:51:25.040 | because let's just say it's as futile

01:51:28.140 | as about any other debate.

01:51:31.120 | You're just never gonna, it's completely circular.

01:51:33.120 | You end up right back in Twitter.

01:51:34.840 | - Yeah, and I think that, I mean,

01:51:36.560 | when it comes to something like this,

01:51:38.520 | I've not seen any compelling evidence for it.

01:51:40.320 | So I can't, I certainly wouldn't say

01:51:42.240 | that it's a typical side effect that men would experience

01:51:45.400 | is like developing breast tissue in response to cannabis.

01:51:47.600 | I feel like if that was the case,

01:51:49.080 | it would be very known in the scientific community

01:51:51.760 | as something that comes out.

01:51:53.000 | - So this seems to be something that purportedly occurs

01:51:58.000 | on a backdrop of elevated androgens,

01:52:00.800 | meaning in puberty or a backdrop

01:52:03.900 | of some other form of androgen increase.

01:52:06.920 | - Like someone who's on steroids or something.

01:52:08.120 | - Yeah, but that's not the community I'm referring to.

01:52:09.880 | It seems that because transient gynecomastia

01:52:13.240 | during puberty is actually fairly common

01:52:15.580 | because of there's just so much androgen being produced

01:52:17.960 | in puberty that some gets aromatized.

01:52:19.720 | And that the idea, I'm not stating this as fact,

01:52:22.880 | is that it may exacerbate that.

01:52:24.640 | In any case, it sounds like the takeaway from this

01:52:26.280 | is that there aren't a lot of conclusive studies

01:52:29.320 | about the effects of cannabis on testosterone

01:52:31.400 | or estrogen or aromatization in any direction.

01:52:34.320 | - I don't, I mean, I'd say like,

01:52:36.680 | yeah, enough studies to suggest

01:52:39.320 | that you might see transient drops in testosterone

01:52:41.700 | from cannabis, and it seems to be relatively short-lived.

01:52:44.600 | It doesn't seem to, but again,

01:52:47.800 | a lot of these studies also find

01:52:49.400 | that the basal testosterone is already

01:52:51.240 | kind of high to begin with.

01:52:52.280 | So you're staying in a normal dynamic range.

01:52:54.160 | - There it is again, it's homeostatic,

01:52:55.480 | just like the endocannabinoids.

01:52:57.600 | - Yeah, so, and that's the thing.

01:52:58.600 | I mean, testosterone fluctuates across the day anyway.

01:53:01.380 | So there's already, I mean,

01:53:02.220 | there's other things that fluctuate.

01:53:03.360 | It's like cortisol, all these hormones have cycles.

01:53:05.280 | So as long as you're in this normal range,

01:53:07.960 | there really shouldn't be any kind of like behavioral,

01:53:11.300 | like in terms of sex drive for testosterone

01:53:14.320 | or like physiological, like gynecomastia or some change in,

01:53:18.760 | I mean, now there are potentially effects of THC

01:53:20.960 | directly on the testes that could affect sperm.

01:53:23.440 | That could happen independent of changes in testosterone.

01:53:26.760 | - Are those positive or negative changes?

01:53:28.120 | I'm assuming that the studies you're referring to

01:53:31.080 | saw disrupted what they call sperm quality,

01:53:34.700 | which has to do with motility, et cetera.

01:53:36.440 | - Yeah, I mean, a lot of the kind of in vitro stuff

01:53:39.400 | definitely would suggest that.

01:53:40.580 | Some of the animal stuff as well.

01:53:42.360 | The human stuff is definitely a bit mixed.

01:53:44.160 | I mean, but again, if anything, it would be like,

01:53:46.240 | yeah, it could have some effect on sperm.

01:53:48.160 | So I have like-

01:53:49.000 | - As we say this, I'm just chuckling to myself

01:53:51.600 | 'cause anytime this conversation comes up

01:53:53.240 | about a substance and sperm quality or egg quality,

01:53:57.400 | I always get a barrage of comments of people telling me

01:53:59.800 | how many children they conceived while under the influence.

01:54:02.200 | No one is saying that you're going to be infertile,

01:54:04.800 | but if people are having challenges conceiving,

01:54:08.000 | it might be something to think about.

01:54:09.920 | - I would say that, I would agree on that.

01:54:11.540 | So I would say if someone was asking me this

01:54:14.460 | and they were trying to get pregnant and struggling,

01:54:16.620 | I would say, well, definitely cut cannabis

01:54:18.560 | because some people may be more impacted by it than others.

01:54:21.900 | So for some, you know, various biological reasons

01:54:24.380 | that we don't have a biomarker for,

01:54:26.260 | there may be some men that use cannabis

01:54:27.860 | and it has a profound effect on their sperm quality

01:54:29.780 | or their sperm capacitance,

01:54:30.860 | their ability to maintain fertility.

01:54:33.060 | And for the bulk majority of men,

01:54:34.580 | I'd say it's probably not the case.

01:54:35.860 | But again, if you're someone who is struggling

01:54:38.240 | and you use cannabis, male or female,

01:54:40.700 | I would say cut that out

01:54:42.140 | and see if that has an effect for you.

01:54:44.180 | - Along those lines,

01:54:45.420 | I saw kind of a jaw dropping statistic

01:54:48.460 | and I'm not sure I still believe it,

01:54:52.740 | but you tell me what you know about this,

01:54:55.620 | which is that up to 15% of pregnant women in the US

01:55:00.620 | have used cannabis during pregnancy.

01:55:03.280 | That just seems, that number just seems too high

01:55:06.780 | and yet, you know, it exists out there.

01:55:08.860 | - Yeah, it's very, I mean,

01:55:09.700 | I've heard higher numbers than that.

01:55:11.080 | - In the research literature.

01:55:11.920 | - No, I've heard higher numbers than that as well.

01:55:12.740 | - Okay, so I'm on the low end of this.

01:55:13.580 | - No, I mean, so I've heard as low as two

01:55:15.700 | and I've heard as high as 20.

01:55:17.380 | - Okay, two sounds like, okay, that I could imagine,

01:55:21.300 | but as high as 20.

01:55:23.740 | And do we know what the effects

01:55:25.580 | on the developing fetus are?

01:55:27.380 | - There's a lot to unpack there.

01:55:28.980 | So first thing, going back to the levels,

01:55:32.180 | that's challenging because again, this depends on,

01:55:35.360 | are you talking about self-report

01:55:36.600 | or are you talking about verified blood levels?

01:55:38.620 | 'Cause those have varied.

01:55:39.780 | So some of the higher numbers

01:55:41.140 | actually come from blood levels

01:55:42.660 | where they've taken blood samples and found THC,

01:55:45.380 | but the women have reported not using cannabis.

01:55:47.900 | And so the idea that it's like the self-report numbers

01:55:51.180 | tend to come in around two or three.

01:55:52.300 | My guess is the real number

01:55:53.800 | is probably somewhere around 10%,

01:55:55.380 | but that also is gonna vary

01:55:57.220 | depending on what you're talking about

01:55:58.260 | because there are a proportion of people

01:56:01.240 | who are using cannabis and become pregnant

01:56:04.060 | and are unaware they're pregnant

01:56:05.540 | and are still using cannabis.

01:56:06.980 | And that would still qualify

01:56:09.460 | under the way that it's defined

01:56:11.300 | that someone used cannabis while pregnant.

01:56:13.820 | So the majority, I would say the overwhelming majority

01:56:17.180 | of people, once they learn they're pregnant,

01:56:19.020 | now that can be all the way up

01:56:20.500 | to almost the end of the first trimester,

01:56:22.720 | typically stop using cannabis.

01:56:24.820 | That seems to be the norm, I would say.

01:56:27.380 | - Important point there.

01:56:28.300 | - Yeah, and I think also the number that carry on

01:56:31.420 | through the entire gestational period

01:56:33.540 | is gonna be a lot less, I would guess.

01:56:35.980 | Now, the motivations for this quite often

01:56:38.940 | are more in the capacity of the kind of anti-nauseant

01:56:42.740 | qualities that cannabis can have for some people

01:56:46.260 | and for women struggling with morning sickness.

01:56:48.780 | Now, anecdotally, I have heard women say,

01:56:51.380 | with the history of things like thalidomide

01:56:54.560 | and other anti-nauseant drugs

01:56:56.580 | that had profound traitogenic effects on the fetuses,

01:56:59.700 | women have said that they would rather use cannabis

01:57:02.820 | than one of these other compounds

01:57:04.380 | because they're less concerned about the impacts of cannabis

01:57:06.860 | than they are because of the thalidomide effects

01:57:10.920 | that happened.

01:57:11.760 | - Thalidomide effects are malformation of the limbs

01:57:14.820 | and other bodily structures in fetuses.

01:57:17.420 | It was an absolute tragedy of medicine

01:57:19.560 | that this occurred in even one birth.

01:57:23.940 | But yeah, it's the reason why thalidomide is now,

01:57:27.260 | I believe, banned as a drug for use during pregnancy.

01:57:30.660 | - Yeah, I actually have no idea,

01:57:32.340 | but I would imagine.

01:57:33.740 | I think it would be one of those hard things to sell,

01:57:35.700 | given its history, especially.

01:57:37.340 | But so I think there's a reticence of a lot of people

01:57:41.520 | to consider using pharmaceuticals to regulate nausea

01:57:44.580 | because they're uncertain of the consequences of it.

01:57:47.140 | And they feel that cannabis may be safer.

01:57:50.300 | Now, that in and of itself could present some problems

01:57:54.540 | in terms of that thought process.

01:57:56.120 | Now, there was also a study that I thought was like,

01:58:00.500 | some of these things just frustrate you.

01:58:02.980 | It's where they actually decided to call,

01:58:05.500 | this was done in Colorado,

01:58:06.460 | where they called dispensaries and just acted naive

01:58:09.020 | and asked what their recommendations were.

01:58:10.860 | And it was something like 80 to 85% of them

01:58:13.140 | were actually recommending that people would use cannabis

01:58:16.420 | to manage morning sickness.

01:58:18.020 | And I thought that was like,

01:58:19.340 | it's just one of these disappointing things

01:58:20.900 | where you're like, why are you being so wildly irresponsible

01:58:24.060 | to kind of promote these things?

01:58:25.460 | And this is-

01:58:26.300 | - You're talking about the irresponsible

01:58:27.320 | that the dispensaries would say that?

01:58:28.700 | - Yeah.

01:58:29.540 | - It's irresponsible that the study

01:58:30.380 | was carried out that way,

01:58:31.300 | because it's a little bit of-

01:58:33.500 | - Entrapment.

01:58:34.540 | - You said it, not me.

01:58:35.980 | - Could be.

01:58:36.820 | I mean, you can balk at either side of this.

01:58:40.140 | I think it's, I mean, I have a lot of frustration

01:58:45.140 | in general with the information

01:58:47.260 | that bud tenders put out into the world.

01:58:49.100 | - Is that what they're called, bud tenders?

01:58:49.940 | - Yeah, bud tenders.

01:58:50.760 | That's kind of the colloquial term

01:58:52.140 | that people will use for someone who sells cannabis

01:58:54.020 | at a dispensary, which is in Canada.

01:58:55.620 | And I've heard this throughout the States as well.

01:58:58.520 | I personally have been a huge advocate

01:59:01.500 | for the fact that I think,

01:59:03.140 | so I worked in restaurants and bars and stuff

01:59:06.560 | when I was younger.

01:59:07.400 | And for me to serve alcohol, I had to undergo,

01:59:09.980 | I don't know if you do this in the States.

01:59:11.060 | In Canada, you have to do like a,

01:59:12.740 | it's like a weekend course essentially,

01:59:14.140 | called like serving it right, or some other terminology,

01:59:16.740 | where you learn the basics of alcohol, harms, blah, blah, blah

01:59:20.380 | how to tell if someone's intoxicated,

01:59:21.820 | when you have to cut them off,

01:59:22.780 | all these things that you have to do

01:59:23.820 | to be able to serve alcohol.

01:59:24.900 | I have no idea if this exists in the States,

01:59:26.820 | but it was a thing in Canada.

01:59:29.040 | - Bartenders in the US put in the comments on YouTube,

01:59:32.600 | do you have to undergo training about alcohol

01:59:34.400 | to be a bartender?

01:59:35.240 | - Like anything, even if it's just like an online quiz.

01:59:36.960 | But like, so I, my perspective is because pre-legalization,

01:59:41.960 | at least in Canada, there was somewhat of,

01:59:44.240 | I think of a misguided thought

01:59:45.400 | that people would leverage their physicians

01:59:47.040 | for knowledge about cannabis.

01:59:48.560 | And what's become very apparent

01:59:50.320 | is that the overwhelming majority of people

01:59:52.040 | talk to the people selling them the cannabis.

01:59:54.320 | And yet those people selling cannabis

01:59:56.180 | don't need to have undergone any form of education.

01:59:59.940 | And so like, this kind of kills me

02:00:01.860 | because we've worked very hard

02:00:04.060 | to try and create educational platforms

02:00:05.820 | that are like agnostic in terms of our position on cannabis

02:00:08.580 | that are just based on the science.

02:00:09.780 | I'm an executive director of an organization

02:00:11.820 | called the Canadian Consortium

02:00:13.100 | for the Investigation of Cannabinoids, the CCIC.

02:00:15.180 | And it's, we've done CME courses for physicians

02:00:18.260 | to try and train them about cannabis,

02:00:19.760 | because I think it's important

02:00:20.740 | that physicians understand this.

02:00:21.780 | But I've tried suggesting that I think

02:00:24.020 | that anyone selling cannabis should undergo

02:00:26.560 | a course like this, just so that there's some consensus

02:00:30.180 | in the informed level that someone who comes in,

02:00:33.420 | because a lot of people going to buy cannabis

02:00:34.980 | are quite naive about it.

02:00:35.900 | And they just, I mean, even when we're talking about dosing,

02:00:38.100 | what we've talked about with edibles or smoking

02:00:39.900 | or how people consume it, like,

02:00:42.380 | you need to have a reliable source of information

02:00:44.340 | at the front line that is able to relay that to people.

02:00:46.700 | And it becomes very frustrating to me

02:00:48.940 | that they have become the main source of information

02:00:52.460 | that people go and I'm uncertain

02:00:54.580 | of what their level of training is.

02:00:56.140 | - You're certainly doing your part

02:00:57.340 | to provide the public education about cannabis now.

02:01:00.460 | So we all appreciate your highly informed

02:01:02.900 | and broad distribution of this information.

02:01:05.340 | Because this is also an issue with psychedelics,

02:01:08.020 | which currently don't have legal status in the US.

02:01:10.740 | This is an ongoing process of whether or not it will.

02:01:13.340 | Right now, things are really on the teeter totter

02:01:15.420 | with MDMA, where we await the decision from the FDA,

02:01:18.260 | but the early recommendation to the FDA

02:01:22.460 | was to not approve MDMA as a treatment for PTSD.

02:01:24.940 | That's sort of today and mid to late June, 2024,

02:01:28.740 | we'll see what happens.

02:01:29.780 | But this is also the case for ketamine,

02:01:33.260 | which has legal status,

02:01:34.700 | but many people are accessing ketamine

02:01:36.620 | not through a physician, but through online sources.

02:01:38.940 | So what you're speaking to here is a much larger issue.

02:01:42.220 | And I absolutely agree with you.

02:01:45.180 | I mean, I think most people are probably not aware,

02:01:48.420 | except by experience, positive or negative in some cases,

02:01:51.980 | about the differences in blood concentration

02:01:54.280 | as it relates to number of tokes

02:01:55.780 | versus concentration versus edible.

02:01:58.140 | I mean, these are critical themes,

02:01:59.860 | especially for where we're gonna go next,

02:02:01.260 | which is all the discussion about high THC and psychosis.

02:02:04.780 | - Yeah, yeah, exactly.

02:02:05.820 | So I think that, I just wish, I mean, again,

02:02:08.300 | even if this was just like an online course

02:02:10.180 | that wasn't that much,

02:02:11.180 | but at least had some consensus of information

02:02:13.920 | that was the basics about how to have conversations.

02:02:17.240 | And I mean, some of the, our system, at least,

02:02:20.420 | is somewhat provincially regulated.

02:02:22.160 | So like, our organization has worked

02:02:24.860 | with like the Ontario group

02:02:26.420 | that deals with cannabis distribution,

02:02:27.980 | the OCS, which is Ontario Cannabis Stores,

02:02:31.060 | and helped to create some information pamphlets and stuff.

02:02:34.340 | Again, it's not the same as a teaching course,

02:02:36.700 | but at least it's like these little infographic stuff

02:02:39.820 | that kind of like gives people rough breakdowns of things

02:02:42.980 | and kind of gives you a little bit of information

02:02:45.160 | about dosing and understanding things,

02:02:46.840 | like especially with something like edibles,

02:02:47.880 | how long you should wait, just stuff like this.

02:02:50.240 | - It sounds like the take-home message

02:02:51.440 | is proceed with caution, you know, low and slow.

02:02:55.140 | - I mean, that's the, yeah, the-

02:02:56.800 | - Like don't ingest too much too quickly.

02:02:58.600 | Like really, you know,

02:02:59.760 | if one is going to explore this legally, of course,

02:03:02.320 | you know, take a little bit, wait, take a little bit, wait,

02:03:06.640 | because otherwise you're gonna get the,

02:03:08.480 | what was the reporter?

02:03:09.800 | - Oh, I think it was Maureen Dowd, but I-

02:03:11.360 | - Right, you're gonna-

02:03:12.200 | - I don't know, actually, when I say that-

02:03:13.520 | - Is she still on the floor in a Colorado hotel?

02:03:16.040 | - She may have recovered by now.

02:03:16.880 | - Reporting from the floor in Colorado.

02:03:19.180 | - But like, yeah, it can become very frustrating

02:03:24.180 | at just the kind of lack of understanding

02:03:26.480 | that exists in this space.

02:03:27.800 | And so I think this is one of the reasons why

02:03:30.460 | we've really kind of tried to push the public health side

02:03:32.520 | of this a lot more.

02:03:33.760 | And we have, I mean, there was the Center for Addiction

02:03:37.040 | and Mental Health in Canada,

02:03:38.200 | which does a lot of the organization of these things.

02:03:40.800 | They did kind of put together

02:03:42.120 | what I found to be really useful,

02:03:43.720 | which again, could be leveraged in the States.

02:03:45.440 | These are all accessible online.

02:03:46.560 | It's called the Lower Risk Cannabis Use Guidelines.

02:03:48.560 | They kind of tried to create a framework

02:03:50.520 | that is similar to how people have done stuff with alcohol,

02:03:53.800 | that just kind of goes through,

02:03:54.620 | and a lot of it is this low and slow approach,

02:03:56.740 | but it's like, obviously, you want no risk, you abstain.

02:03:59.520 | If you're gonna use, these are the different ways

02:04:01.120 | to engage in harm reduction.

02:04:03.320 | You know, like, obviously, oral consumption has,

02:04:05.960 | you avoid the issue of lung damage

02:04:08.720 | that you could get from smoking.

02:04:10.920 | But then, you know, with oral consumption,

02:04:12.520 | you have to be aware of dosing and timing

02:04:13.960 | and all these other considerations, but-

02:04:15.280 | - What about vaping?

02:04:17.080 | Can people self-regulate their THC concentration

02:04:19.660 | in the blood by vaping as well as they can

02:04:21.600 | by joint or bong or other forms of smoking?

02:04:23.600 | - I think that will depend on exactly what you're vaping.

02:04:25.880 | So in the States, I've noticed when people say vaping,

02:04:28.380 | they almost exclusively refer

02:04:29.740 | to some kind of oil-based product that's in a pen.

02:04:32.280 | So in those situations,

02:04:34.800 | that's gonna really heavily depend

02:04:36.240 | on what the concentration of THC in that product is.

02:04:38.960 | Now, the other form of vaping

02:04:41.500 | that I think is a little bit more common in Canada, maybe,

02:04:44.080 | is vaping of the plant matter itself.

02:04:45.980 | And so this is where they have like a vaporizer device

02:04:48.500 | that heats the cannabis to a point

02:04:50.800 | that will essentially hit the lift point

02:04:53.200 | to vaporize THC in the cannabinoids.

02:04:55.080 | - In a big bag.

02:04:55.920 | - Yeah, yeah, like a volcano.

02:04:57.560 | - I've seen it.

02:04:58.400 | - Yeah, but it doesn't create any plant combustion.

02:05:00.580 | And so there are studies that have been run on that

02:05:02.600 | that have shown that you avoid the combustion by-products.

02:05:06.440 | So people don't like exhale carbon monoxide

02:05:08.360 | or these other things that we know can be damaging

02:05:11.440 | if they're vaping plant matter.

02:05:13.120 | That was actually somewhat approved

02:05:14.840 | as like a medical device.

02:05:15.920 | Pre-legalization when cannabis in Canada

02:05:18.040 | was only under medical authorization.

02:05:20.100 | Because of the reduced harm associated

02:05:23.640 | with vaporizing the plant matter versus smoking it,

02:05:26.880 | that is, I would say, a safe guideline for harm reduction

02:05:30.240 | that if you're gonna try and avoid,

02:05:32.360 | there's still gonna be some issues

02:05:33.400 | that happen with vaporization of plant matter,

02:05:35.080 | but it's not the same as combustion.

02:05:36.860 | So you avoid some of the other issues that come out.

02:05:39.560 | When we're talking about oil-based vapor products

02:05:42.640 | or whatever they're in,

02:05:43.520 | they're usually in some kind of oil-based solution.

02:05:46.000 | Who knows?

02:05:48.440 | I mean, we don't have the research on this.

02:05:49.680 | We just don't know.

02:05:50.600 | I mean, we certainly know there have been

02:05:53.800 | some pretty big errors of the things

02:05:55.960 | that happen in the States.

02:05:56.800 | There was that problem where all those people

02:05:58.160 | developed kind of, I don't know, popcorn lung

02:06:00.440 | or that lung inflammation where several people died

02:06:02.900 | from vaping products, which seemed to be a by-product,

02:06:05.840 | I believe, of them adding like vitamin E acetate

02:06:08.340 | or something into the...

02:06:09.920 | Because again, everyone just assumes it's inert,

02:06:12.080 | but then when it combusts through the vaporization process,

02:06:15.280 | it creates a massive irritant on lung tissue.

02:06:18.040 | And so that was just, you know...

02:06:20.800 | Again, in my mind, this is a problem

02:06:22.680 | with a lack of a federal regulatory framework

02:06:25.840 | because stuff like this happens.

02:06:27.960 | You would not see that on a federal landscape

02:06:30.120 | because you'd have to go through testing.

02:06:32.880 | It's kind of the Wild West you get down here.

02:06:34.460 | Every state has its own rules.

02:06:36.320 | People, there's not really a lot of regulation of things.

02:06:39.020 | - But if you go overseas, it's even more wild.

02:06:41.560 | I mean...

02:06:42.400 | - I mean, then you have no idea

02:06:43.440 | what you're consuming anywhere, I would say.

02:06:44.940 | Just because outside, I mean, again,

02:06:47.440 | Netherlands is a little bit of a different situation.

02:06:50.360 | They're not legal, they're decriminalized.

02:06:52.280 | I don't know how well the regulation over there,

02:06:53.880 | the product is.

02:06:54.720 | - No, I mean, we're going to be doing episodes on stem cells

02:06:56.960 | and you've got people flying out of country

02:06:58.480 | to do stem cell injections.

02:06:59.660 | People were getting them down in Florida

02:07:00.920 | who went blind from the injections of stem cells

02:07:02.840 | into the eye in an attempt to save

02:07:04.300 | what little vision they already had.

02:07:06.540 | Probably don't want to get me started on that one.

02:07:09.220 | I'm in total agreement with you, by the way.

02:07:12.540 | I want to make sure that I ask about psychosis and paranoia.

02:07:16.880 | I've previously said, and I was sort of,

02:07:20.740 | I wasn't joking, but I have observed in my history

02:07:25.740 | that when people started to experience some degree

02:07:30.460 | of anxiety or paranoia when smoking cannabis,

02:07:35.460 | that sometimes the message they would receive back

02:07:39.040 | is to take more, to just adjust the subjective experience.

02:07:42.720 | I think that's a terrible idea, terrible idea.

02:07:45.400 | - I am baffled that you heard that.

02:07:46.640 | I have no idea.

02:07:47.960 | - Well, let's just say I did more than hear it.

02:07:50.240 | See, I've observed it.

02:07:51.560 | - I cannot even understand that.

02:07:53.360 | That is the strangest thing I've ever heard, but okay, yeah.

02:07:55.440 | - Well, usually the advice of people in terms of,

02:07:59.720 | that was recreational drug taking,

02:08:01.280 | is rarely excellent advice.

02:08:03.760 | - Yeah, no, no, no, that's, so, yeah.

02:08:06.560 | I mean, I agree with you on that point, for sure,

02:08:09.040 | that you should not be consuming more

02:08:10.680 | if you're having a bad reaction to it

02:08:12.120 | 'cause that will just like grease the wheels

02:08:14.360 | going downhill, for sure.

02:08:15.720 | - Yeah.

02:08:17.240 | I also am aware that there are some very high profile papers

02:08:21.320 | that have been published in the last,

02:08:22.760 | really five years or so,

02:08:24.520 | pointing to potential increased risk for psychosis

02:08:29.520 | of lasting duration,

02:08:30.920 | even after the effects of cannabis have worn off

02:08:35.120 | in high THC cannabis users,

02:08:37.120 | in particular high THC cannabis users

02:08:39.800 | that initiate that cannabis use young,

02:08:42.160 | and this might be preferentially impacting males.

02:08:45.400 | I want to make clear that what I just said

02:08:47.000 | is not a statement of absolute fact.

02:08:49.240 | It's my understanding of the conclusions of these papers.

02:08:53.400 | There are other conclusions in these papers also,

02:08:56.980 | but that particular conclusion seems to be important enough

02:09:00.320 | that they place it in the abstract

02:09:01.840 | and it's reached major press headlines.

02:09:04.160 | So I guess the simple question,

02:09:05.920 | which probably doesn't have a simple answer,

02:09:08.880 | is does THC cause psychosis?

02:09:13.120 | - So yeah, there's not a simple answer to that.

02:09:14.720 | And I think that also is a question

02:09:16.720 | over whether you're talking

02:09:17.560 | about acute drug-induced psychotic episode

02:09:19.920 | versus the development of a chronic psychotic disease

02:09:23.640 | like schizophrenia.

02:09:25.120 | So the first arm of that is just,

02:09:28.040 | can people acutely have a psychotic episode

02:09:30.060 | to THC or cannabis?

02:09:30.900 | And the answer to that is yes, it's not common.

02:09:33.440 | I would say in terms of adverse events

02:09:35.280 | that happen with people consuming cannabis,

02:09:36.840 | it's on the rarer side, but it definitely can happen.

02:09:39.960 | - So less than 5% of people that-

02:09:42.120 | - Much less than that.

02:09:43.000 | I mean, it's certainly, I mean,

02:09:44.080 | if something like this was happening at a regular frequency,

02:09:46.720 | it would be very well-known.

02:09:49.440 | - What about anxiety attack?

02:09:50.960 | - Yeah, anxiety attack is, I'd say,

02:09:52.360 | more of a standard indication

02:09:54.320 | that someone's kind of gone overboard.

02:09:55.640 | Like that's not-

02:09:56.840 | - Dosage overboard, or does it carry the same set

02:09:59.360 | in setting considerations that, you know,

02:10:02.880 | psychedelics like psilocybin have?

02:10:05.040 | - Both.

02:10:05.860 | So I think there's some contextual component to it.

02:10:08.080 | There was like, I mean, back in the '70s

02:10:10.040 | when they did more, let's say, interesting studies,

02:10:13.040 | there's one where basically they dosed people on THC

02:10:15.680 | and then had them undergo oral surgery,

02:10:18.120 | which seems like, in hindsight, a very bad idea.

02:10:20.520 | And I think virtually everyone in that study

02:10:22.140 | had a panic attack.

02:10:23.720 | So it really potentiated the stress

02:10:25.860 | of what they were undergoing.

02:10:26.960 | And had they been given that same dose

02:10:29.520 | in a different setting,

02:10:30.400 | I'm not sure it would have evoked that kind of response,

02:10:32.680 | but there is definitely a dose effect to this

02:10:35.640 | in terms of like, you know,

02:10:37.880 | the kind of classic low-dose aspects of THC or cannabis,

02:10:42.640 | like that are usually considered

02:10:44.240 | more of the positive, pleasurable responses

02:10:47.380 | that are why people use, like it reduces anxiety,

02:10:49.720 | it relaxes, blah, blah, blah.

02:10:52.280 | That is more of like a low-to-normal-ish dose, let's say,

02:10:56.200 | of what someone consumes to produce those responses.

02:10:58.340 | If they start going upwards, though,

02:10:59.800 | it's not like it's graded, it's like a full flip.

02:11:02.760 | Like, it's not linear at all.

02:11:04.480 | It's almost like it goes in the opposite direction.

02:11:06.080 | So, you know, someone can use cannabis to reduce anxiety,

02:11:08.880 | but then cannabis can also trigger anxiety in other people,

02:11:11.820 | and even in the same person if they consume too much.

02:11:14.440 | And a lot of this, at least we think,

02:11:17.560 | has to do with the ability of it

02:11:19.240 | to regulate both excitatory neurotransmission

02:11:21.560 | and inhibitory.

02:11:22.400 | And so for reasons that we don't totally understand,

02:11:25.360 | there's like way more cannabinoid receptors

02:11:27.560 | on inhibitory neurons than there is on excitatory neurons.

02:11:31.100 | But in the early days of creating the genetic lines,

02:11:35.240 | Giovanni Maricicano and Beat Lutz were over in Europe,

02:11:37.960 | created like deletion of CB1 only from excitatory neurons

02:11:41.920 | or only from inhibitory neurons.

02:11:43.720 | - Okay, so to just clarify for people,

02:11:45.360 | these are laboratory mice that are genetically modified

02:11:49.280 | so that they contain or lack specific receptors

02:11:52.580 | on particular neuron types

02:11:55.480 | so that researchers can parse the effects of THC

02:11:58.640 | on what we're referring to as inhibitory neurons,

02:12:01.600 | which quiet other neurons versus excitatory neurons,

02:12:04.840 | which excite other neurons and so forth.

02:12:06.800 | And in doing so, to understand some of the network biology,

02:12:10.680 | which is basically impossible to do in a typical mouse,

02:12:14.080 | what's called a wild type mouse or a human,

02:12:17.640 | because when one ingests the drug

02:12:20.060 | or when the mouse is given the drug,

02:12:21.800 | it affects any site in the brain,

02:12:24.000 | potentially any site in the brain

02:12:25.240 | where the CB1 receptor is expressed.

02:12:26.760 | - If you do like a full body deletion of CB1

02:12:29.920 | and you give a mouse THC,

02:12:31.360 | doesn't respond to it at all, not surprisingly.

02:12:33.600 | - That's a comforting experiment.

02:12:34.800 | You want to see that result.

02:12:35.920 | - Yeah, exactly.

02:12:36.760 | So that's how we know CB1 drives

02:12:38.400 | all the kind of psychoactive effects of THC.

02:12:40.520 | So if you delete CB1 off of inhibitory GABA neurons,

02:12:44.320 | even though that removes like 70%

02:12:47.000 | of the CB1 receptors in the brain,

02:12:49.560 | those animals look just like wild type.

02:12:51.440 | They still get, like they still exhibit

02:12:53.800 | all the classic signs of intoxication

02:12:55.560 | in terms of how they would respond

02:12:57.280 | to like pain sensitivity or locomotion

02:12:59.560 | or these other like assays we use in mice

02:13:02.040 | to tell if they're high.

02:13:03.500 | If you delete the CB1 only off of excitatory neurons,

02:13:07.160 | the glutamate neurons,

02:13:08.160 | then you see what looks like the full knockout.

02:13:12.080 | So now the animals don't seem to get high.

02:13:13.680 | So even though the majority of CB1 receptors

02:13:16.760 | seem to be on these inhibitory GABA neurons,

02:13:19.040 | it's the CB1 on the glutamatergic excitatory neurons

02:13:21.640 | that mediate most of the classic signs

02:13:23.800 | of what we would consider intoxication from THC or cannabis.

02:13:27.240 | But what's interesting is,

02:13:28.840 | Beat worked with the Spanish group 10, 12 years ago.

02:13:33.480 | Then they showed, they're looking at anxiety,

02:13:35.640 | that if you delete CB1 only off of excitatory neurons,

02:13:39.600 | you lose the anti-anxiety, anxiolytic effects of THC,

02:13:43.840 | but you still have the panicky,

02:13:46.280 | anxiogenic effects of high dose.

02:13:48.600 | If you delete CB1 off of only the inhibitory GABA neurons,

02:13:52.640 | you still have the low dose anti-anxiety effect,

02:13:55.320 | but now you don't have the high dose

02:13:57.200 | anxiogenic panicky effect.

02:13:59.480 | So what that was suggesting was that for some reason,

02:14:03.600 | CB1, like THC will initially hit CB1

02:14:07.720 | on kind of glutamatergic neurons.

02:14:09.560 | And essentially the thought is,

02:14:12.040 | this will reduce excitatory transmission

02:14:14.240 | and probably quiet down circuits.

02:14:16.000 | And if we're talking about something like the amygdala,

02:14:17.680 | this is probably how it's reducing anxiety.

02:14:20.320 | Whereas as dosing starts to increase

02:14:22.480 | and you start to saturate the CB1 on the GABA neurons

02:14:25.080 | and turn off inhibition,

02:14:26.840 | then the network effect is more of an amplification.

02:14:29.560 | And that seems to result in the development

02:14:31.920 | of kind of an anxiogenic pro-anxiety response

02:14:35.120 | that's obviously undesirable.

02:14:37.280 | Why there's this differential shift,

02:14:39.760 | it's not exactly clear.

02:14:41.120 | I mean, it's probably either due to some of the biology

02:14:44.120 | of exactly where the CB1 receptors sit

02:14:46.800 | on excitatory or inhibitory neurons

02:14:48.720 | relative to all the machinery

02:14:50.400 | that regulates transmitter release.

02:14:52.360 | I mean, Biat-Lutz has definitely done some stuff

02:14:54.400 | looking at the ability of cannabinoid receptors

02:14:56.880 | to evoke signaling responses in a cell.

02:14:58.920 | And on glutamate neurons,

02:15:00.560 | they're much more sensitive than they are in GABA neurons.

02:15:02.600 | So there's probably a dose threshold.

02:15:04.760 | So it does look like this kind of low dosing,

02:15:08.080 | what most people are trying to achieve,

02:15:09.560 | I would assume, when they consume cannabis

02:15:10.960 | is probably these effects mediated

02:15:12.520 | by quieting down excitatory transmission.

02:15:15.480 | And then the adverse effects

02:15:16.760 | when someone consumes too much

02:15:18.040 | and they have a negative response,

02:15:19.280 | that's probably due to the higher dose

02:15:21.240 | starting to saturate on the inhibitory neurons.

02:15:24.000 | Now, we obviously can never test something like that

02:15:25.720 | in humans 'cause we can't know.

02:15:27.360 | But based on what we've seen in animals,

02:15:28.960 | that's my theory of kind of how this is working

02:15:31.880 | and why we see these kind of classic biphasic effects.

02:15:34.200 | So yeah, too much THC, not a good thing

02:15:37.200 | 'cause then you start maybe disinhibiting things

02:15:39.280 | like the amygdala and producing these kind of panicky,

02:15:42.560 | anxiogenic-like outcomes.

02:15:44.840 | On that scale though, I mean, paranoia, obviously,

02:15:47.400 | that's a hard, I don't know how you study that in a rodent.

02:15:49.440 | I mean, that's just a strange thing.

02:15:52.120 | But I mean, that's kind of the precedent

02:15:54.360 | of when you start going into the psychosis

02:15:56.360 | 'cause obviously paranoia would be a big component of that.

02:15:59.880 | Someone once asked me a question about,

02:16:03.120 | what happens in the brain, like imaging-wise,

02:16:06.440 | when someone's having like a psychotic episode from cannabis?

02:16:08.920 | And I was kind of thinking like,

02:16:10.000 | how would that study get done?

02:16:11.520 | - Probably on accident because somebody takes cannabis,

02:16:14.780 | is in the scanner and then starts having a psychotic episode

02:16:19.600 | but chances are they're going to try and get out.

02:16:21.600 | For those that don't know, these,

02:16:22.780 | I don't want to scare people out of doing MRI or fMRI,

02:16:25.040 | but you're typically told to stay extremely still.

02:16:28.800 | There's sometimes even a bite bar.

02:16:30.920 | This is a very controlled environment,

02:16:32.160 | not an environment that you would want to be in

02:16:34.800 | during a psychotic episode.

02:16:35.640 | - No, I can't actually even imagine how that would go down.

02:16:38.280 | So I'm like, this is something I don't think

02:16:40.080 | we're ever gonna have an answer to

02:16:41.040 | 'cause I don't think you can actually ever test it.

02:16:42.840 | But in terms of people having this kind of

02:16:45.320 | psychotic response, it is pretty rare.

02:16:48.680 | I mean, and I say this because I can think of in Canada,

02:16:51.880 | kind of whenever it's happened

02:16:53.280 | and someone has actually done something wildly unpredictable

02:16:57.480 | because they've had a psychotic response to cannabis,

02:16:59.400 | it tends to make headlines.

02:17:00.400 | So it's not common.

02:17:02.100 | I could not give you an actual number,

02:17:05.280 | but it's certainly not a frequent thing

02:17:07.400 | because we would hear about this a lot more if we did.

02:17:09.720 | - And there's also the issue of polypharmacology,

02:17:11.840 | which is simply when people take one drug,

02:17:13.680 | then there's often the tendency to take another drug,

02:17:15.980 | either because it's available in those conditions

02:17:18.760 | or because their threshold to saying yes

02:17:21.360 | is a little bit lower.

02:17:23.120 | Do most people who take cannabis and achieve the high

02:17:27.880 | have a tendency to do other drugs?

02:17:29.560 | It doesn't seem like a drug that people combine

02:17:31.280 | with a lot of other drugs.

02:17:33.300 | - I wouldn't say, I mean, there's certainly

02:17:35.920 | cannabis is used in tandem with other drugs,

02:17:38.200 | alcohol, psychedelics at times, for sure.

02:17:40.800 | But that being said, I mean,

02:17:44.520 | there is clearly a population of people that use cannabis

02:17:46.960 | as their only drug that they use.

02:17:48.160 | I don't think that's that uncommon.

02:17:50.020 | But in the context of the psychosis stuff,

02:17:53.440 | I would definitely say, sure.

02:17:55.840 | I mean, if someone mixed it with amphetamine

02:17:57.560 | or something, you could have a very unpredictable response.

02:18:00.280 | But I mean, I think the psychotic responses

02:18:01.920 | that have been documented

02:18:02.760 | that are usually purely due to cannabis.

02:18:04.440 | Like it's not necessarily due

02:18:06.560 | to some kind of drug interaction there.

02:18:08.480 | There is something about the way that cannabis is changing,

02:18:11.680 | the way the brain functions in a way that for people

02:18:14.360 | who seem to be prone to this,

02:18:15.760 | they can have a psychotic response.

02:18:18.000 | Again, I don't think it's a very typical thing,

02:18:19.740 | but we're talking about what that means in the context

02:18:22.600 | of like an actual disorder, like a chronic disorder,

02:18:25.760 | like schizophrenia, which is characterized by psychosis.

02:18:28.880 | I think we're talking about

02:18:29.720 | a whole different ball game here.

02:18:30.640 | And this is an area that is,

02:18:32.360 | I mean, I think it's an important thing to discuss

02:18:35.080 | in the context of science

02:18:36.000 | because you can't establish causality.

02:18:40.080 | Like in my view, it's virtually impossible

02:18:43.360 | because there's just no way to control all the variables

02:18:45.640 | that play into this.

02:18:46.800 | What we can say definitively is individuals

02:18:51.640 | who have schizophrenia, first of all,

02:18:53.880 | they use cannabis at a higher rate

02:18:55.280 | than the general population.

02:18:56.360 | That's very clear.

02:18:57.200 | Yeah, they definitely use cannabis at a higher rate

02:18:59.380 | than the general population.

02:19:01.360 | There is definitely a relationship between using cannabis

02:19:06.360 | and having the initiation

02:19:09.440 | of the development of schizophrenia.

02:19:11.240 | And this is where a lot of the statistics

02:19:13.200 | that have been used to develop the risk assessment,

02:19:16.400 | essentially, like so that you have a greater risk.

02:19:18.580 | If you know, like you were saying,

02:19:20.040 | if you've used cannabis as a teenager,

02:19:21.560 | you use high potency as a lot of the research has shown,

02:19:24.040 | though they've done these studies

02:19:25.200 | and they say it relates to a greater risk of schizophrenia.

02:19:29.320 | Essentially, this is just a statistical association

02:19:33.340 | that they found that people who use cannabis,

02:19:35.960 | the conversion into schizophrenia happens at a higher rate

02:19:38.400 | and there's more people with schizophrenia

02:19:39.840 | who are using cannabis.

02:19:41.400 | - Is there a bias towards males developing psychosis?

02:19:44.680 | I know there may be a bias initially

02:19:47.320 | toward males in schizophrenia that could confound this.

02:19:50.940 | So we wanna be careful.

02:19:52.280 | - To be honest, in all the research I've,

02:19:54.200 | in all the literature I've read on this,

02:19:55.560 | I don't ever remember there being clear sex descriptions

02:19:59.240 | of the differences of males and females.

02:20:00.800 | I mean, again, historically cannabis was more used

02:20:04.040 | by males than females.

02:20:04.920 | So that could lean towards any bias that may be out there

02:20:08.680 | in the media, the popular, like just in general,

02:20:12.760 | what people talk about.

02:20:13.920 | I can't think of any study that I've ever read

02:20:15.960 | that explicitly said this was male bias per se.

02:20:19.160 | They usually just report numbers or proportions of people.

02:20:23.180 | The issue is, so yes, there's this relationship that exists

02:20:29.800 | and yes, we know that cannabis

02:20:32.680 | can trigger psychotic episodes.

02:20:33.880 | So if there's an individual who has schizophrenia,

02:20:36.480 | we know for certain that cannabis can lead to the onset

02:20:39.400 | of increases in positive symptoms like hallucinations

02:20:43.400 | and delusions and a full-blown psychotic episode.

02:20:46.640 | So I think the first thing to say, which is very clear,

02:20:49.560 | is in my view, if someone has schizophrenia,

02:20:52.040 | cannabis is contraindicated.

02:20:53.440 | Like you shouldn't be using cannabis

02:20:54.640 | if you have schizophrenia.

02:20:55.480 | I think that's a risk across the board.

02:20:57.240 | - What about a first relative who has schizophrenia?

02:20:59.680 | Because there's a strong genetic component to schizophrenia.

02:21:02.000 | - So I was gonna say, then the next question

02:21:03.720 | is knowing who's gonna develop schizophrenia.

02:21:06.480 | Obviously we don't know this.

02:21:07.600 | And as you say, the only real predictive variable

02:21:10.560 | that we know of is a first degree family member

02:21:12.880 | that has schizophrenia, means that you have a higher risk

02:21:15.440 | of developing schizophrenia.

02:21:16.600 | So again, same with bipolar.

02:21:19.160 | I would say if there's bipolar or schizophrenia in a family,

02:21:21.600 | to me, those are the people who should avoid cannabis.

02:21:25.120 | Just in terms of the likelihood,

02:21:27.040 | there's a much greater likelihood that they'd have,

02:21:29.380 | it would relate to the onset of a disease

02:21:31.560 | or could accelerate its presentation in some capacity.

02:21:35.720 | I think where things get really complicated

02:21:38.280 | in this whole cannabis schizophrenia story is the causality.

02:21:42.000 | And there is a camp of people who have looked

02:21:45.120 | at this literature and definitively believe

02:21:47.520 | that cannabis causes schizophrenia.

02:21:50.160 | And they attribute a proportion of people

02:21:53.560 | who have schizophrenia to only having that schizophrenia

02:21:56.520 | because of the fact that they used cannabis.

02:21:59.520 | And I think you'd had some discussion about this

02:22:01.240 | in the last podcast.

02:22:02.080 | I can't remember exactly the way that you described it.

02:22:03.920 | - Yeah, I was looking toward some of the recent studies

02:22:07.600 | in Lancet, JAMA Psychiatry.

02:22:10.520 | I believe we can provide links to these again.

02:22:13.760 | And now more recently, there's been a lot of,

02:22:16.500 | let's just call it mainstream media coverage

02:22:18.240 | of this potential, I think is the right way to refer to it,

02:22:21.920 | potential linkage between adolescent teen

02:22:25.860 | and young adult use of high THC cannabis

02:22:29.880 | and lasting psychosis.

02:22:32.200 | But the more I hear you talk about this,

02:22:34.480 | the more I'm wondering if that idea is being amplified

02:22:39.720 | more than perhaps we ought to let it be amplified.

02:22:43.860 | - I mean, I think this is what happens when you have,

02:22:46.560 | I mean, obviously you're familiar with this.

02:22:49.340 | In science, there's different,

02:22:50.680 | some things that we can be a little bit

02:22:51.760 | more definitive about.

02:22:52.880 | And then there's some things

02:22:53.720 | that we just can't know for certain.

02:22:55.560 | It's just the way it is

02:22:56.400 | because of the way that we gather data

02:22:58.120 | and because of the way humans are.

02:23:00.080 | And this isn't a question I believe we can ask

02:23:01.840 | from an animal model perspective in the same capacity.

02:23:04.540 | So I don't think anyone would deny,

02:23:07.320 | at least anyone who's read the literature,

02:23:08.440 | that there's this relationship between cannabis use,

02:23:10.360 | especially in adolescence

02:23:11.320 | and the development of schizophrenia.

02:23:13.000 | Now, my perspective on this is,

02:23:15.560 | and I'll explain why I have this perspective

02:23:17.720 | and how I justify it, is to me,

02:23:19.800 | cannabis is fuel on a fire.

02:23:21.760 | So if someone is prone to developing schizophrenia,

02:23:25.080 | adding cannabis into the mix,

02:23:26.360 | I think will make it kick in faster and harder.

02:23:28.640 | So if there is a genetic vulnerability

02:23:31.940 | for developing schizophrenia

02:23:34.240 | or some biological predisposition that's there,

02:23:37.360 | I would say in that situation,

02:23:39.040 | cannabis can trigger an initial onset of the first episode

02:23:42.640 | and it can make the prognosis of the disease

02:23:44.520 | in the long-term a lot worse, let's say.

02:23:46.840 | - As I recall, and I may have this incorrectly,

02:23:49.360 | but as I recall from my undergraduate years,

02:23:53.820 | what you just said is also true for military service,

02:23:57.720 | for people that have a predisposition

02:23:59.780 | to develop schizophrenia,

02:24:01.320 | that active military duty can exacerbate it as well.

02:24:04.560 | - I mean, I've never heard that,

02:24:05.480 | but that would be a stressor.

02:24:07.060 | And stressors are other ways.

02:24:08.400 | I mean, a lot of, you know, the situations where,

02:24:11.880 | I mean, some of it's the age, but like, you know,

02:24:13.820 | for example, if someone is prone to develop schizophrenia,

02:24:16.080 | they move away to college.

02:24:17.120 | Even that stressor can be something

02:24:18.800 | that brings on an episode.

02:24:19.680 | But cannabis, very specifically,

02:24:22.600 | like different than any other drugs,

02:24:24.720 | like alcohol or cigarettes,

02:24:26.160 | as far as I understand it, at least,

02:24:27.920 | the temporal relationship between cannabis use

02:24:30.200 | and the development of a first episode

02:24:32.040 | can be pretty linked.

02:24:34.900 | But the arguments that I've always had

02:24:37.140 | with people in this area who are very definitive

02:24:39.340 | on their end of the spectrum,

02:24:40.500 | that this is a causal relationship is,

02:24:43.380 | first of all, we have a few things

02:24:48.500 | that like I would leverage as kind of real world evidence

02:24:50.900 | that makes this questionable.

02:24:52.160 | So the first one is,

02:24:53.000 | like I was saying earlier in the episode,

02:24:54.740 | I mean, we really didn't have cannabis use in the West,

02:24:57.900 | like as a normal thing,

02:24:59.380 | as one of the drugs that was part of the repertoire

02:25:00.980 | of what people use recreationally until like the '60s.

02:25:04.380 | So unlike alcohol, which has like been there for centuries,

02:25:07.700 | we have a little bit of a before and after,

02:25:10.060 | what we can look at.

02:25:11.220 | - The Grateful Dead.

02:25:12.140 | - Yeah.

02:25:12.980 | So now granted, we don't have like really good prevalence data

02:25:16.660 | of what schizophrenia was in the era prior.

02:25:20.020 | I mean, even nowadays our prevalence data is not perfect,

02:25:23.060 | but if cannabis as a solitary variable

02:25:26.580 | was driving the genesis of schizophrenia de novo,

02:25:29.820 | in the absence of any kind of biological predisposition

02:25:32.220 | or genetic predisposition,

02:25:33.660 | I find it very hard to believe

02:25:35.300 | that we wouldn't have seen a shift

02:25:36.740 | in the prevalence of the disease

02:25:38.100 | as cannabis became more mainstream and more widely used.

02:25:41.420 | And generally schizophrenia rates

02:25:43.740 | have remained largely stable.

02:25:46.300 | People can make arguments about that, better care,

02:25:48.380 | other things to challenge that argument, sure.

02:25:50.340 | So another modern perspective would be,

02:25:52.100 | okay, well, let's look at Canada and the States, let's say,

02:25:54.660 | where we have, as I said earlier,

02:25:56.540 | teenagers in Canada and the States,

02:25:58.340 | by grade 12, 35 to 40% of teenagers

02:26:01.340 | have at least used cannabis somewhat sporadically,

02:26:03.940 | and somewhere around 5%-ish

02:26:06.500 | are probably using almost daily.

02:26:07.820 | So we have a concentrated group

02:26:10.340 | of what would be the high-risk population here

02:26:12.820 | that are using at a pretty high rate.

02:26:14.700 | And then we compare that to somewhere like, let's say,

02:26:16.540 | Norway or Sweden or any of the Scandinavian countries

02:26:18.820 | where cannabis is like not a thing,

02:26:21.580 | certainly not at a recreational level and not in teenagers.

02:26:23.900 | And I mean, the rate use rates there

02:26:25.060 | are probably under 5% globally for teenagers,

02:26:28.300 | like probably closer to two or 3%.

02:26:30.860 | So you have two countries that have pretty similar

02:26:34.340 | social structures and other capacities of things.

02:26:36.580 | We're both Western countries,

02:26:38.300 | and yet our schizophrenia rates, prevalence-wise,

02:26:41.780 | are relatively comparable.

02:26:43.580 | And yet in Canada and the States,

02:26:45.100 | our cannabis use rates in adolescents

02:26:46.780 | are wildly amplified compared to those countries.

02:26:49.940 | So again, if this was causing schizophrenia

02:26:53.020 | to develop as a disease out of nowhere,

02:26:55.900 | how would that not track?

02:26:57.300 | Like, how would that not be seen

02:26:59.100 | when you just look at individual variances

02:27:01.060 | across countries and prevalence rates?

02:27:02.780 | - Yeah, I hear your point loud and clear.

02:27:06.380 | I seem to recall that there is a higher incidence

02:27:08.820 | of schizophrenia independent of cannabis use

02:27:12.420 | closer to the poles and less so at the equator.

02:27:16.820 | I don't know if those statistics still hold up, but-

02:27:19.660 | - I have no idea.

02:27:20.500 | - Okay. - I don't know.

02:27:21.340 | - It'd be interesting for us to look into that

02:27:22.500 | because then it would argue that since we're comparing

02:27:27.420 | very Northern locations to less Northern locations,

02:27:30.440 | that perhaps cannabis was sort of exacerbating-

02:27:33.580 | - Yeah, I mean, you could probably use Greece or Italy.

02:27:35.900 | I mean, they're gonna have cannabis use

02:27:37.380 | higher than Scandinavian countries,

02:27:38.760 | but it's gonna be way lower than North America still.

02:27:40.740 | 'Cause it's just-

02:27:41.820 | - What is it about North Americans and cannabis use?

02:27:44.080 | - I have no idea.

02:27:45.100 | I mean, I think it's just part of the culture here.

02:27:47.140 | It's just evolved totally differently.

02:27:48.940 | I mean, I think- - The Grateful Dead.

02:27:49.900 | No, I'm just kidding.

02:27:50.740 | I'm not picking on The Grateful Dead.

02:27:51.560 | I like The Grateful Dead.

02:27:52.400 | Rick Rubin convinced me to start listening to them again

02:27:55.100 | 'cause my sister used to listen to them,

02:27:56.220 | and there's some great songs,

02:27:57.300 | and they're from Menlo Park, Palo Alto.

02:27:58.620 | So I've done my duty to listen.

02:28:01.660 | There's some great songs, so I'm not picking on them.

02:28:03.300 | But- - But I mean, like you also have,

02:28:05.180 | like in Europe though, alcohol is also much more normal,

02:28:08.260 | normalized in general.

02:28:09.380 | Like kids will drink, it's not abnormal

02:28:11.500 | for kids who are teenagers to drink.

02:28:12.980 | Alcohol is just much more of a cultural thing as well.

02:28:15.180 | And there are just differences.

02:28:17.100 | I mean, it's the same thing.

02:28:17.940 | You look at like the opioid crisis that we're going through.

02:28:20.540 | Sure, it's there to some degree in Europe,

02:28:22.060 | but it's nothing like it is in North America.

02:28:23.740 | We are just a different beast for a lot of drug use.

02:28:26.980 | - Do you see differences between United States and Canada

02:28:30.220 | with respect to either cannabis or opioid use?

02:28:32.860 | - I don't think dramatically.

02:28:33.900 | I think we're pretty comparable from,

02:28:35.580 | I mean, for cannabis rates,

02:28:36.840 | I would say they're almost the same.

02:28:38.220 | I've not seen, sure you might get some regional differences.

02:28:40.940 | Like we, I think Quebec has much lower rates of cannabis use

02:28:43.820 | than some other parts of Canada.

02:28:44.940 | And you guys probably in some Southern states maybe

02:28:47.060 | are a bit different than other states.

02:28:48.460 | So I don't know about that.

02:28:50.940 | But again, overall at a federal level,

02:28:53.420 | I think the, which is where most of the data aggregates,

02:28:56.500 | I would say that they're pretty comparable with each other.

02:28:58.860 | So they're not wildly different at all.

02:29:00.380 | And again, even if you talk about climate,

02:29:01.780 | a lot of the U.S. is a lot warmer than Canada

02:29:04.180 | and you guys are certainly closer to the equator than we are.

02:29:06.260 | So I mean, we know like you do see higher rates

02:29:09.860 | of schizophrenia in urban settings

02:29:11.360 | than you do in rural settings.

02:29:12.700 | And so, I mean--

02:29:13.540 | - It's a stressor argument.

02:29:14.580 | - There's other, I mean, you also have more,

02:29:16.220 | like there's just, yeah,

02:29:17.420 | there's a lot of transitory populations

02:29:20.140 | that come in and out of cities

02:29:21.180 | that you don't see as much in rural communities.

02:29:22.940 | There's a lot more mental health services.

02:29:24.900 | There's other variables that can influence that.

02:29:26.700 | I mean, no one's really, I think,

02:29:28.380 | sussed out a mechanism to explain why you see that.

02:29:31.140 | But so there are things that shift across places,

02:29:35.300 | but I don't think it has anything to do

02:29:36.500 | with the rates of cannabis use.

02:29:38.300 | And I mean, the other thing that became very interesting

02:29:40.220 | in this whole debate over the last 15 odd years

02:29:42.880 | that people have really been talking about this a lot more

02:29:45.160 | is the fact that there's also been several studies now

02:29:48.700 | that have done genetics either at the GWAS level

02:29:50.860 | or just even just looking at polygenic risk scores.

02:29:54.460 | And there's at least three papers

02:29:56.180 | that I can think of off the top of my head

02:29:57.500 | that I could put the citations down for, for sure,

02:30:00.020 | after this, that do look at this

02:30:04.060 | from a somewhat, let's say, unbiased perspective

02:30:06.100 | where they see, you know, there's some,

02:30:07.660 | there's certainly some genetic architecture

02:30:09.360 | that relates to people either initiating cannabis use

02:30:13.020 | or people developing cannabis use disorder.

02:30:15.540 | And there's clearly some genetic architecture

02:30:17.300 | that relates to risk for schizophrenia.

02:30:19.940 | And what these studies have found

02:30:22.180 | kind of across the three of them was quite similar,

02:30:24.000 | which was from their analysis,

02:30:26.420 | the directionality suggested much more

02:30:29.260 | that having genetic risk for schizophrenia

02:30:32.360 | predicted cannabis use,

02:30:34.560 | more so than cannabis use predicted

02:30:36.740 | the development of schizophrenia.

02:30:38.100 | - Interesting.

02:30:38.940 | - So what that would mean

02:30:39.760 | is that there is some underlying biology

02:30:42.040 | that might be shared between a biological vulnerability

02:30:46.360 | to develop schizophrenia

02:30:47.780 | and some factor that relates to people using

02:30:51.180 | and/or liking and/or excessively using cannabis.

02:30:54.620 | - I've spoken to many psychiatrists

02:30:57.660 | in an effort to find someone expert in ADHD.

02:31:01.140 | We've done two episodes on ADHD,

02:31:02.780 | focusing on everything from behavioral to nutritional,

02:31:05.420 | but also prescription drug treatments for ADHD.

02:31:08.020 | And what's interesting is that all of them

02:31:10.860 | have relayed the fact that many people,

02:31:13.540 | not just young people, but adults with ADHD

02:31:17.020 | will often use, not necessarily abuse,

02:31:19.820 | but will use stimulants like coffee

02:31:22.440 | and other forms of stimulants to a high degree.

02:31:24.660 | And then of course you can say,

02:31:26.660 | well, perhaps the stimulants are causing ADHD,

02:31:28.900 | but they actually argue for the opposite,

02:31:31.020 | which is that people are attempting to self-medicate.

02:31:33.500 | And then it's perhaps no surprise that most,

02:31:36.820 | not all, but most of the medications

02:31:38.820 | that are approved for the treatment of ADHD

02:31:40.880 | are variants of amphetamine or similar.

02:31:43.560 | So it's another case where,

02:31:45.820 | depending on whether or not you look through the lens

02:31:47.380 | of the drug leading to the condition

02:31:48.900 | or through the lens of the condition

02:31:51.940 | leading to the use of the drug,

02:31:53.980 | you can end up in two very different places,

02:31:56.620 | but it looks exactly the same through each lens,

02:31:59.700 | so to speak.

02:32:00.540 | - I think you, so, I mean, and this is, you know,

02:32:03.260 | I've debated with other researchers in the area,

02:32:05.420 | in print and in person,

02:32:07.780 | about the different interpretations of this.

02:32:10.100 | And one of the possibilities is, again,

02:32:12.220 | this idea of self-medication.

02:32:13.900 | I mean, independent of there being

02:32:15.100 | some underlying biological thing

02:32:17.180 | that just is a third variable

02:32:18.700 | that explains the relationship

02:32:20.500 | between cannabis and schizophrenia,

02:32:22.580 | the other possibility is self-medication.

02:32:24.820 | And there are some studies that suggest this

02:32:27.220 | and others that don't support it.

02:32:29.300 | Anecdotally, from having done work in the community

02:32:32.660 | and talked to individuals who have schizophrenia,

02:32:34.860 | who use cannabis, what their perspective on it is,

02:32:37.140 | what I've heard from a few of them is,

02:32:39.140 | you know, the medications that they're provided

02:32:41.840 | to manage the disease are relatively effective

02:32:45.300 | at managing, let's say, the positive symptoms,

02:32:47.120 | like hallucinations, delusions,

02:32:48.960 | that aspect of the disease is somewhat well-managed.

02:32:52.420 | But then there's another component,

02:32:53.980 | which is the negative symptoms,

02:32:55.140 | which is kind of like things that, you know,

02:32:57.300 | abolition, so they don't like engaging in stuff.

02:33:00.180 | There's some anxiety, some depression,

02:33:01.940 | some social withdrawal.

02:33:03.480 | And a lot of the medications don't manage

02:33:05.860 | that component of the disease,

02:33:07.200 | and they have said that they find cannabis

02:33:09.240 | helps that side of it,

02:33:10.280 | or it helps them de-arouse a little bit,

02:33:12.460 | even though a lot of them recognize it may trigger

02:33:15.780 | the development of some of the positive symptoms,

02:33:18.220 | they feel that they don't have any tool in their kit

02:33:20.240 | to manage the negative symptoms.

02:33:21.520 | And so it could be, in my mind, when I look at that,

02:33:24.660 | it could be a bit of a vicious cycle,

02:33:26.020 | where someone's using it to kind of band-aid one aspect,

02:33:28.300 | but making other aspects of the disease

02:33:30.020 | worse at the same time.

02:33:31.060 | So it can get very complicated.

02:33:33.060 | But so, I mean, there are various ways of looking at this

02:33:37.400 | in terms of, you know, so it's either you could say

02:33:39.820 | there's a causal argument, which is made by many,

02:33:42.340 | saying cannabis causes schizophrenia,

02:33:44.020 | and therefore if we eradicated it,

02:33:46.580 | I think you had alluded to something like that

02:33:48.160 | in the last podcast,

02:33:49.000 | that if you removed it, it would have this big effect

02:33:50.820 | in terms of reducing schizophrenia rates.

02:33:52.480 | And that's similar to the argument

02:33:53.900 | that a lot of the researchers in Britain have made,

02:33:55.820 | and I'm not personally convinced of that.

02:33:58.200 | And I say that simply because I look at the data

02:33:59.980 | from Scandinavia, and I'm like,

02:34:01.860 | well, there you have a population

02:34:03.140 | that barely uses any cannabis,

02:34:04.680 | and yet their schizophrenia rates are the same.

02:34:06.220 | So the only way in my mind,

02:34:08.540 | if I look at this kind of scientifically

02:34:10.220 | from a data perspective,

02:34:11.740 | that cannabis could be causing schizophrenia de novo

02:34:14.580 | in a subset of people,

02:34:16.220 | is that there must be an equal proportion of people

02:34:18.740 | for whom, for some reason and somehow,

02:34:21.020 | cannabis is preventing them from developing schizophrenia

02:34:24.060 | so that it's a zero-sum game at the end of the day,

02:34:26.260 | and there's no change in rates.

02:34:27.560 | Like, I can't actually understand any other model

02:34:30.540 | that could explain this.

02:34:31.900 | - Yeah, no, the way you're explaining it now

02:34:34.240 | makes perfect sense.

02:34:35.680 | I do want to make sure that we distinguish

02:34:37.340 | between schizophrenia, like psychosis,

02:34:41.100 | or schizophrenia itself induced by cannabis,

02:34:43.780 | and manic bipolar episode.

02:34:46.980 | So people who have a predisposition

02:34:49.140 | or full-blown manic bipolar,

02:34:50.900 | sometimes called manic depression,

02:34:52.940 | but there's still a lot of nuance there.

02:34:54.660 | We did an episode about this

02:34:56.500 | that people can also find linked in the show note captions.

02:34:59.420 | But in any case, is there any evidence

02:35:02.540 | for the fact that people who suffer from

02:35:04.300 | or have a predisposition to manic bipolar

02:35:07.140 | conditions like bipolar depression, for instance,

02:35:11.540 | should avoid high THC cannabis?

02:35:14.400 | - So, well, first of all, I mean,

02:35:18.860 | in like hereditability family trees, for example,

02:35:23.060 | where you look at something like bipolar schizophrenia,

02:35:24.940 | the two do kind of track together.

02:35:26.820 | - Sure.

02:35:27.640 | - So it's not, I mean, I think it's hard to separate these

02:35:30.140 | in some capacity because, you know,

02:35:33.440 | I remember years ago at Society for Neuroscience,

02:35:35.820 | Glenn Close was one of the,

02:35:37.140 | I don't know if you were at that meeting,

02:35:38.280 | but Glenn Close was one of the-

02:35:39.120 | - The actress.

02:35:39.940 | - Yeah, she was one of the public speakers

02:35:40.780 | and she had talked about schizophrenia in her family tree.

02:35:43.920 | And she kind of put up this family tree of like,

02:35:45.980 | you know, her family and the one,

02:35:48.300 | the previous relatives in her family

02:35:49.860 | and showed like the individuals who had schizophrenia

02:35:53.500 | and bipolar as well.

02:35:54.780 | And this is something I think

02:35:55.620 | that's been seen a fair amount is,

02:35:57.900 | there is some co-relationship in the way that these track

02:36:00.940 | at a hereditability level.

02:36:02.140 | And so I don't know that area really well enough

02:36:04.460 | to be able to comment on it.

02:36:05.940 | And from the cannabis perspective,

02:36:08.500 | bipolar is definitely much less studied

02:36:12.020 | and focused on than schizophrenia is.

02:36:13.740 | But I think also to the comment about the high THC thing,

02:36:16.160 | I think this is the other part of the argument

02:36:18.700 | that's emerged out of this.

02:36:20.140 | And this is the other part where I see a lot

02:36:22.380 | of the causality arguments kind of crumble

02:36:25.660 | onto themselves to some degree.

02:36:26.700 | And there's been others who've made these very similar

02:36:28.500 | arguments to what I'm making here,

02:36:29.740 | which is the push that came out of this out of the UK,

02:36:34.220 | at least was much more that it's this high potency

02:36:36.640 | kind of skunk cannabis they referred to,

02:36:38.220 | which first of all was based on a smell,

02:36:40.540 | which they didn't really hadn't done a lot of analytics on.

02:36:42.820 | So it was people make the assumption of it smells stronger,

02:36:45.220 | it's more potent cannabis.

02:36:46.180 | That's not really true 'cause THC doesn't dictate the odor.

02:36:48.580 | That's, as I was saying, more of a terpene thing,

02:36:50.600 | but certainly I'm sure some of the skunk cannabis

02:36:53.300 | they were referring to is high potency cannabis.

02:36:55.100 | And so the analysis on this,

02:36:56.980 | if you actually go back to those papers and read

02:36:58.420 | is they often use like hash or low potency cannabis

02:37:01.660 | as their control where they show

02:37:02.700 | no association with cannabis.

02:37:04.500 | And so that's what's used this argument

02:37:06.460 | that it's the high potency cannabis that has driven this.

02:37:10.540 | So now the problem with this argument in my view,

02:37:12.820 | again, I look for what is the answer

02:37:17.820 | that fits in with the data?

02:37:19.380 | Like what's the most parsimonious explanation here

02:37:21.560 | that everything can be explained by?

02:37:23.580 | And so the problem with that argument is if you look

02:37:25.660 | at the cannabis schizophrenia literature,

02:37:27.260 | everything goes back to this one 1987 Lancet paper

02:37:29.740 | out of Sweden, where in that paper,

02:37:32.300 | they essentially looked at,

02:37:35.100 | they have really detailed life records and health records.

02:37:37.600 | And this was Swedish conscripts.

02:37:39.400 | And they essentially found that if someone had used cannabis

02:37:42.260 | the rate, the risk of developing schizophrenia

02:37:44.060 | had gone up and up.

02:37:45.380 | And so this was based on a cohort of people

02:37:48.380 | when it was published in '87,

02:37:49.540 | that the data would have been collected

02:37:51.180 | through like the '60s, '70s, early '80s.

02:37:53.520 | So we're talking about Sweden and cannabis,

02:37:56.340 | where it's not a country that has high cannabis use rates.

02:37:58.180 | And in an era when cannabis was hovering

02:37:59.880 | in a two to 5% THC range,

02:38:02.620 | that was the initial finding

02:38:04.820 | that provided this association between it.

02:38:06.660 | And yet the cannabis in that study

02:38:09.060 | that they would have been referring to

02:38:10.140 | would have been incredibly low potency

02:38:12.420 | compared to what has happened or like what it is today.

02:38:15.540 | So if the argument is that it's only related

02:38:18.180 | to high potency, how would that initial finding

02:38:21.040 | have ever been found?

02:38:22.820 | Because it doesn't make any sense.

02:38:24.060 | Whereas the alternate explanation

02:38:25.940 | that others have put forward,

02:38:27.120 | which I agree with and is far more sound,

02:38:29.020 | is that there is some biological reason

02:38:33.140 | why individuals who are either prone to develop

02:38:35.060 | or who have schizophrenia like cannabis.

02:38:38.220 | And they will tend to seek out

02:38:40.220 | the highest potency product they can get access to.

02:38:42.940 | So in the '70s in Sweden,

02:38:44.500 | that would have been two to 5% THC cannabis.

02:38:47.580 | Nowadays it's higher potency cannabis.

02:38:50.180 | - Or maybe they seek out lots of different forms

02:38:52.420 | of recreational drugs and cannabis just happens

02:38:54.700 | to be one that they land on.

02:38:56.060 | Which raises the other question,

02:38:57.860 | which is it's hard to imagine

02:39:00.620 | that these people who develop psychosis

02:39:02.980 | who happen to be using cannabis are only using cannabis.

02:39:06.920 | It could be, but-

02:39:08.220 | - I mean, they also, there's no question

02:39:09.940 | there's a lot of nicotine consumption.

02:39:11.940 | I mean, individuals with schizophrenia use,

02:39:13.840 | they smoke a lot of cigarettes.

02:39:14.960 | I mean, that's also much higher

02:39:17.020 | than the general population rate.

02:39:18.340 | - Which is known to stimulate dopaminergic

02:39:20.480 | and other path.

02:39:21.320 | - There could be other reasons.

02:39:22.820 | Again, there may be some reason why they like it.

02:39:26.100 | And I think this is something

02:39:28.460 | that I think we just don't understand.

02:39:29.640 | It's a very challenging thing to figure out why it is

02:39:31.980 | that individuals that have certain diseases

02:39:33.700 | may like certain substances.

02:39:35.460 | Is it helping them?

02:39:37.740 | I mean, some people have argued that perhaps nicotine,

02:39:40.160 | for example, might enhance cognition

02:39:42.340 | in individuals with schizophrenia.

02:39:43.900 | And that may be why they like it.

02:39:45.140 | - I think it enhances cognition in everybody.

02:39:47.260 | It just carries certain health concerns.

02:39:49.180 | And by the way, it doesn't enhance all forms

02:39:51.020 | of cognition, but there is a nice body of work

02:39:54.940 | to support the idea that nicotine delivered

02:39:57.740 | in any number of different forms

02:39:59.020 | can improve cognitive function to some extent.

02:40:02.120 | But I don't suggest people run out and do it.

02:40:03.780 | And in fact, it's one of the more quickly

02:40:07.220 | abused drugs nowadays

02:40:10.760 | because of the non-smoking delivery routes

02:40:13.400 | that are becoming really popular, pouches and things.

02:40:16.180 | In fact, I was chewing a little bit of Nicorette gum

02:40:18.340 | to kind of do an experiment.

02:40:19.980 | I liked it a lot.

02:40:20.980 | And then I decided to stop completely recently

02:40:23.220 | because it just, it wasn't having the same effect.

02:40:26.700 | And I found myself reaching for more

02:40:28.100 | and that's the time when I usually back out.

02:40:30.980 | - Well, yeah, no.

02:40:32.660 | Nicotine's a whole other thing, which I, yeah.

02:40:36.100 | - We'll have you back to talk about nicotine.

02:40:37.500 | - No, I definitely do not know enough about that

02:40:39.480 | to have any kind of informed conversation.

02:40:41.780 | So I don't know.

02:40:44.100 | I would say to me at the end of the day,

02:40:45.780 | if I put all the data together,

02:40:47.620 | what I would kind of,

02:40:49.820 | the perspective that I have on this is

02:40:52.380 | for some reason, be it genetic architecture

02:40:54.980 | or biological predisposition,

02:40:56.580 | individuals who are prone to develop schizophrenia

02:40:58.620 | also seem to be prone to use cannabis

02:41:01.940 | and use it possibly at excessive levels

02:41:04.720 | or possibly at higher potency products they seek out.

02:41:07.420 | Using cannabis, if someone is prone to develop it,

02:41:10.980 | may initiate or trigger the onset of the disease.

02:41:14.380 | And I think in the longterm,

02:41:15.820 | it will likely make the prognosis of the disease worse.

02:41:18.340 | So if you were a psychiatrist in a clinic

02:41:23.340 | and you consistently see patients presenting saying,

02:41:28.100 | I didn't have psychosis, I used cannabis,

02:41:30.060 | now I have psychosis, and it converts into schizophrenia,

02:41:34.260 | I can understand why the association would be made

02:41:38.420 | regularly that there's kind of a domino effect here

02:41:42.280 | and causality becomes attributed.

02:41:44.700 | But I think when we take a step back

02:41:46.780 | and look at the larger data in its kind of entirety,

02:41:50.880 | to me, it's a very tricky argument to make

02:41:52.940 | because there's a lot of things

02:41:53.820 | that you just can't explain from that perspective.

02:41:56.380 | And this is also one of the things

02:41:58.620 | that I find absolutely bizarre about cannabis in general

02:42:01.540 | is it's a wildly polarizing topic of conversation.

02:42:06.540 | And people have incredibly deep rooted opinions

02:42:09.580 | on both sides of the spectrum.

02:42:11.820 | And for some reason, if I don't say cannabis is the devil

02:42:16.220 | and causes disease, that means I'm an advocate.

02:42:19.060 | And then on the other side of the coin,

02:42:20.400 | if I don't say cannabis cures everything,

02:42:22.220 | I'm a prohibitionist.

02:42:23.140 | So like, I'm in this fun position

02:42:24.980 | where I get hate mail from both sides.

02:42:26.620 | And everyone just generally,

02:42:28.180 | depending on their perspective,

02:42:29.180 | thinks that I have a bias

02:42:30.260 | kind of going in one way or the other.

02:42:31.540 | And I'm very, you know, want it this way

02:42:33.400 | or want it this way.

02:42:34.240 | And at the end of the day, I'm just like,

02:42:35.060 | no, I just like data.

02:42:36.100 | So I'm like, I'm gonna try and answer things

02:42:38.300 | as best as I can with that.

02:42:39.280 | And to me, that's the perspective I've maintained.

02:42:42.180 | And I do think that like, these aren't trivial questions

02:42:46.580 | because when we went through

02:42:48.020 | the legalization process in Canada,

02:42:49.600 | this was something that came up again and again and again,

02:42:52.420 | was this association with schizophrenia.

02:42:54.780 | And in the UK, this is something that comes up again

02:42:57.780 | and again and again,

02:42:58.660 | because whenever there's any discussion

02:43:00.220 | about the UK moving forward to legalization,

02:43:02.280 | these ideas come back.

02:43:03.380 | And so the public health kind of consequence of this

02:43:07.260 | is not intangible.

02:43:08.900 | And so for people to be making

02:43:11.040 | these very strong causality arguments

02:43:13.180 | and having this kind of opinion

02:43:16.640 | that a lot of people just take up,

02:43:19.660 | I think can have a lot of influence.

02:43:21.020 | And so that's why like,

02:43:22.480 | there's literally no reason

02:43:23.540 | I should have a dog in this fight.

02:43:24.780 | I don't study schizophrenia in any capacity.

02:43:27.440 | And it's not my area of research,

02:43:30.280 | but because I'm in the cannabis field,

02:43:32.560 | I always feel very strongly that we need to maintain clarity

02:43:36.100 | over what the data says

02:43:37.100 | and not get caught in these opinion-based arguments.

02:43:39.660 | And I feel like this is one of these areas

02:43:41.620 | that has just kind of,

02:43:42.900 | the amount of people I talk to that regularly tell me

02:43:45.180 | that they know that cannabis causes schizophrenia

02:43:47.380 | and they're terrified if someone uses it,

02:43:48.780 | 'cause it's gonna cause them to become schizophrenic,

02:43:51.700 | I am just kind of shocked by.

02:43:53.580 | So this has clearly permeated the general population

02:43:56.980 | that there's a widespread belief of this.

02:43:58.740 | - You know, I think it's because of these

02:44:00.740 | very high profile papers

02:44:01.980 | and the way those were picked up by traditional media.

02:44:05.240 | And this seems to be something that every couple of years,

02:44:08.520 | there's a resurgence of this idea.

02:44:10.720 | Clearly people are curious about it.

02:44:12.200 | And so I just want to say,

02:44:14.000 | thank you for clarifying what is now to me obvious

02:44:18.680 | that it could be that there's a relationship there.

02:44:21.880 | It's clearly not the case yet.

02:44:24.880 | And it may never be the case

02:44:25.820 | that there's a causal relationship there.

02:44:27.580 | And it could just as well be

02:44:28.660 | that people who have a predisposition to schizophrenia

02:44:31.020 | are seeking out cannabis use and engaging in cannabis use.

02:44:33.520 | And I think that's a very important principle

02:44:35.420 | for our listeners and viewers to just hear and understand

02:44:38.260 | anytime we're talking about a substance and a condition.

02:44:41.900 | - Yeah, and I mean, I think, again,

02:44:43.420 | this is, again, no endorsement

02:44:44.980 | that that doesn't mean that it's safe

02:44:46.460 | and that that's without harm.

02:44:47.620 | I'm just strong of the opinion

02:44:49.460 | that I don't think individuals with schizophrenia

02:44:51.860 | or who have, you know, first degree relatives

02:44:53.780 | should use cannabis

02:44:54.620 | because I think there's a high degree of risk there.

02:44:56.520 | But that's a very different argument

02:44:58.000 | than making saying cannabis causes schizophrenia.

02:45:00.740 | And if we remove it from society,

02:45:02.260 | we'll see drops in rates of schizophrenia.

02:45:03.880 | I don't believe there's any evidence

02:45:05.480 | that actually could support that.

02:45:07.600 | So it's just a nuanced argument.

02:45:10.280 | And this is a good thing about more of a long-form podcast

02:45:13.040 | is it allows for nuance.

02:45:14.320 | - Yeah, absolutely.

02:45:15.740 | Let's talk about strains of cannabis.

02:45:19.080 | I've spoken before about the sativa

02:45:23.400 | versus the indica strains.

02:45:25.140 | And certainly there is a lot, a lot, a lot

02:45:28.200 | of subjective anecdotal descriptions

02:45:31.560 | about differences in the "effects" of those

02:45:35.500 | as reported by users.

02:45:37.160 | When I talked about this before in the cannabis episode,

02:45:40.520 | I leaned on a paper that took those subjective reports

02:45:44.040 | of arguably many, many people,

02:45:46.200 | pushed those subjective reports

02:45:48.980 | through what was known about the strains

02:45:50.640 | they claim to have used.

02:45:51.900 | So this is, you know, people are reporting their use.

02:45:54.340 | We assume honestly, but you always have to assume

02:45:56.680 | that there, I guess people could be lying

02:45:58.500 | about which strains or misinformed.

02:46:00.620 | But, and then using machine learning

02:46:03.040 | to couple their subjective experiences

02:46:07.380 | as they report them to indica versus sativa strains.

02:46:10.700 | And then by looking at the chemical composition

02:46:13.360 | of those different products,

02:46:14.860 | because these were products that they had consumed,

02:46:16.780 | trying to tap chemical composition to strain,

02:46:20.620 | in this case, that mainly the indica sativa discrepancy

02:46:24.900 | to subjective experience.

02:46:26.860 | And I know that you and presumably others

02:46:30.660 | in the field of cannabis research

02:46:32.460 | take real issue to that sort of approach.

02:46:35.460 | And perhaps I have the feeling

02:46:38.640 | this is what you're gonna say,

02:46:40.140 | rest on the idea that we, at least at this point in time,

02:46:45.140 | really can't say anything about

02:46:47.140 | the different biological effects of sativas versus indicas.

02:46:51.140 | And yet at the beginning of the episode,

02:46:52.560 | you said that there are many, many different

02:46:54.900 | cannabinoid compounds in cannabis.

02:46:57.460 | So three questions, and I'll keep these very short.

02:47:01.540 | One, do you think that there are different

02:47:04.180 | subjective effects of different strains of cannabis

02:47:07.100 | that can be attributed to the different strains, right?

02:47:10.520 | Not just to individual differences in experience.

02:47:13.020 | And then the second is, do you think that

02:47:15.900 | there will ever be a time in which we can understand

02:47:18.260 | this plant flower, right?

02:47:20.740 | To the extent that we can engineer it

02:47:22.880 | to provide specific subjective experiences,

02:47:25.560 | perhaps more positive than negative, et cetera.

02:47:27.940 | And then there's a third question, but I'll hold off.

02:47:30.980 | - Okay, so, yes.

02:47:34.180 | So going back to just the idea with the indica sativa thing.

02:47:38.940 | So the indica and sativa names,

02:47:43.700 | at least from everything I've understood

02:47:45.780 | from everyone that I talked to and being in this field,

02:47:47.980 | is those are botanical terms

02:47:50.140 | that largely refer to shape of the plant,

02:47:52.540 | the way the bud grows, blah, blah, blah.

02:47:55.020 | They do not track with chemical composition in any way.

02:47:58.400 | In fact, Nick Jacobus has done like a lot of analysis

02:48:03.700 | of like thousands and thousands of different kinds

02:48:07.160 | of cannabis that have been submitted

02:48:08.900 | for kind of biochemical analysis to understand THC, CBD,

02:48:13.820 | terpenes, minor cannabinoid content.

02:48:16.020 | And essentially his work, as well as from all the people

02:48:20.740 | that have done the genetics on this is the variability

02:48:25.260 | that exists within what someone calls an indica or a sativa

02:48:29.340 | is greater than the variability that there is between them.

02:48:33.540 | And there is no such thing as a chemical profile

02:48:37.560 | that exists in something that's a sativa

02:48:39.260 | versus something that's an indica.

02:48:40.900 | - Is it possible that there's a chemical profile

02:48:43.020 | that relates to the most common indicas

02:48:45.500 | or most common sativas?

02:48:46.980 | - I mean, I think in Nick's analysis,

02:48:48.660 | there was like a couple of terpenes

02:48:50.980 | that may have loaded on a little bit

02:48:53.180 | onto things that were sativas,

02:48:54.380 | but there was tons of sativas

02:48:56.260 | that didn't fall into that bracket.

02:48:57.700 | - Okay, well then that immediately to me negates

02:49:00.700 | the sort of premise of this paper that I was referring to

02:49:03.860 | that divides according to indica sativa.

02:49:06.420 | And yet the paper is also trying to distinguish

02:49:08.640 | among all the different types or products of cannabis.

02:49:12.060 | Meaning, is there some other feature of the cannabis plant

02:49:16.420 | that does relate to these different subjective effects?

02:49:18.860 | Because people do seem to get different subjective effects

02:49:23.000 | from different products that relate in some way to things

02:49:26.060 | other than the concentration of THC.

02:49:28.180 | - Yeah, I would, my honest opinion

02:49:30.620 | is this is expectancy bias.

02:49:32.020 | This is all expectancy bias.

02:49:33.540 | I mean- - I see.

02:49:34.380 | So they purchase something that they think

02:49:35.700 | is gonna make them calm and it makes them feel calm.

02:49:37.420 | - If 20 people tell you that taking this makes you calm,

02:49:40.400 | you cannot remove your expectation bias

02:49:42.460 | from the fact that when you consume it, you feel calm.

02:49:44.660 | Like, and this has been, I think,

02:49:47.460 | one of the most common things with cannabis

02:49:49.820 | is like this whole area is so ripe

02:49:52.140 | with these expectancy biases that people have

02:49:54.880 | about what they assume.

02:49:56.940 | If you go, someone goes into, you know,

02:49:58.940 | and a bud tender tells them,

02:50:00.340 | "This is a sativa, it's gonna energize you."

02:50:03.000 | There's no way to remove that expectancy bias

02:50:05.260 | from what you get.

02:50:06.800 | And I mean, like from talking to a lot of people

02:50:10.040 | that kind of study this more explicitly,

02:50:11.860 | they always say the biggest predictor

02:50:13.140 | of what someone feels when they consume cannabis

02:50:15.140 | is what they're told on the label it's gonna do to them.

02:50:17.780 | I mean, and a lot of- - It's pretty wild.

02:50:19.600 | It speaks to, you know,

02:50:20.440 | I did an episode on the placebo effect.

02:50:21.980 | - Yeah, it's similar. - And a lot of people

02:50:23.020 | hear placebo effect and they go,

02:50:24.100 | "Okay, well, then everything's a placebo."

02:50:25.580 | The placebo effect is amazing.

02:50:27.260 | There's dose response to the placebo effect

02:50:29.300 | of nicotine on cognition, dose response.

02:50:31.660 | If you're told you got a high dose

02:50:33.080 | when you actually got a low dose,

02:50:34.840 | you will exhibit the high dose

02:50:36.620 | neurocognitive enhancement effect.

02:50:39.240 | And by brain imaging,

02:50:40.500 | it shows a high dose-like enhancement

02:50:43.300 | of the relevant brain areas.

02:50:44.700 | In other words, the expectancy drives changes

02:50:46.900 | in brain activity. - It's across the board.

02:50:48.300 | I mean, again, this is not unique to cannabis in any way.

02:50:51.300 | It's just cannabis is so ripe for this

02:50:53.440 | because of the lore that it just exists.

02:50:57.140 | Like people say this.

02:50:58.780 | I mean, the issue has been,

02:51:00.440 | and I just asked Ryan Vandery this.

02:51:03.020 | As far as I know,

02:51:04.200 | I don't believe there's actually ever been a clinical trial

02:51:06.980 | that has blinded people

02:51:08.340 | and given them sativas or indicas

02:51:10.780 | and actually had them predict what they are

02:51:12.620 | or been able to characterize

02:51:14.380 | any kind of phenotypic description

02:51:16.380 | of what that intoxicated state feels like.

02:51:19.100 | And because all the,

02:51:21.600 | like the paper that you were referring to

02:51:23.460 | where it was users who had got the product,

02:51:26.740 | they can't remove their own inherent biases

02:51:29.780 | from their own experience.

02:51:31.660 | It's gonna influence it.

02:51:33.500 | There's no way around it.

02:51:34.660 | And so people kind of lean into this

02:51:38.420 | and probably not consciously,

02:51:41.060 | but they, I mean, the amount of people I've talked to

02:51:42.820 | that really genuinely believe this to their core

02:51:46.540 | that sativa does this and indica does this

02:51:49.680 | is fascinating to me.

02:51:51.340 | Because again, like you have these two,

02:51:53.660 | like THC is what drives the high.

02:51:55.580 | That's very clear.

02:51:56.900 | And you can take a sativa and an indica

02:51:58.860 | that have virtually identical levels of THC

02:52:02.260 | and yet people will report

02:52:03.660 | very different intoxicating states that come out of that.

02:52:05.860 | - Do you think this also explains the lore

02:52:10.500 | or perhaps it's real

02:52:12.460 | that different alcohols produce different drunks?

02:52:15.280 | You know, I mean, I've heard of,

02:52:18.140 | I've got friends who will swear

02:52:19.220 | that whiskey makes them feel aggressive

02:52:21.020 | and vodka is mellow

02:52:23.140 | and white tequilas feel different than the other tequilas.

02:52:27.060 | And for people listening to this,

02:52:28.980 | they go, okay, well, that's not science.

02:52:30.140 | I agree, that's not science.

02:52:31.240 | That's just anecdote.

02:52:33.020 | And yet, you know,

02:52:36.300 | the chemical composition of these different drinks

02:52:38.460 | is different, but ultimately we're talking about alcohol,

02:52:41.300 | right?

02:52:42.140 | Different sugar contents, you know,

02:52:43.360 | different hangover propensity.

02:52:44.540 | - I mean, I have to believe the majority

02:52:46.020 | that's an expectancy bias.

02:52:47.540 | I have a hard time believing that these things

02:52:49.180 | are really driven by fundamental biological differences

02:52:51.660 | within, 'cause anything else that's,

02:52:53.020 | I mean, that's the thing like,

02:52:55.180 | sure, some of the labs now,

02:52:56.540 | there is a movement to start looking at

02:52:58.420 | can certain compositions of other things in cannabis

02:53:01.760 | start to maybe modulate or influence?

02:53:04.160 | This is called, like I think I've said this before,

02:53:05.760 | the entourage effect, this idea

02:53:07.520 | that THC alone might do one thing,

02:53:09.200 | but then layering in other terpenes

02:53:12.120 | or minor cannabinoids may influence that effect.

02:53:14.200 | That is a theory.

02:53:15.600 | That's not a thing that we know definitively in any way.

02:53:18.420 | And in fact, there's virtually no research

02:53:19.840 | that's ever been done to test this.

02:53:21.440 | There's some stuff that's starting to come out now,

02:53:23.360 | like Ryan Vandrie at Hopkins recently published a paper

02:53:27.060 | where they kind of, in a dose-dependent manner,

02:53:28.920 | added limonene, which is one of these terpenes,

02:53:31.240 | like I said, I think gives it like a citrusy odor,

02:53:33.440 | into the THC and did find at a really high dose,

02:53:38.000 | probably a dose that I don't think

02:53:39.320 | you could actually find in cannabis.

02:53:41.000 | It's a little bit higher

02:53:41.920 | than what you would have gotten there,

02:53:43.080 | but limonene did seem to be able to curb

02:53:45.600 | the ability of high-dose THC to make someone feel anxious.

02:53:48.120 | And this was done in a blinded manner.

02:53:49.620 | So there's, I think, some validity to the interaction,

02:53:53.620 | whether that's occurring in cannabis, naturally,

02:53:56.000 | because of the levels of THC to limonene, I don't know,

02:53:58.760 | but it really was one of the first demonstrations

02:54:00.780 | that adding in a terpene could actually influence

02:54:03.840 | a component of the intoxicated state in a blinded manner,

02:54:08.840 | I think is interesting.

02:54:09.840 | And Ziva Cooper, who's here at UCLA,

02:54:11.560 | is doing some work with beta-caryophyllene,

02:54:13.600 | which is probably the second most abundant terpene,

02:54:17.800 | I think, from Nick Giacomas' work.

02:54:19.320 | I think myrcine may have been the highest prevalent terpene

02:54:21.720 | across all types of cannabis.

02:54:23.480 | Beta-caryophyllene's probably the second,

02:54:25.040 | and limonene, I think, is probably the third.

02:54:27.960 | And so, I think they, I mean, and so they're looking at,

02:54:32.780 | I think Ziva's work is in the context of pain.

02:54:34.920 | So they're trying to look at if a fixed dose of THC,

02:54:37.160 | if you add in varying levels of beta-caryophyllene,

02:54:39.160 | does this influence this?

02:54:40.040 | So, because again, you do see this in patient communities

02:54:42.760 | where they say, well, this strain helps my pain

02:54:44.440 | better than that strain.

02:54:45.800 | And so it's like, okay, is there actual legitimacy to this?

02:54:48.440 | Or again, is this just an expectancy bias

02:54:50.320 | because someone who sold this to you told you

02:54:52.680 | that this strain is better for pain?

02:54:54.660 | And the problem is these are all subjective endpoints.

02:54:57.120 | I mean, this is like pain, sleep, anxiety.

02:54:59.600 | These are all, I mean, it's how someone

02:55:01.120 | personally experiences it.

02:55:01.960 | And we know from all the clinical trials that study

02:55:04.860 | pain, sleep, and anxiety, there's massive placebo effects

02:55:07.840 | that happen in all these conditions.

02:55:09.840 | And so it's very difficult to actually make any kind

02:55:13.600 | of sound statements about this in the absence

02:55:16.240 | of there being kind of clinical trials

02:55:18.520 | that have clearly started to do this.

02:55:19.860 | But it's like, as you can imagine,

02:55:21.920 | when you start doing the math,

02:55:23.040 | given the amount of terpenes and the amount of combinations

02:55:25.260 | at different levels, how overwhelming this could become.

02:55:27.680 | 'Cause maybe, you know, there's a few that you need

02:55:29.280 | in there that interact with THC, not just one.

02:55:31.840 | There is like a lot of work that's happened

02:55:33.680 | in the last few years that has really started

02:55:35.660 | to try and look at if these terpenes

02:55:37.240 | or minor cannabinoids act at the cannabinoid receptor,

02:55:39.880 | which none of them seem to.

02:55:40.960 | So this isn't like you've got things that modulate

02:55:43.960 | how THC is binding to CB1.

02:55:46.220 | If they're doing something else,

02:55:47.660 | it's probably through an interaction

02:55:49.480 | with another neurochemical system

02:55:50.760 | that's influencing what THC is doing.

02:55:53.080 | So I'm not against the idea that like different chemovars

02:55:57.400 | or what people call strains of cannabis

02:56:00.960 | could do different things subjectively.

02:56:03.680 | I just am remiss to believe this

02:56:05.120 | until I see some blinded data.

02:56:06.480 | Because I think outside of that,

02:56:08.980 | we know how powerful an expectancy bias is.

02:56:10.960 | So it makes it very, very challenging

02:56:13.380 | to make any kind of firm statements.

02:56:15.760 | And so kind of in the context of like how you introduce this,

02:56:19.880 | that was, again, I think like one of the issues

02:56:22.880 | that I took with the other podcast

02:56:24.480 | was because as you've said,

02:56:27.180 | I understand the thought process you went through.

02:56:29.360 | Like you had this paper

02:56:30.900 | where people were reporting subjective effects.

02:56:32.920 | There's some neuroimaging data

02:56:34.120 | that's been done with cannabis.

02:56:35.000 | So you kind of said, okay, this is what that was.

02:56:37.960 | And that was what Sativa did

02:56:39.360 | and versus this is what Indica did.

02:56:41.680 | So I think it's important that you explain that.

02:56:43.680 | 'Cause I do think that like-

02:56:44.680 | - Well, that's what the data pointed to.

02:56:46.240 | But now what I'm realizing is that

02:56:47.840 | anytime we're talking about cannabis,

02:56:49.960 | because of the 70 plus cannabinoids present

02:56:53.620 | that could modify or join,

02:56:57.320 | so work in parallel with the effects of THC,

02:56:59.980 | we're really talking about polypharmacology.

02:57:01.960 | It's not a pure subject.

02:57:02.880 | It's not like giving anandamide

02:57:04.840 | or it's not like adjusting levels of endogenous anandamide.

02:57:08.640 | This raises, I think, an equally important issue

02:57:10.900 | for us to resolve, which is CBD,

02:57:13.320 | which we didn't talk about earlier.

02:57:14.400 | When Nolan Williams, who's a psychiatrist,

02:57:17.360 | he's one of these phenoms,

02:57:18.440 | triple board certified psychiatry neurology,

02:57:21.960 | colleague of mine from Stanford School of Medicine,

02:57:23.960 | who mainly works on Ibogaine

02:57:25.600 | and transcranial magnetic stimulation.

02:57:27.080 | But we talked about cannabis a bit

02:57:30.180 | when he was on the podcast.

02:57:31.160 | And he mentioned a strain of cannabis

02:57:33.800 | that is available in Colorado, which is pure CBD.

02:57:37.440 | I think it's called Charlotte's Web.

02:57:40.800 | And the parents of children who have epilepsy

02:57:46.520 | will move there or go there just to get this strain

02:57:50.560 | because it seems to help their epileptic seizures.

02:57:53.400 | - Yeah, I mean, I would say

02:57:54.240 | that's definitely not true nowadays.

02:57:55.360 | That pre-legalization anywhere outside of Colorado,

02:57:58.780 | that was true.

02:57:59.620 | People were gravitating there towards it.

02:58:01.640 | - Yeah, so the questions are,

02:58:03.560 | could you tell us a little bit

02:58:04.400 | about the biology of the CBD receptor,

02:58:07.000 | mainly as it relates to CB1 or not?

02:58:09.760 | Does it bind CB1 as well?

02:58:12.040 | If not, how is it working?

02:58:13.560 | And you mentioned that people will not report

02:58:15.280 | any subjective effect of taking a pure CBD compound,

02:58:18.000 | so lacking THC.

02:58:19.420 | But it sounds like it may have some usefulness

02:58:21.920 | for treatment of epilepsy.

02:58:24.040 | And what are some other established,

02:58:27.240 | meaning clinical trials and/or lab data

02:58:31.680 | to support the use of CBD for any type

02:58:33.940 | of either psychiatric condition, pain, et cetera?

02:58:38.200 | - So, I mean, the first thing that's interesting

02:58:39.900 | that I think a lot of people don't understand

02:58:41.560 | about CBD is CBD doesn't really exist

02:58:46.560 | in any form of street cannabis.

02:58:48.080 | And it hasn't for a very long time.

02:58:49.680 | - You mean there's no CBD in there?

02:58:51.480 | - There's some.

02:58:52.300 | There's very, very low levels of CBD.

02:58:54.160 | And the reason that is is because THC and CBD

02:58:58.000 | are both made from the same precursor molecule.

02:59:00.440 | And which direction it goes in is based purely

02:59:02.600 | on which synthetic enzyme converts it to either THC or CBD.

02:59:06.600 | And so as people have clearly chased THC

02:59:10.680 | and wanted cannabis that's rich in THC,

02:59:12.520 | and so cannabis has been bred

02:59:13.680 | to become higher content in THC,

02:59:15.680 | by default, CBD has been bred out of the plant.

02:59:18.880 | And it has largely been bred out of the plant

02:59:20.700 | for quite some time.

02:59:22.440 | And so this, I always find it interesting

02:59:25.400 | that there's this community that's like,

02:59:27.200 | oh, well, THC is the recreational cannabis

02:59:29.600 | and CBD is the medical cannabis.

02:59:31.000 | And I'm always like, that's bizarre.

02:59:32.640 | Because historically, there's always been,

02:59:35.360 | like THC has been what people have bred cannabis for.

02:59:38.400 | And so kind of any medical benefits

02:59:40.680 | that people have reported from cannabis per se,

02:59:42.880 | usually are THC and CB1 driven.

02:59:45.960 | CBD is this other molecule that,

02:59:48.880 | we can go into the pharmacology in a second,

02:59:50.200 | but again, it's just, it's, I mean,

02:59:53.520 | I think in the analysis that Nick Jachomas did

02:59:56.000 | of all these strains and types of cannabis that exist

02:59:59.380 | in the United States, when they went through their thing

03:00:01.400 | of thousands and thousands of kinds of cannabis,

03:00:03.400 | it was like 3% of them maybe had like more than 1% CBD.

03:00:07.500 | Like it's very low, like there's almost none.

03:00:09.640 | And in Canada to get a CBD rich strain,

03:00:13.000 | you have to basically explicitly buy it

03:00:15.160 | because it has to be bred to make CBD.

03:00:18.120 | And so this is the kind of chemo of our distinction.

03:00:20.240 | I think you did allude to this last time,

03:00:21.680 | which is the type one, type two, type three.

03:00:23.160 | So type one is high THC, type two is like somewhat balanced

03:00:27.080 | and type three is high CBD.

03:00:28.280 | And now I think like 90 to 90 something low percent

03:00:32.320 | of all cannabises that are out there are type one.

03:00:34.360 | Like they're all high THC 'cause that's what's been bred.

03:00:36.960 | There's a few that have been mixed.

03:00:39.120 | And so are kind of equal proportions,

03:00:40.840 | but you're never gonna get high equal proportions.

03:00:43.200 | So like a high THC cannabis is like 20 to 30%.

03:00:47.380 | If you go for type two, which is mixed,

03:00:49.160 | they're both gonna fall around 12%,

03:00:52.240 | maybe a little more, but in that range.

03:00:53.720 | And then same if you've got a type three, it's high CBD,

03:00:55.720 | it's gonna be 20-ish percent CBD and very low THC.

03:00:59.040 | And so no one has ever kind of grown CBD rich cannabis

03:01:02.520 | outside of this recent boom in the last decade

03:01:05.720 | that's happened about people wanting CBD

03:01:08.000 | because of the Charlotte's Web,

03:01:09.120 | which was popularized by I think Sanjay Gupta on CNN

03:01:13.600 | in like 2012 or something, it was a while ago.

03:01:16.200 | But that was what got a huge movement

03:01:17.740 | going around this idea of CBD.

03:01:20.120 | And yeah, so the Charlotte's Web was like,

03:01:22.760 | I believe that was what they had named

03:01:24.120 | that kind of cannabis that they'd extracted it from.

03:01:25.920 | And so it was a tincture that they were using

03:01:28.280 | that was very high CBD content that they were finding

03:01:31.000 | was controlling pediatric seizures in kids.

03:01:34.420 | Now, this has actually been studied pretty effectively.

03:01:38.480 | Most of it's come out of Boston.

03:01:40.380 | Elizabeth Thiel has been one of the main leads on this

03:01:44.720 | and she's a neurologist there

03:01:46.400 | that has done a lot of the work on this.

03:01:48.320 | And so they have, I think very clearly,

03:01:50.760 | and the data is incredibly compelling.

03:01:52.700 | Their research is one of the reasons

03:01:54.040 | why CBD has been descheduled or changed in its scheduling

03:01:57.240 | down to a, what is it, five?

03:01:59.320 | What is it, class?

03:02:00.240 | - CBD?

03:02:02.320 | - Yeah, like CBD.

03:02:03.400 | I mean, given the availability of CBD everywhere

03:02:07.640 | in gummies and drinks.

03:02:09.240 | And I mean, you can get it in a convenience store.

03:02:12.360 | - So it's been kind of, a lot of it's been like shifted

03:02:14.840 | in its classification status

03:02:16.320 | because it actually has been shown very clearly

03:02:19.320 | to have medical benefit.

03:02:20.500 | And so it was very specific.

03:02:23.160 | It was a very specific form of pediatric epilepsy

03:02:25.360 | called Dravet syndrome.

03:02:26.540 | Now, there's other forms of pediatric epilepsy.

03:02:29.680 | I know Elizabeth has studied in addition

03:02:32.080 | that has found comparable levels of efficacy,

03:02:34.640 | but essentially what they have shown

03:02:36.680 | is that like very high doses of CBD

03:02:40.440 | are relatively effective at calming down the seizures.

03:02:45.040 | In some kids, it's profound.

03:02:46.980 | Like in some kids, you're talking about kids

03:02:48.720 | that were having dozens of seizures a day

03:02:50.760 | to essentially none.

03:02:51.920 | And so, and I can understand.

03:02:54.140 | - Yeah, that's super impressive.

03:02:55.240 | - From a grassroots perspective,

03:02:56.520 | I can understand if you were a parent

03:02:58.240 | who had a child with a disease like this

03:03:00.240 | that was largely intractable and not that well controlled

03:03:03.320 | from the medications they were on.

03:03:04.400 | And then something came around

03:03:06.300 | that showed this level of efficacy,

03:03:07.800 | you would gravitate towards it.

03:03:09.200 | Like that makes sense to me.

03:03:10.600 | And I think the work that Elizabeth

03:03:12.160 | and her colleagues have done has been really important

03:03:14.120 | to establish the efficacy of this,

03:03:17.080 | of CBD in these disease states.

03:03:21.240 | And so I don't think at this point,

03:03:23.120 | there's a lot of controversy around that.

03:03:25.040 | The question that comes out though is,

03:03:27.240 | so how is it working?

03:03:28.480 | And we don't have a mechanism.

03:03:30.240 | So as you had said, like CBD receptor,

03:03:32.840 | there is no CBD, like there's no receptor that CBD binds to.

03:03:35.520 | - I was under the impression that CBD

03:03:37.160 | also bound to the CB1 receptor.

03:03:40.520 | - No, I mean, certainly not.

03:03:42.480 | - Or that under some conditions,

03:03:44.600 | it can modulate the shape of the receptor

03:03:47.920 | to adjust THC binding.

03:03:49.600 | But now you're telling me

03:03:50.480 | that these two things rarely coexist together.

03:03:52.720 | So I guess the question--

03:03:53.760 | - You can dose them.

03:03:54.860 | Like you can certainly, I mean,

03:03:56.160 | you can have products that are made

03:03:57.680 | that are like oil-based products, at least,

03:03:59.720 | that have a certain amount of CBD

03:04:01.120 | and a certain amount of THC, and people do go for those.

03:04:03.400 | And there's this, I mean,

03:04:04.680 | one of the arguments people make is they say,

03:04:05.920 | oh, introducing CBD reduces the adverse effects of THC.

03:04:09.000 | And like, well, if you're using it in a strain,

03:04:10.840 | that's simply because the strain of cannabis has less THC.

03:04:13.520 | - Right, so it's impossible to separate.

03:04:14.480 | - So you bred it out.

03:04:15.320 | But I mean, like a lot of this was based on some work

03:04:17.840 | that came out a long time ago from Brazil,

03:04:19.940 | where they showed that like giving CBD

03:04:22.760 | with a relatively high dose of THC

03:04:24.360 | could curb some anxiety that came out from high dose THC.

03:04:28.240 | - I thought the explanation for that

03:04:29.760 | was that CBD can modify the CB1 receptor

03:04:34.720 | in some way that makes THC less able

03:04:36.880 | to engage with the THC. - There is some evidence

03:04:39.360 | to support that,

03:04:40.320 | that like we would call these allosteric modulators.

03:04:42.880 | There's some evidence to suggest that CBD

03:04:44.920 | may interact with a allosteric site

03:04:48.020 | on the cannabinoid receptor that makes THC bind less.

03:04:51.680 | - Doesn't sound like you're particularly convinced

03:04:53.300 | by that evidence.

03:04:54.140 | I'm looking at the look on your face.

03:04:56.200 | For those listening, I'm looking at Matt,

03:04:58.040 | and I think he's being generous here.

03:05:00.180 | Let me ask it a little differently.

03:05:02.000 | - It's definitely more complex than that.

03:05:02.840 | - Does anyone know what CBD binds to?

03:05:05.280 | - So the most convincing thing that I've seen

03:05:07.320 | that CBD binds to is the work that C.C. Hilliard has done

03:05:09.960 | looking at its ability

03:05:11.080 | to essentially block adenosine uptake.

03:05:14.120 | And so it can inhibit the adenosine transporter.

03:05:16.920 | - So that should make people feel more alert.

03:05:19.080 | - No, because you're getting more adenosine.

03:05:20.920 | So you get an accumulation.

03:05:22.040 | It blocks the adenosine transport mechanism.

03:05:24.260 | - I see.

03:05:25.100 | - So you get an accumulation of adenosine,

03:05:27.140 | which is more sedative.

03:05:28.740 | And that, I mean, in the PNAS paper

03:05:31.540 | that C.C.'s lab had from 2006,

03:05:34.780 | they showed that that also mediated,

03:05:36.580 | it was the adenosine, I think, 2A receptor

03:05:38.180 | that drove the anti-inflammatory effects of CBD.

03:05:42.060 | So it was the secondary effect by--

03:05:43.820 | - Sort of the opposite of--

03:05:45.580 | - Caffeine.

03:05:46.400 | - Of caffeine.

03:05:47.240 | - Yeah, no, if I remember doing--

03:05:48.080 | - The way you're describing this,

03:05:48.900 | it sounds like the anti-caffeine.

03:05:50.340 | - That's kind of how I describe to people

03:05:51.700 | if they ever ask me for what the pharmacology of CBD is.

03:05:54.160 | I'm like, that's not the only mechanism,

03:05:55.940 | but the thing that was important in C.C.'s studies

03:05:58.360 | that I think is relevant is that it was

03:06:00.340 | not super high concentrations of CBD that caused that.

03:06:03.500 | So you could get this adenosine accumulation at,

03:06:06.700 | you know, you're not talking like micromolar levels of CBD,

03:06:10.780 | which is what a lot of studies have done.

03:06:12.420 | And so even when we're talking about

03:06:14.020 | the allosteric modulatory site,

03:06:15.620 | yes, there's evidence for it.

03:06:17.020 | And it is convincing evidence,

03:06:18.400 | it's just the dose range in there.

03:06:20.180 | You're kind of like, who's getting hit with CBD

03:06:22.980 | at that level where you're getting these effects?

03:06:24.700 | And more so when they've done the blinded work,

03:06:27.580 | like when Ryan Vandery at Hopkins again,

03:06:29.500 | who is one of the main people who's done a lot of this work,

03:06:32.660 | has actually blindly given people CBD dosing with THC,

03:06:36.940 | finds the opposite, that it actually amplifies

03:06:39.100 | some of the effects of THC.

03:06:40.820 | And this was something we learned

03:06:42.100 | from the pediatric epilepsy world was that

03:06:44.560 | when you start giving CBD at relatively high doses,

03:06:46.660 | one of the things it does is saturate

03:06:48.060 | a lot of liver enzymes.

03:06:49.500 | And so some of the efficacy in the pediatric epilepsy space

03:06:53.420 | may be a secondary effect due to an accumulation

03:06:57.060 | of some of the anti-epileptics as well,

03:06:59.480 | because they're not being metabolized the same way.

03:07:01.660 | And this has now been very well replicated.

03:07:03.620 | We know that once you start taking CBD,

03:07:06.460 | when they hit doses that are at the clinical level,

03:07:08.580 | you're gonna start having hepatic effects.

03:07:10.860 | So it's gonna affect the liver,

03:07:12.100 | and it's gonna affect the ability of the liver

03:07:13.720 | to chew up other drugs.

03:07:15.840 | And there's very specific SIP enzymes,

03:07:20.120 | like the cluster of enzymes that metabolize things,

03:07:22.120 | there's very specific ones that CBD hits.

03:07:24.200 | And so as a consequence, one of them is what chews THC up.

03:07:27.600 | So you can get a potentiation of THC

03:07:30.560 | by inhibiting its metabolism

03:07:31.880 | if you have high enough CBD on board.

03:07:33.600 | - Given the effects on adenosine that you described before,

03:07:35.880 | that it's sort of what we're calling,

03:07:37.720 | just for sake of discussion, the anti-caffeine,

03:07:40.380 | how do we explain the preponderance of CBD

03:07:42.840 | added to energy drinks that also contain caffeine?

03:07:45.360 | There's like no logic there. - Expectancy bias.

03:07:47.520 | - There you go, everything can't be expectancy bias.

03:07:50.480 | I have a feeling it's gonna be interesting

03:07:51.920 | to see in the comment section on YouTube.

03:07:54.000 | I mean, presumably there's some regular pot smokers

03:07:58.000 | listening to this.

03:07:58.960 | And the expectancy bias is so strong,

03:08:01.640 | as I allude to in the placebo episode

03:08:03.400 | and we've been talking about here.

03:08:04.880 | And yet it's so strong that I think

03:08:08.120 | people will also be convinced

03:08:09.600 | that there are real differences between different strains

03:08:11.840 | because they've maybe done the non-formal blind,

03:08:15.740 | someone gave them their weed and someone else,

03:08:19.760 | and then they got a completely different effect, right?

03:08:21.520 | They're not expecting something different necessarily

03:08:25.240 | in a particular direction,

03:08:26.320 | but they get a very different effect.

03:08:27.760 | But that to me just speaks to the idea that,

03:08:30.560 | again, cannabis sounds like polypharmacology,

03:08:33.480 | 70 different cannabinoids,

03:08:35.100 | THC being among the more powerful components,

03:08:38.080 | but it's yoked in the sense that, as you said,

03:08:42.700 | people self-regulate their intake,

03:08:44.120 | provided they're smoking, not ingesting it by edible.

03:08:46.520 | And so it's almost like THC is being held constant.

03:08:48.640 | And then there's this constellation

03:08:49.840 | of other things around it that are modified.

03:08:51.840 | And people eventually veer towards what they like,

03:08:54.360 | what they can afford, what works with their lifestyle.

03:08:57.040 | And then they come up with a bunch of theories

03:08:59.360 | based on packaging, what they're told,

03:09:01.120 | but presumably also some real effects of these terpenes,

03:09:04.240 | the CBD component, et cetera.

03:09:06.280 | It can't all be just psychological interpretation.

03:09:08.560 | - So what you're saying is like what we said

03:09:10.160 | is the entourage effect.

03:09:11.200 | And I think that is a theory that is held

03:09:13.080 | by a lot of people that this exists.

03:09:14.440 | I mean, the reality is these terpenes

03:09:16.700 | and minor cannabinoids exist at such low levels

03:09:19.400 | that there's a couple of kinds of cannabis

03:09:22.220 | that might have a high enough level

03:09:24.200 | where you're seeing something.

03:09:25.040 | But yeah, I mean, I agree to the extent

03:09:28.360 | that it would be a little wild

03:09:30.840 | if everyone's subjective experience

03:09:32.800 | across different kinds of cannabis

03:09:34.440 | was entirely driven by some kind of expectancy,

03:09:36.960 | which I can't imagine is accounting for all of it.

03:09:38.600 | But I think when we talk about sativa versus indica,

03:09:43.320 | I think there's a huge bias that's going into there.

03:09:45.920 | But one of the things with CBD that's interesting,

03:09:49.440 | unlike THC, is you can actually do

03:09:52.120 | pretty clean blinded studies

03:09:54.320 | because it's really hard to give someone THC

03:09:56.280 | and them not know they're on THC.

03:09:58.720 | - This was the big problem with the MDMA trial

03:10:00.640 | that happened recently is that people who got the placebo

03:10:03.560 | knew they got placebo.

03:10:04.680 | People who got the drug knew they got the drug.

03:10:06.320 | It's very hard.

03:10:07.400 | You could do a dose response, but it's very difficult.

03:10:09.560 | - It's very challenging to give someone a psychoactive drug

03:10:12.240 | and a placebo and them not know which one they have.

03:10:14.480 | Whereas because CBD doesn't produce an intoxicating state,

03:10:17.400 | it's not really perceptible from the person who's taken it,

03:10:20.740 | that it's doing anything,

03:10:22.720 | that actually does make it far more amenable

03:10:24.560 | to do blinded trials with.

03:10:25.960 | And so, I mean, the interesting thing with CBD,

03:10:28.760 | and this is where I get a lot of people

03:10:30.480 | that get angry at me as well,

03:10:32.300 | is that I would argue that the overwhelming majority

03:10:36.120 | of the effects of CBD that people report

03:10:38.040 | are all placebo effects.

03:10:39.320 | And I say that because people leverage the epilepsy stuff

03:10:43.480 | and some of the clinical work and say,

03:10:44.840 | but we know it does things.

03:10:45.880 | And my response to them is,

03:10:47.460 | do you know what dose those people are getting?

03:10:50.080 | 'Cause this is something that for some reason

03:10:51.840 | has not made the transition from science into pop culture.

03:10:55.000 | - This is a similar phenomenon with GLP-1.

03:10:57.460 | I and other people have pointed to the fact

03:11:01.280 | that certain food products or certain drinks

03:11:05.160 | or certain activities can increase GLP-1,

03:11:07.280 | glucogon-like peptide,

03:11:08.380 | which is now becoming more commonplace knowledge

03:11:13.160 | because of ozempic, manjaro, et cetera,

03:11:15.080 | as very powerful weight loss tools,

03:11:17.400 | although there's questions about muscle loss, et cetera.

03:11:19.760 | And then we had Dr. Zachary Knight on,

03:11:22.560 | who explained that even a fourfold increase in GLP-1

03:11:26.760 | brought about through a prescription drug

03:11:28.880 | or ingestion of a particular food or drink

03:11:31.660 | does not lead to any appreciable weight loss.

03:11:34.120 | However, when one achieves a thousand fold increases

03:11:37.320 | in GLP-1 through the use of things like ozempic, manjaro,

03:11:39.960 | you see profound weight loss,

03:11:41.400 | meaning that you need enormous effects

03:11:44.460 | in order to see the clinically relevant changes

03:11:47.840 | in that case, weight loss.

03:11:49.160 | So it sounds like a similar thing with CBD.

03:11:52.040 | So if somebody takes a CBD gummy

03:11:54.680 | and they feel that they sleep better,

03:11:56.740 | you would argue that that's entirely expectation bias.

03:11:59.400 | - I think that's a placebo effect.

03:12:00.240 | And I say that because the majority of gummies

03:12:02.120 | are about like two megs, five megs, 20 megs maybe.

03:12:04.720 | - I don't know, I've never taken a CBD product.

03:12:06.600 | I know a few years ago, they were all the rage.

03:12:08.400 | I just, I was never tempted to do it.

03:12:10.960 | And I'm aware,

03:12:11.840 | and we'll talk about this a little bit more,

03:12:13.120 | that there is evidence, according to Matt Walker,

03:12:15.820 | who did a six episode series with us on sleep,

03:12:18.360 | that THC does help certain people fall asleep,

03:12:21.800 | but it can dramatically alter the architecture of sleep

03:12:25.480 | in ways that are probably not great.

03:12:28.240 | - Yeah, yeah.

03:12:29.080 | I mean, THC in sleep is definitely a whole other thing.

03:12:32.760 | But sure, a lot of people report this with CBD.

03:12:34.600 | But again, so most CBD edibles

03:12:37.320 | or things that people take

03:12:38.560 | that are sold through commercial markets

03:12:39.960 | are in the range of two to 25 megs of CBD.

03:12:44.000 | So then I say to them,

03:12:45.680 | so you're aware that in the pediatric epilepsy studies,

03:12:48.520 | the dose ranges are like 1,500 to 2,000 megs.

03:12:52.200 | And then you're talking about a child

03:12:54.440 | who weighs on the order of, what, 20 kilos, maybe,

03:12:57.440 | you know, like 40, 60 pounds, somewhere in that range,

03:13:00.400 | versus, so if you start dosing by weight,

03:13:04.240 | which is how most of these things are done,

03:13:05.600 | well, they'll say 20 megs per kig or whatnot.

03:13:07.860 | So someone my size, so I weigh a bit over 200 pounds,

03:13:12.800 | for me to take that dose of CBD,

03:13:16.680 | and let's say 20 megs per kig at like 90-odd kilos,

03:13:21.440 | I mean, you're talking about me taking-

03:13:23.680 | - A liver-damaging dose.

03:13:24.840 | - An insane, or maybe I wouldn't say damaging.

03:13:28.000 | It's definitely influencing

03:13:29.980 | how the liver metabolizes other things,

03:13:31.720 | 'cause it's gonna saturate those enzymes,

03:13:33.080 | but you're taking a very high dose.

03:13:35.000 | - So if, for instance, you were to take a high dose of CBD

03:13:37.760 | and then maybe have a couple alcohol-containing drinks,

03:13:41.280 | that could be problematic, right?

03:13:42.440 | Because you're talking about the two-hit model.

03:13:44.360 | - Yeah, I can't speak to that,

03:13:45.880 | 'cause I actually do not know

03:13:46.920 | the metabolism of alcohol well enough.

03:13:48.480 | I don't believe so, 'cause that's alcohol dehydrogenase.

03:13:50.600 | So that would probably be a separate enzyme pathway

03:13:53.720 | than the SIPs.

03:13:54.560 | This is more like-

03:13:55.400 | - Separate enzyme pathway,

03:13:56.320 | but you're challenging the liver.

03:13:58.880 | - Yeah, but I don't know if it would have an effect

03:14:00.800 | in that capacity.

03:14:01.640 | I mean, they've definitely seen this,

03:14:02.800 | like they know the list of medications

03:14:04.840 | that this is a problem for.

03:14:06.000 | So it's things like warfarin, and like blood thinners,

03:14:09.980 | and the anti-epileptics funnel

03:14:11.360 | into the same metabolic pathway as this THC.

03:14:13.400 | So there's certain things that this would influence.

03:14:15.960 | I don't know if I would say

03:14:17.120 | this would be in the context of alcohol,

03:14:18.680 | but I think more so, I mean,

03:14:20.960 | what I try and point out to people repeatedly

03:14:22.480 | is I have yet to see a blinded clinical study

03:14:25.760 | that has found any effect of CBD that's efficacious,

03:14:28.880 | that's under 300 to 500 milligrams.

03:14:32.280 | And yet, in the wild,

03:14:35.120 | and people who are using it on their own,

03:14:37.080 | we're using doses of 10 to 20 milligrams,

03:14:39.160 | and reporting these effects.

03:14:40.800 | And the thing is,

03:14:41.640 | that I think a lot of people don't also realize,

03:14:43.080 | is CBD has absolutely horrific bioavailability.

03:14:46.760 | Like, so if you take it orally in an oil,

03:14:49.360 | or in a gummy, or whatever you consume it in,

03:14:51.480 | now this might be different

03:14:52.800 | with some of these beverages that are out there.

03:14:54.200 | I don't know if anyone's actually ever done

03:14:55.360 | the pharmacokinetics on them, at least I've never seen it.

03:14:58.400 | But standard routes, we're talking 4%.

03:15:00.960 | Like, very, very little.

03:15:02.860 | Actually leaves your gut into your bloodstream.

03:15:05.200 | Now, we do know from the studies from GW,

03:15:07.960 | who created the pharmaceutical version of CBD

03:15:10.160 | that was used for a lot of the pediatric epilepsy studies,

03:15:13.320 | that they did, I don't know if it was random

03:15:15.680 | or intentional, find that opposite to something like alcohol,

03:15:19.560 | if you had just eaten a fatty meal,

03:15:21.640 | that actually enhanced the bioavailability

03:15:23.640 | of CBD dramatically.

03:15:25.240 | So then it went up to like maybe 20%, got into the blood.

03:15:28.080 | But that's probably because, again, CBD is a fatty molecule,

03:15:31.080 | it likes fatty environments.

03:15:32.480 | And for some reason, having fat in the stomach

03:15:34.480 | and in the gut seems to promote its ability

03:15:36.880 | to get into the bloodstream.

03:15:38.040 | - Can see now, it's the steak and CBD,

03:15:40.720 | or the CBD with omelet protocol.

03:15:44.520 | I'm just kidding, folks.

03:15:45.620 | I'm not suggesting that protocol.

03:15:48.000 | - But yeah, I mean, and so because of this,

03:15:50.760 | it's like you're taking very low doses of CBD

03:15:53.100 | that have very poor bioavailability,

03:15:55.440 | and then people really stand by the effects of these.

03:15:58.040 | And so I'm like, you know, what I would always say

03:16:00.120 | is if it works for you, there's no reason to stop it,

03:16:02.300 | but because you're having benefit from it.

03:16:06.280 | But would I ever recommend someone do this?

03:16:08.000 | No, I wouldn't, because I can't say

03:16:10.440 | that I think that this has any biological activity.

03:16:12.940 | Because even when we start looking at

03:16:14.920 | these potential targets of what CBD could interact with,

03:16:17.720 | and there's a couple of receptors people have said,

03:16:19.320 | you know, it might interact with serotonin receptor,

03:16:21.600 | there's some of these like random orphan receptors

03:16:24.080 | that we don't know a lot of what they do

03:16:25.200 | that CBD might interact with,

03:16:26.520 | but like the concentrations you need to hit those

03:16:28.920 | are reasonable, and you're not getting that in the blood,

03:16:33.400 | and certainly not in the brain of people

03:16:35.340 | from consuming incredibly low doses of CBD.

03:16:37.480 | So the whole market that exists for CBD,

03:16:41.300 | to me is a little bizarre.

03:16:43.080 | And I think for a lot of us in the cannabis field,

03:16:45.140 | this has been one of the most bizarre social experiments

03:16:47.400 | we've ever watched, because like, you know,

03:16:49.540 | if you asked me in 2010 to walk into a room

03:16:51.480 | and ask how many people knew what CBD is,

03:16:53.320 | like maybe one out of a hundred,

03:16:54.880 | like no one knew what CBD was.

03:16:57.080 | And now it's like 80 to 90% would know what it is.

03:17:00.480 | 'Cause everyone, you can't walk down a street

03:17:02.780 | in any city in North America and not see CBD products,

03:17:06.000 | whether it's some kind of cream or like a shake

03:17:08.880 | or some random like concoction that people have added CBD,

03:17:12.460 | 'cause now it's gonna, you're saying the energy drinks,

03:17:14.820 | like it's just, it's bizarre to me

03:17:16.420 | how much this has taken off,

03:17:17.540 | because it seems to have somehow migrated

03:17:19.760 | into being a health product in some capacity, so.

03:17:22.380 | - Yeah, I've never tried

03:17:23.220 | any of these CBD containing products.

03:17:25.220 | I think a lot of what you're describing

03:17:27.540 | speaks to the fact that, you know,

03:17:29.660 | people are eager for things that can help them

03:17:34.420 | adjust their anxiety and sleep better.

03:17:36.300 | You know, which is a large reason

03:17:39.200 | why a lot of this podcast has focused

03:17:41.720 | on respiration-based tools and other base tools

03:17:45.040 | that can help people with anxiety.

03:17:46.960 | I think that many people suffer from just too much activation

03:17:51.960 | in their autonomic nervous system.

03:17:54.000 | And I would argue there are much better things

03:17:56.960 | that are not of a ingestible type, you know,

03:18:00.600 | things that one can do that are science supported, right?

03:18:02.840 | There are clinical studies, meditation, breath work,

03:18:06.200 | any, not so much breath work, I would argue,

03:18:07.940 | but certain patterns of breathing, meditation,

03:18:10.480 | cognitive behavioral therapy.

03:18:11.500 | There are a whole bunch of different things, as you know.

03:18:14.200 | So I don't know what explains the CBD craze,

03:18:16.360 | but you certainly have shed light on what is,

03:18:19.520 | and mainly what is not known about CBD.

03:18:22.240 | And I think it's really important for people to hear.

03:18:24.080 | - Yeah, I mean, again, it's, I think from my point of view,

03:18:27.520 | it's an ethical thing as well,

03:18:28.720 | because like this isn't covered by insurance.

03:18:30.740 | People are spending their own money on this.

03:18:32.120 | And so I find it really challenging

03:18:34.120 | to recommend someone to be spending what can,

03:18:36.000 | I mean, if you're, especially if you're talking

03:18:37.040 | about an actual clinical dose,

03:18:38.200 | I mean, for someone to take CBD at the level

03:18:40.380 | where it could actually be shown to have some benefit

03:18:43.140 | in some condition, of which currently

03:18:45.140 | it really is just pediatric epilepsy,

03:18:47.240 | like this idea with sleep, pain, anxiety,

03:18:49.820 | there's not a lot of super conclusive data.

03:18:52.640 | And I'd say most of the trials that have been done

03:18:54.740 | have not found really good evidence

03:18:57.880 | of benefit in any capacity.

03:18:59.280 | So it makes it very challenging

03:19:01.280 | to recommend this in any capacity,

03:19:03.660 | especially, I mean, if someone,

03:19:04.840 | if finances aren't an issue, sure, go for it.

03:19:06.800 | But, you know, I understand people are,

03:19:09.520 | like you say, looking for solutions.

03:19:11.000 | - So it doesn't sound like CBD is the solution.

03:19:13.200 | - I would, I am not convinced by the data that exists

03:19:16.240 | that it's really doing what a lot of people claim it's doing.

03:19:19.920 | - Except supporting the placebo effect, perhaps, perhaps.

03:19:22.720 | - It's a great study of the placebo effect.

03:19:24.860 | - I want to make sure before we close

03:19:26.120 | that we touch on some of the potential harms

03:19:29.400 | or asserted harms of THC,

03:19:32.960 | because I think there's a lot of misunderstanding

03:19:34.600 | about this.

03:19:35.440 | We talked about psychosis and the lack of evidence

03:19:39.120 | for a direct causal effect.

03:19:41.520 | You give a beautiful description

03:19:42.720 | as to how we should think about all of that

03:19:44.640 | based on the current literature.

03:19:46.180 | But cannabis and driving is a potential hazard, right?

03:19:51.180 | And some people will laugh.

03:19:53.480 | They'll be like, oh, driving too slow,

03:19:55.040 | as opposed to, you know, driving drunk or driving too fast.

03:19:57.440 | Okay, we can talk about that.

03:19:59.640 | We talked about the potential for addiction

03:20:02.040 | and the evidence potentially for and against that, right?

03:20:05.980 | There's also this, the big black or gray box of, you know,

03:20:11.640 | all the things we don't know

03:20:12.640 | about what regular cannabis use could do.

03:20:15.240 | And yet I know a lot of people

03:20:16.920 | who've used cannabis for years,

03:20:19.280 | mainly as a replacement for alcohol,

03:20:21.480 | at least that's how they describe it.

03:20:22.480 | Well, it's not as bad as alcohol,

03:20:23.880 | but you hear that a lot, okay?

03:20:25.720 | But what are some actual, if any,

03:20:29.720 | what are some actual harms of cannabis use

03:20:32.320 | that people need to take into account

03:20:33.600 | and just weigh against the fact that every compound,

03:20:36.280 | caffeine, even water can kill you

03:20:38.120 | if you drink too much of it.

03:20:39.440 | And then let's make sure that we touch on this issue

03:20:41.680 | of cannabis and driving or operating machinery.

03:20:44.500 | But I think the machine most people are thinking about

03:20:47.380 | these days is driving.

03:20:49.160 | - Yeah, so health harms.

03:20:52.640 | I mean, someone smoking,

03:20:55.220 | obviously there's risks for lung damage.

03:20:57.340 | I would say the evidence for things like lung cancer

03:21:00.340 | certainly don't hold the way they do with cigarette smoke.

03:21:03.240 | - Because people are smoking less of it

03:21:04.640 | or there's just fewer carcinogens in there.

03:21:06.940 | - I don't think you could make the argument

03:21:08.560 | about fewer carcinogens per se.

03:21:10.280 | I think probably it relates more to the frequency.

03:21:12.980 | I mean, Donald Tashkin, who's in California here,

03:21:15.560 | I think he was at UCLA, I'm not a hundred percent sure,

03:21:17.560 | but I know he was in California.

03:21:18.600 | He did like very long-term studies

03:21:20.360 | tracking cannabis smokers

03:21:21.900 | and basically did not find associations with lung cancer

03:21:24.800 | the way that you do with cigarette smoking.

03:21:26.480 | Why that's the case, I don't think anyone has,

03:21:28.220 | like people have theories.

03:21:29.500 | Some suggest because a lot of this in vitro animal work

03:21:32.080 | with really high dosing

03:21:33.040 | suggests it could have anti-proliferative effects for tumors.

03:21:35.900 | Whether that's real or not, I don't know.

03:21:38.000 | But like, I think more likely it's because most people

03:21:41.440 | who smoke cigarettes, at least,

03:21:42.720 | that were, you know, the relationship with lung cancer

03:21:45.840 | were people who were smoking regularly throughout the day.

03:21:48.080 | And it's very rare someone smokes cannabis at that frequency.

03:21:51.280 | Maybe if they isolated that population,

03:21:53.000 | they would see relationships with lung cancer.

03:21:54.440 | I just don't think it's been borne out by the data

03:21:56.560 | the same way.

03:21:57.400 | Certainly lung damage, emphysema,

03:21:59.200 | things like that are on par.

03:22:01.160 | If you have any combustion product,

03:22:02.420 | you're gonna have damage there.

03:22:03.360 | There's no question about that.

03:22:04.880 | So again, harm reduction perspective would be, you know,

03:22:08.000 | oral routes of administration bypass lung damage.

03:22:10.400 | They come with their own issues with dosing and whatnot.

03:22:12.400 | But if you're talking about physical harms,

03:22:14.760 | that's one thing to avoid,

03:22:15.800 | that you could bypass that aspect of it with.

03:22:18.040 | There is some, I don't think we are at a point

03:22:23.660 | where we can say the state of it.

03:22:26.320 | There is something with cardiovascular function

03:22:28.880 | and cannabis that relates to higher frequency

03:22:33.880 | of strokes, perhaps, or cardiac events in some capacity.

03:22:39.240 | The data is not entirely clear in this sense yet.

03:22:42.000 | I mean, we don't see, again,

03:22:43.220 | it's not like super clean relationships

03:22:45.080 | like we're seeing that were there

03:22:46.720 | when they established, you know,

03:22:48.120 | cigarette smoking and lung cancer kind of thing.

03:22:49.800 | I think that effect was so profound.

03:22:51.360 | And the population of smokers used to be so high it was.

03:22:54.980 | - Can this potential, I wanna highlight potential,

03:22:58.140 | relationship between cannabis use

03:23:00.060 | and cardiovascular issues be bypassed, no pun intended,

03:23:05.060 | by using edibles, not inhalants,

03:23:08.180 | or is it related to THC itself?

03:23:10.140 | - I would probably guess, and this is a guess,

03:23:15.260 | that the, you know, anything, again, combustion smoke-wise,

03:23:18.300 | I mean, maybe not vaping plant matter,

03:23:19.860 | but at least the combustion from smoking

03:23:22.100 | probably exacerbates this,

03:23:23.580 | just because any kind of combustion product

03:23:26.120 | is gonna have some vascular effects

03:23:27.620 | to some degree on the system.

03:23:29.040 | So I imagine it would make it worse,

03:23:30.060 | but THC itself has a very complex effect

03:23:32.980 | on cardiovascular function

03:23:34.580 | because it tends to cause, typically, vasodilation.

03:23:39.580 | So you get widening of the blood vessels,

03:23:42.500 | which is why it relates to a lot of people

03:23:44.460 | will experience postural hypotension.

03:23:46.700 | So sometimes when, what that is is

03:23:48.820 | if you stand up and your blood pressure

03:23:50.180 | doesn't catch up with you,

03:23:51.520 | so you get really lightheaded and people will collapse.

03:23:53.740 | And so this is not uncommon to happen to people

03:23:56.420 | and with edibles as well.

03:23:57.700 | So it's not just from smoking.

03:23:59.940 | But when they've consumed cannabis in some capacity,

03:24:01.980 | there are some people that seem to be very sensitive

03:24:03.680 | to the vasodilating effects.

03:24:04.900 | And so when they stand up,

03:24:06.160 | their blood pressure can't match

03:24:07.380 | the shift in gravity that happens.

03:24:08.780 | And so not enough blood perfuses the brain and they go down.

03:24:11.700 | And that can be transient.

03:24:12.700 | They'll come to a minute or two later, but it happens.

03:24:16.300 | But as a consequence of the vasodilation

03:24:19.980 | is it triggers tachycardia,

03:24:21.340 | which is an accelerated heart rate.

03:24:22.860 | And so that's a very reliable physiological response

03:24:26.380 | for a lot of people who use cannabis.

03:24:27.920 | And so it's a bit of a tricky thing

03:24:32.060 | because obviously if there is some underlying heart

03:24:36.740 | or a cardiac sensitivity or issue,

03:24:39.640 | the tachycardia itself can be a problem.

03:24:42.060 | I mean, so like, you know,

03:24:44.420 | if someone has like an underlying heart condition

03:24:46.740 | where at rest it may not present itself,

03:24:49.040 | but the shifts into that kind of beating faster

03:24:52.380 | to compensate for the fact

03:24:53.460 | that you've got a drop in blood pressure

03:24:55.500 | can put strain on the heart

03:24:58.300 | in a way that could unmask a vulnerability or an event.

03:25:01.340 | And again, this is me theorizing

03:25:03.400 | what I think it could be based on what we understand

03:25:05.300 | to some degree about how it affects cardiovascular function.

03:25:08.300 | There are occasionally people who have reported

03:25:12.940 | having like elevated blood pressure.

03:25:14.540 | I mean, some of that also could be from like an anxiety state

03:25:16.740 | or whatnot coming around, but the typical response,

03:25:19.540 | and this is usually driven by cannabinoid receptors

03:25:21.460 | that are in the vascular beds themselves,

03:25:24.060 | that it causes a vasodilatory response.

03:25:26.060 | And so that is usually the first step.

03:25:28.500 | The second is the uptick in the heart rate.

03:25:31.500 | So you get these kind of effects over time.

03:25:33.820 | There's some work looking at like, you know,

03:25:37.580 | vascular stiffness that can evolve over time.

03:25:40.300 | And cannabis users, there's some evidence to suggest

03:25:42.700 | that you might get more of that emerging.

03:25:44.740 | And so again, that could relate to a vulnerability

03:25:47.900 | to have strokes or other kind of cardiovascular events

03:25:51.260 | in that sense.

03:25:52.140 | So I think the issue in terms of like

03:25:55.780 | why it is more difficult for us to say anything

03:25:58.620 | definitively at this point,

03:25:59.660 | it's just obviously the timeline of this.

03:26:01.700 | I mean, you know, cigarette smoking was an easier thing

03:26:04.860 | to establish in that context because, you know,

03:26:06.900 | once antibiotics and medicine advanced in like the forties

03:26:09.400 | and the thirties and stuff,

03:26:10.240 | and people started living longer,

03:26:11.700 | you started seeing a lot of these effects

03:26:13.500 | of cigarette smoking emerge because-

03:26:14.940 | - And yet it took a while for the medical community

03:26:17.820 | to adopt the idea that cigarette smoking was bad.

03:26:20.020 | - Oh, I know.

03:26:20.980 | It's wild-

03:26:21.820 | - Physicians would smoke in clinic,

03:26:23.340 | there were ashtrays in the doctor's office.

03:26:25.340 | - I mean, my grandparents grew up in Belfast.

03:26:28.100 | They had smoked for years and they had even said like,

03:26:30.020 | when they were younger, doctors would say,

03:26:31.020 | oh, have a cigarette after a meal, it promotes digestion.

03:26:33.080 | So it was kind of wild to hear that stuff

03:26:34.900 | when you think of how cigarettes are viewed nowadays.

03:26:36.620 | But it is, I don't think we've kind of been able

03:26:41.380 | to track this long enough to be able to say

03:26:43.540 | with certainty what we're seeing.

03:26:44.740 | But I think there's like, if people ask me about risks

03:26:47.940 | and harms of cannabis, the first thing I always say is,

03:26:50.500 | you know, schizophrenia and bipolar.

03:26:52.100 | Those are the main concern areas, I think,

03:26:54.500 | where you want to avoid cannabis.

03:26:56.260 | And I would also say, if anyone has cardiovascular issues,

03:26:59.660 | they should avoid cannabis.

03:27:00.980 | Just 'cause that's more of like, I would say a being safe,

03:27:03.860 | 'cause I don't know how to actually explicitly say

03:27:06.020 | what I would say the harms associated with it are.

03:27:08.220 | But I think there is something there.

03:27:09.420 | I've seen enough evidence that's like,

03:27:11.260 | starting to coalesce into a story

03:27:14.380 | that's like, there's something here.

03:27:16.540 | So I would, that's where I would say

03:27:18.420 | that I think there's risk.

03:27:19.300 | There's also things like

03:27:21.220 | this bizarre cyclic vomiting syndrome,

03:27:23.180 | which is this really strange thing

03:27:24.660 | that has become really apparent.

03:27:27.040 | We've seen this in Canada a bit more now with legalization,

03:27:29.180 | again, 'cause people are going into ERs more,

03:27:31.140 | where it's this somewhat strange phenomenon

03:27:34.500 | where it's usually people

03:27:36.180 | who are pretty excess cannabis users,

03:27:39.180 | they just start puking and they can't stop it.

03:27:42.460 | And it's like this intractable vomiting that they get into.

03:27:45.500 | And then bizarrely,

03:27:47.400 | one of the things that seems to cure it is a hot shower,

03:27:50.860 | which is, I can't even begin to understand this.

03:27:53.340 | I mean, there's also--

03:27:54.700 | - I'm chuckling at the example

03:27:56.020 | 'cause you are so very clearly rooted in science,

03:27:59.060 | but that just came out of nowhere.

03:28:00.540 | Like, okay, cool, a hot shower,

03:28:02.020 | deliberate heat exposure, folks.

03:28:03.980 | There it is.

03:28:04.820 | - I have been trying to understand how this was--

03:28:07.100 | - I'm not enjoying it because it's deliberate heat exposure,

03:28:09.120 | but it just speaks to the fact that we're talking about

03:28:11.820 | smoking being a regular part

03:28:16.060 | of the medical community's behaviors

03:28:18.460 | up until a few decades ago.

03:28:20.800 | And then a hot shower being the treatment

03:28:25.100 | for this chronic vomiting.

03:28:26.580 | And it speaks to the fact that with science and medicine,

03:28:29.740 | we do know a ton.

03:28:31.020 | It's amazing how much we've progressed this,

03:28:32.580 | especially in the last 100 years, last 25 years even.

03:28:35.940 | But it's also astounding

03:28:37.920 | how these seemingly surprising antidotes

03:28:41.960 | to uncomfortable conditions can hold up over time

03:28:45.320 | in the absence of any randomized control trials

03:28:47.960 | or mechanistic data.

03:28:48.880 | - I mean, I really struggled to understand,

03:28:51.200 | 'cause certainly I don't think it was doctors

03:28:52.760 | that figured this out.

03:28:53.600 | This was people, I think, who were experiencing this.

03:28:56.120 | And then they started telling doctors this.

03:28:58.320 | And then I think, and I can only imagine,

03:29:01.000 | I'm like, maybe they're going in the shower

03:29:02.480 | 'cause they're like vomiting on themselves.

03:29:04.640 | - Probably.

03:29:05.480 | - I inadvertently realized that being in a hot shower

03:29:07.580 | somehow seemed to calm this down.

03:29:09.100 | I have seen a study

03:29:10.180 | where they actually applied capsaicin cream,

03:29:12.260 | and that also seemed to provide benefit.

03:29:13.880 | - So something about activation of the heat, thermal--

03:29:16.240 | - It's something with thermoregulation,

03:29:17.700 | 'cause the other thing

03:29:18.540 | that seems to have shown some benefit is propanolol,

03:29:20.860 | which again would suggest some kind of sympathetic.

03:29:22.780 | - Which is a beta blocker.

03:29:23.740 | - It's a beta blocker.

03:29:24.580 | So yeah, it's your effect.

03:29:25.500 | So there's something with autonomic.

03:29:27.060 | It must be messing up some kind of autonomic balance

03:29:30.060 | or something with thermoregulation.

03:29:31.780 | Why that results in this kind of bizarre vomiting syndrome

03:29:35.300 | I have no idea,

03:29:36.240 | but I remember when I first started hearing

03:29:38.100 | the stories of this years ago,

03:29:39.820 | and I was just like, how?

03:29:40.660 | 'Cause I mean, it is again, surprisingly counterintuitive

03:29:43.120 | because one of the medical uses

03:29:46.600 | that people have used cannabis for is as an antinauseant,

03:29:49.000 | especially in the context of chemotherapy.

03:29:50.680 | And so something that typically has antinauseant qualities

03:29:54.160 | suddenly triggering a vomiting syndrome

03:29:56.280 | is kind of a paradoxical.

03:29:59.440 | - And yet we started off today's conversation

03:30:01.960 | with you explaining beautifully

03:30:03.240 | how activation of these CB1 receptors

03:30:07.200 | are homeostatic in some sense, the thermostat analogy.

03:30:10.880 | And maybe after chronic use,

03:30:13.680 | there's some, the seesaw sort of gets flipped to one side

03:30:16.920 | and gets stuck.

03:30:17.760 | - I think that's how most people have tried

03:30:19.080 | to kind of conceptualize what's going on is maybe like,

03:30:22.400 | and it seems to involve the insular cortex,

03:30:24.080 | at least the antinauseant effects of cannabinoids

03:30:26.040 | are involved through the insular cortex.

03:30:27.960 | And so maybe you like have burned out those receptors

03:30:31.140 | from chronic use.

03:30:31.980 | And so that endogenous mechanism isn't working

03:30:34.760 | or it's somehow flipped in the other direction

03:30:36.480 | now in that circuit becomes sensitized,

03:30:38.160 | but it is a very bizarre,

03:30:40.880 | but very real thing that seems to happen.

03:30:43.320 | Again, this isn't common.

03:30:44.640 | Like I've heard a couple of people I've met describe it,

03:30:48.960 | but it's not like it's happening

03:30:51.160 | to every 10th or 20th person or something.

03:30:52.840 | It's a little more infrequent,

03:30:54.680 | but it's certainly happening enough

03:30:56.160 | that we've now captured it at a federal data level

03:30:58.980 | that this is a thing that people are showing up

03:31:00.680 | in the ER for.

03:31:01.520 | - Interesting, so a hot shower.

03:31:03.760 | - Yeah, so apparently if it happens,

03:31:05.480 | hot shower is what people claim.

03:31:07.040 | So yeah, so for me, I would say the main harms

03:31:10.620 | that people need to be aware of

03:31:11.460 | are the schizophrenia bipolar,

03:31:13.640 | possible cardiovascular effects.

03:31:15.440 | And then this is one of these syndromes

03:31:17.120 | that can come out of it,

03:31:17.960 | as well as possible lung damage from smoking.

03:31:20.620 | Those are the main, I think genuine bonafide health issues

03:31:23.960 | associated with cannabis that people should be aware of.

03:31:26.000 | I mean, I know we're not gonna probably go into depth

03:31:28.760 | with it, on the other side with the medical stuff,

03:31:30.480 | it's a little bit more challenging.

03:31:32.160 | I mean, a lot of this is just because

03:31:33.900 | we really don't have good studies that have been done

03:31:37.560 | in any capacity that have really definitively told us

03:31:40.200 | if cannabis has like really bonafide medical benefit.

03:31:43.640 | - Yeah, I was gonna ask you about that.

03:31:44.720 | It's always nice to end on a positive side

03:31:47.200 | and we don't wanna demonize cannabis,

03:31:49.160 | nor do we wanna glorify it.

03:31:51.360 | But the examples that I've heard of medical uses

03:31:55.000 | for cannabis include appetite stimulation.

03:31:57.280 | We talked about that.

03:31:59.560 | For glaucoma, lowering eye pressure and glaucoma,

03:32:01.960 | the age and age-related increase in eye pressure

03:32:06.440 | are two of the major risk factors for glaucoma,

03:32:09.500 | which is the most common blinding disease,

03:32:12.760 | second to cataract.

03:32:14.600 | More than 70 million people suffer from it.

03:32:16.480 | Everybody, regardless of age,

03:32:17.880 | get your eye pressures checked.

03:32:19.400 | There are drops for this, but okay,

03:32:21.000 | cannabis can reduce eye pressure and glaucoma.

03:32:23.700 | Nausea, you mentioned, and then anxiety.

03:32:28.280 | It sounds like if people get the dose right

03:32:31.820 | and it's right for them,

03:32:33.120 | that in some cases it can help them with their anxiety.

03:32:35.320 | And the reason I raised that one

03:32:36.560 | is because it seems that most people

03:32:39.040 | who decide to use cannabis regularly

03:32:42.040 | are using it as perhaps for its euphoric effects,

03:32:45.360 | but as kind of a mild sedative,

03:32:47.120 | a way to relax in the same way

03:32:48.440 | that they would use a glass or two of wine.

03:32:50.280 | What are your thoughts on that?

03:32:51.400 | Because I think this is the most common use case.

03:32:53.520 | - Yeah, I mean, you look at, I mean,

03:32:55.480 | the other one that wasn't on there,

03:32:56.980 | but you've mentioned this before

03:32:58.000 | and I have as well as pain.

03:32:58.960 | So chronic pain. - The pain, thank you.

03:33:00.240 | - Pain is, I would say, the number one.

03:33:01.640 | So pain is certainly the one

03:33:02.720 | that there's the most amount of evidence for.

03:33:04.660 | And I would say when you talked about this

03:33:08.120 | in the previous podcast,

03:33:09.080 | you were mostly correct about this component of it

03:33:11.600 | in the sense that it's not that cannabis

03:33:13.380 | is a profound analgesic.

03:33:15.240 | It's that cannabis, it has some analgesic properties,

03:33:18.880 | but it's not like super sledgehammer in that sense.

03:33:21.580 | But what it does seem to do is

03:33:22.920 | it seems to strip away the affective component of pain

03:33:25.200 | to some degree.

03:33:26.040 | And so what I have consistently heard

03:33:28.120 | from chronic pain patients when they use cannabis

03:33:30.200 | is they say, "Yeah, my pain's still there,

03:33:32.460 | "but now the pain's background noise.

03:33:34.240 | "So I can sleep at night."

03:33:35.680 | And just being able to sleep, I think,

03:33:37.080 | is actually providing a huge amount of the benefit

03:33:38.800 | to that community.

03:33:39.720 | But it's the day-to-day.

03:33:42.560 | Like they're able to function with the pain

03:33:43.960 | because it doesn't,

03:33:45.760 | they don't become focused on it the same way

03:33:47.240 | because they're able to kind of push it to the background.

03:33:49.280 | That seems to be the main ability of cannabis.

03:33:52.520 | I mean, yes, there's some mild analgesic properties to it

03:33:55.340 | to some degree, but it really seems to be much more

03:33:57.080 | that component of it.

03:33:57.920 | And I think you alluded to something like that

03:33:59.560 | in the previous podcast.

03:34:00.900 | You'd said something about how it's changing

03:34:02.680 | the emotional state of pain.

03:34:04.200 | - And we know from the biopsychosocial model of pain

03:34:06.400 | that emotions and interpretation of the sensation of pain

03:34:11.380 | is a huge component of what people refer to

03:34:13.800 | as chronic and acute pain.

03:34:15.160 | - Yeah, so the pain thing, I think, is a central one.

03:34:18.200 | And that's one of the only ones

03:34:19.240 | that there's a little bit of actual research on.

03:34:21.320 | Most of it's either with isolated THC.

03:34:22.720 | I think there's one or two studies

03:34:23.720 | that have actually looked at smoked cannabis

03:34:24.920 | and found small signals of benefit.

03:34:27.100 | But so anxiety is an interesting one.

03:34:30.900 | And so, I mean, obviously this is more near and dear

03:34:32.400 | to my heart because I study stress and anxiety

03:34:35.000 | as my primary area and cannabinoids and endocannabinoids

03:34:38.280 | in that space.

03:34:39.640 | And yeah, you look at questionnaire-based studies

03:34:43.500 | about why people smoke cannabis and like 85% of them

03:34:46.120 | will say because it reduces stress

03:34:47.720 | and it makes me feel less anxious.

03:34:49.560 | I mean, that was like a big impetus

03:34:51.040 | as to why we started studying endocannabinoid regulation

03:34:53.720 | of it because similar to feeding and pain,

03:34:55.940 | where we know endocannabinoids are involved

03:34:57.520 | in regulated feeding circuits

03:34:58.800 | and endocannabinoids are also integrated

03:35:00.560 | into pain circuitry and can provide

03:35:02.520 | some endogenous analgesic signals,

03:35:04.360 | we figured the same was gonna be true for stress

03:35:07.040 | and anxiety, which to some degree it is.

03:35:09.720 | But it's very complicated because it can be,

03:35:12.400 | like I said before, biphasic where some lower doses

03:35:15.200 | are anxiolytic, higher doses can promote anxiety.

03:35:18.040 | But for the majority of people who use cannabis regularly,

03:35:20.520 | it's because it helps reduce anxiety.

03:35:22.420 | Now, whether that would hold weight in a clinical trial

03:35:26.720 | is a different story.

03:35:27.640 | There is some old evidence from like,

03:35:30.080 | I'd say the '70s, early '80s,

03:35:31.480 | where they were using synthetic forms of THC,

03:35:34.160 | like nabalone, which is something you can get in Canada,

03:35:36.200 | or Marinol or Dronabinol,

03:35:37.560 | which I think is what's accessible in the States,

03:35:39.580 | where they did find some evidence to suggest

03:35:41.920 | it was on par with like a benzodiazepine,

03:35:44.000 | like diazepam or something.

03:35:45.120 | I can't remember exactly what the comparator

03:35:47.120 | they'd used in there, but there was some evidence

03:35:48.660 | for there being some anti-anxiety properties of THC.

03:35:53.320 | And that tracks generally well

03:35:55.520 | with the self-reported literature that's out there.

03:35:58.860 | Now, whether that's the same as an ability

03:36:03.660 | to have benefit in something like PTSD

03:36:05.280 | is a different question.

03:36:06.620 | It gets a little bit more complicated

03:36:07.800 | 'cause obviously PTSD has an anxiety component to it,

03:36:10.360 | but there's a lot more to it as well.

03:36:12.520 | And again, there's very little research in this space.

03:36:15.040 | There was one really, really small study

03:36:18.380 | done by the Canadian military.

03:36:20.580 | First, they did one version of it that was an open label.

03:36:23.460 | Open label trials for people who don't know,

03:36:25.340 | it's just basically everyone knows what they're getting.

03:36:26.940 | It's not blinded in any way,

03:36:28.020 | but because of the self-reported data

03:36:30.260 | from the veteran population about cannabis helping,

03:36:33.740 | especially with sleep.

03:36:35.220 | And the big thing that they reported

03:36:36.620 | was that it suppressed their nightmares.

03:36:38.380 | And so, post-traumatic stress disorder

03:36:41.020 | is a very complex disease for many reasons.

03:36:43.100 | And one component of it is the re-experiencing events

03:36:46.120 | that happen during sleep where there's a lot of nightmares

03:36:49.160 | and individuals will kind of re-experience the trauma

03:36:52.400 | that led to the development of the PTSD.

03:36:54.880 | And there does seem to be some suggestion

03:36:57.520 | that because they're remembering it

03:36:58.860 | and maybe changing the details

03:37:00.120 | 'cause they're in a dreamscape space

03:37:01.680 | that they reconsolidate it a little bit more.

03:37:03.940 | And there's often a high degree of sympathetic activation

03:37:06.160 | and arousal that goes on with these nightmares.

03:37:08.540 | And some of the belief is that

03:37:11.040 | this is part of the sensitization process

03:37:13.260 | that can happen in PTSD

03:37:14.700 | where the disease can worsen over time

03:37:16.300 | because the re-experiencing and the re-consolidation

03:37:19.200 | and the sensitization of the disease that happens

03:37:21.880 | over time in this kind of sleep state can make it worse.

03:37:24.700 | And so, the majority of veterans who have used cannabis

03:37:28.380 | and report benefit,

03:37:29.500 | if you actually talk to them about it,

03:37:31.980 | as I've done in a few different situations

03:37:33.580 | and also just look at the anecdotal data,

03:37:35.460 | almost all of it talks explicitly about sleep.

03:37:37.360 | And they say, "Oh, we use cannabis or THC before bed.

03:37:40.620 | We find we don't have the nightmares."

03:37:41.940 | And just the simple trickle-down effect of that

03:37:44.660 | is hugely beneficial for them.

03:37:46.340 | And so, the Canadian military did an open label trial

03:37:48.500 | on this, again, not blinded.

03:37:49.780 | It was small numbers, but they basically found,

03:37:52.140 | soon as they put people on Nabilone,

03:37:53.580 | this synthetic version of THC,

03:37:56.180 | it vary in like a large proportion,

03:37:58.340 | I think like 85% of them almost stopped

03:38:00.100 | having these nightmares.

03:38:01.380 | And this was like a treatment-resistant population

03:38:03.580 | that was pretty severe.

03:38:04.980 | So, this was a big benefit.

03:38:06.420 | So, they then took the open label and did what you should

03:38:09.340 | and moved forward to do a double-blind placebo controlled.

03:38:11.540 | Now, it was a very small sampled studies.

03:38:13.740 | And that is obviously always a problem with human work

03:38:16.180 | is if this was like 15 or 17 people.

03:38:18.180 | So, not powered enough to really make

03:38:20.380 | any kind of firm conclusions,

03:38:21.460 | but interesting in the sense that at least it was done

03:38:23.380 | in a proper crossover design

03:38:24.860 | where they got placebo at one point,

03:38:26.660 | they got Nabilone at one point, it was switched.

03:38:28.380 | They didn't know which one they were on.

03:38:30.900 | Because they're taking it right before bed,

03:38:33.460 | maybe that will remove some of the subjective bias.

03:38:35.740 | Again, you can't totally remove it,

03:38:37.160 | but like if someone's taking it within an hour or so

03:38:39.580 | of going to sleep, they may not feel high the same way.

03:38:41.820 | But even under the double-blinded conditions,

03:38:44.140 | they found a very effective suppression

03:38:46.020 | of the nightmares and the re-experiencing.

03:38:48.820 | And then they also, at the same time,

03:38:50.340 | found this increase in kind of quality of life measures,

03:38:52.460 | which tracked with the fact

03:38:53.580 | that they were probably sleeping better.

03:38:55.580 | I don't think they actually reported any change

03:38:58.460 | or even looked at maybe the overall PTSD score.

03:39:01.100 | They only reported or really focused

03:39:02.860 | on the nightmare component of it,

03:39:04.220 | 'cause that was the primary outcome of the study.

03:39:05.860 | But, so I thought that was interesting,

03:39:07.420 | 'cause that's, if you look at the anecdotal data in PTSD,

03:39:09.660 | that's where a lot of it is focused on,

03:39:11.100 | is using it as a kind of,

03:39:13.020 | I wouldn't maybe call it a sleep aid,

03:39:15.220 | because it's really more of a modulator of the dream state.

03:39:18.260 | And I think this is- - Presumably,

03:39:19.500 | because it's reducing the amount

03:39:20.580 | of rapid eye movement sleep you're getting,

03:39:21.940 | which most people will probably hear and interpret as bad.

03:39:25.220 | But you know, REM deprivation

03:39:26.880 | is actually one treatment for depression.

03:39:28.420 | So there are certain case conditions

03:39:30.800 | where dreaming and REM is not advantageous.

03:39:35.260 | - Yeah. - And you're describing one.

03:39:36.100 | - I mean, depression and PTSD are both two disorders

03:39:38.980 | that are characterized by changes in REM.

03:39:41.060 | Like they have earlier onset to REM,

03:39:42.460 | so they go into REM faster.

03:39:43.540 | They tend to have some altered architecture

03:39:45.580 | of the REM component of their sleep.

03:39:46.660 | So in those states,

03:39:48.340 | maybe suppressing REM isn't actually a bad thing.

03:39:50.620 | At least certainly for PTSD,

03:39:52.660 | I would imagine in terms of the context of the nightmares,

03:39:54.680 | that's providing some benefit.

03:39:56.820 | Whether or not it globally is changing the disease severity

03:40:00.820 | or improving the disease,

03:40:01.900 | I don't think we really have any evidence to say.

03:40:05.340 | But again, I can understand the desire

03:40:09.220 | for people to kind of self-medicate, let's say,

03:40:11.460 | by using this as an approach

03:40:12.700 | to try and reduce that component of their sleep

03:40:15.300 | so that they sleep better, they feel better, maybe.

03:40:17.660 | You know, maybe down the road,

03:40:18.740 | it would help the prognosis of the disease long-term

03:40:21.100 | if it's not sensitized in the same way.

03:40:22.540 | But I don't think we have any strong data

03:40:25.660 | that we can leverage in that capacity to be able to say it.

03:40:27.780 | But to me, it's one of the more interesting areas.

03:40:30.820 | I think anxiety disorders in general,

03:40:34.420 | there's definitely some potential.

03:40:35.880 | So as I had mentioned earlier,

03:40:37.660 | the fall inhibitor that elevates anandamide levels.

03:40:41.520 | So Johnson & Johnson did do a trial

03:40:43.500 | on social anxiety disorder.

03:40:44.860 | It's published, I think, from a few years ago,

03:40:47.540 | '21 or something, I can pull up the reference for that,

03:40:49.960 | where they did find some benefit.

03:40:52.460 | It wasn't huge.

03:40:53.340 | And some of this had to do with the design of the study

03:40:55.360 | 'cause they kind of underdosed the patients a bit.

03:40:57.460 | And so not everyone actually showed the elevation

03:40:59.820 | in anandamide when they went back and looked,

03:41:01.500 | but when they actually isolated the group of people

03:41:03.340 | that had higher anandamide,

03:41:04.980 | in that proportion of the patients,

03:41:06.700 | they did see some symptom improvement.

03:41:08.340 | So it did support it.

03:41:10.020 | And this is, I mean, very similar.

03:41:12.500 | Like for us, this is a big thing

03:41:13.820 | because all of the work that we focused on

03:41:15.740 | is looking at how stress and stress hormones

03:41:17.600 | regulate largely anandamide signaling.

03:41:19.940 | And I mean, one of the main things that we've demonstrated

03:41:22.660 | that's been replicated relatively well over the years

03:41:24.560 | is that stress exposure can actually cause

03:41:27.220 | a rapid loss of anandamide signaling.

03:41:28.980 | And it's that loss of anandamide signaling

03:41:30.580 | that seems to facilitate some synaptic strengthening

03:41:33.660 | in the amygdala and promote activity in areas

03:41:36.300 | that are involved in these anxiety circuits.

03:41:38.420 | And so the thought has always been,

03:41:41.620 | well, if anandamide, you know,

03:41:42.900 | it's that job as it's kind of tonic housekeeper,

03:41:45.780 | keeping things in that homeostatic range,

03:41:47.360 | let's say we're talking about explicitly an anxiety circuit,

03:41:50.420 | you know, there's individual variation that exists

03:41:52.580 | in humans across everything.

03:41:53.620 | So one of our predictions has been

03:41:55.500 | maybe people who are on the high end of the anxiety spectrum

03:41:58.460 | might be on the low end of their

03:42:00.020 | tonic anandamide signaling spectrum.

03:42:01.840 | And we've gotten a little bit of support from that

03:42:03.860 | from animal work, where we've screened animals

03:42:05.860 | based on anxiety and looked at endocannabinoid levels

03:42:08.300 | in the amygdala and found lower anandamide.

03:42:10.420 | - That's extremely interesting because it squares

03:42:12.980 | with my, again, non-laboratory observation

03:42:16.700 | that a lot of people use cannabis

03:42:20.380 | to deal with their anxiety, right?

03:42:22.300 | So what you're saying is that, you know,

03:42:23.840 | there's a range of kind of, let's just say,

03:42:26.500 | baseline circuit activation within the amygdala

03:42:28.740 | and related structures in mice, in humans,

03:42:30.500 | presumably in other animals also.

03:42:32.180 | If people take a compound that adjusts

03:42:36.420 | the sort of homeostatic level of what's considered

03:42:40.280 | low, moderate, and high activation of those circuits

03:42:43.040 | that include the amygdala,

03:42:44.400 | then perhaps they're bringing their anxiety into range.

03:42:47.500 | In a way that perhaps is different than with alcohol,

03:42:50.840 | which is more acute, you know,

03:42:52.020 | people have a couple of drinks, they'll feel relaxed,

03:42:53.660 | but then there's this phenomenon of anxiety, you know,

03:42:56.640 | the next day, feeling a little anxious

03:42:59.020 | when they're not drinking.

03:42:59.860 | Whereas it's interesting that many people

03:43:01.940 | who use cannabis for this purpose

03:43:03.820 | are not using it all day long.

03:43:05.700 | They are perfectly able to wait

03:43:07.380 | until the nighttime or evening.

03:43:09.060 | And of course people can wait for their happy hour

03:43:10.900 | for a drink as well, but it's far and away different

03:43:13.780 | than the way we envision something like alcohol use disorder

03:43:16.020 | where somebody discovers that alcohol really helps

03:43:18.460 | with their anxiety and then they're drinking, you know,

03:43:20.640 | maybe one at lunch, maybe a couple at dinner,

03:43:23.000 | and then in the evening to fall asleep at night.

03:43:25.420 | I'm describing extremes here,

03:43:26.740 | but I find your hypothesis to square really well

03:43:29.340 | with the real world observations.

03:43:30.980 | And it's an interesting one.

03:43:32.500 | - There is some evidence to actually support it.

03:43:33.780 | So my buddy, Sachin Patel, who's at Northwestern now,

03:43:36.420 | but he was at Vanderbilt when he did this study.

03:43:39.140 | They basically played with these drugs

03:43:41.740 | that you can use to prevent endocannabinoid synthesis.

03:43:44.100 | So you can create a state of like

03:43:46.220 | impaired endocannabinoid function.

03:43:48.660 | - In humans.

03:43:49.500 | - And they did this in rodents.

03:43:50.860 | So this was done in mice and they basically,

03:43:52.540 | but one of the questions was is,

03:43:54.680 | so A, does like, you know,

03:43:56.940 | reductions in endocannabinoid function

03:43:58.580 | produce states of anxiety?

03:43:59.940 | And they did demonstrate that.

03:44:01.620 | So you could deplete endocannabinoid levels

03:44:03.420 | and you got the emergence of an anxiety state.

03:44:05.580 | So then you could give drugs

03:44:06.540 | that would boost the endocannabinoids to normalize this.

03:44:09.940 | So again, it kind of fit with the idea,

03:44:11.380 | but then they did one key study where then they gave THC

03:44:14.340 | and saw could THC fill in the gap?

03:44:16.700 | And they found that like boosting endocannabinoids,

03:44:19.100 | giving THC on a background of low endocannabinoids

03:44:21.900 | was able to reverse that anxiety phenotype

03:44:25.260 | and bring it back into more of the normal range.

03:44:27.060 | So again, maybe for some people,

03:44:30.020 | this is if this, again, this is theoretical.

03:44:32.060 | So I don't know how much of a spectrum there is

03:44:34.100 | if there are people that are at this low end,

03:44:35.500 | but certainly I think from the animal literature,

03:44:37.920 | there's some foundation for making a theory

03:44:39.800 | that's similar to what you're saying,

03:44:40.820 | which is maybe some people are trying to fill in a gap

03:44:44.260 | of something that's deficient in them

03:44:45.820 | and therefore that can help them feel less anxious.

03:44:48.420 | And that again, may be very different

03:44:50.300 | than someone who is like, you know,

03:44:52.740 | very anxious for different reasons

03:44:54.100 | or has normal endocannabinoid function

03:44:55.500 | or something else might be at play there.

03:44:56.880 | So- - Very interesting.

03:44:58.340 | - Yeah, I think I could explain some of the heterogeneity

03:45:00.520 | that exists out there for sure, yeah.

03:45:01.940 | - So perhaps genetic differences

03:45:03.700 | in sort of baseline levels of anxiety,

03:45:06.140 | perhaps map to endogenous levels of anandamide

03:45:09.040 | and might predict propensity for THC use.

03:45:11.820 | - Yeah, I mean, we have definitely found

03:45:14.140 | in human populations through work I've done

03:45:15.940 | with a lot of clinical collaborators and others,

03:45:18.140 | like, you know, we look at endocannabinoids in the blood

03:45:21.100 | and it's not in the brain,

03:45:22.300 | but they are lipids that can move

03:45:23.940 | pretty easily back and forth.

03:45:25.420 | And we have found relationships

03:45:27.600 | between peripheral endocannabinoid levels

03:45:29.420 | and mood states, both anxiety

03:45:31.460 | and kind of depressive measures,

03:45:33.300 | which does, you know, somewhat relate to the possibility

03:45:38.100 | that this could be real, we don't know.

03:45:40.860 | It's been hard obviously for various reasons

03:45:43.420 | to really track this,

03:45:44.260 | but we've never looked at an anxiety disorder population.

03:45:47.060 | We've done some work with post-traumatic

03:45:48.600 | stress disorder populations.

03:45:50.220 | There's been work in depression populations

03:45:51.780 | that have found some relationships that are pretty similar.

03:45:53.660 | So it's certainly a possibility,

03:45:56.300 | but again, this is all like our theory at this point.

03:45:58.700 | So we'll see as things kind of move forward

03:46:00.500 | if they pan out, but yeah.

03:46:02.380 | - Fantastic, and I really appreciate

03:46:04.460 | that you're able to share some of what your laboratory

03:46:06.460 | is working directly on now and looking into the future.

03:46:09.360 | And I want to thank you for what has been

03:46:13.540 | an incredibly clear, precise, and in many cases actionable,

03:46:18.540 | whether or not it leads to a yes or a no,

03:46:20.840 | actionable information here, because cannabis and CBD,

03:46:26.220 | as you pointed out, are kind of everywhere around us.

03:46:29.940 | And people are making decisions about cannabis and CBD.

03:46:34.860 | And I also want to thank you because

03:46:38.260 | what initially started off as a bit of a confrontation

03:46:40.900 | online, which I alluded to in the introduction

03:46:43.380 | that I gave, has now evolved into a collaboration

03:46:46.700 | that I'm certain based on the exquisitely clear

03:46:50.460 | and generous information that you've provided

03:46:53.220 | has led to better education, more clarity,

03:46:56.860 | and therefore better informed choices

03:46:58.820 | for all the people listening and watching.

03:47:00.380 | So I really, truly appreciate you coming out here,

03:47:03.500 | sitting down with me, discussing these issues,

03:47:05.840 | clarifying points that were unclear before,

03:47:09.580 | and also pointing to the fact that this is a complex system,

03:47:14.100 | a complex biology.

03:47:15.440 | There are a lot of things about psychosis,

03:47:18.780 | about negative effects, about potential positive uses

03:47:22.820 | of cannabis that just are not yet clear.

03:47:25.740 | And thanks to excellent researchers like you

03:47:28.860 | are likely going to be clarified in the years to come.

03:47:31.440 | So thank you ever so much for your time, for your research,

03:47:35.860 | and for your attention to the public health education effort

03:47:39.140 | around cannabis.

03:47:40.140 | - Thanks, and I think it's also important,

03:47:41.860 | I think it's good as you had said that like,

03:47:44.540 | for people to see that scientists can have disagreements,

03:47:47.820 | I think it's important.

03:47:49.220 | I think it's good that you kind of provided me

03:47:51.820 | an opportunity to correct the record

03:47:53.780 | and did so in a very appropriate manner.

03:47:57.540 | I think this was a great discussion

03:47:58.940 | for people to understand, different perspectives,

03:48:02.420 | also good to highlight where it was that I had had issue

03:48:07.720 | with your previous podcast.

03:48:09.360 | And I think the discussions that came out of that

03:48:11.640 | were for the better, so that's all the best.

03:48:14.120 | And hopefully if there's other contentious issues

03:48:16.760 | that happen down the road, similar things, move forward

03:48:19.400 | and you chat with people in that area as well, yeah.

03:48:21.540 | - Yeah, if somebody who is expert in a particular area

03:48:24.560 | takes issue with something specific

03:48:26.160 | and can substantiate it with something

03:48:27.960 | that can foster better understanding,

03:48:30.920 | without fail, I'll reach out to them.

03:48:33.520 | Now, how quickly we're able to get them here, et cetera,

03:48:36.920 | is always an issue.

03:48:37.920 | Sometimes we can put an addendum to a podcast.

03:48:41.160 | Nowadays, that's easier using what's called

03:48:44.000 | dynamic insertion, where we can go back

03:48:45.680 | and actually make a correction.

03:48:47.080 | But listen, the best situation is always when

03:48:49.920 | this podcast can mimic the real world of research science

03:48:53.600 | as you and I both know it to exist,

03:48:55.080 | where if we had been in a meeting and you presented data,

03:48:58.160 | I presented data and we disagreed,

03:48:59.900 | what we would probably do would be to head,

03:49:01.920 | well, traditionally it would be to the bar,

03:49:03.400 | but we'd grab a cup of coffee or go for a walk

03:49:05.360 | and we would talk about it, hash it out,

03:49:08.080 | and then potentially bring it up again at the next meeting.

03:49:11.720 | So in some sense, what we've done here

03:49:13.540 | over the last month or so,

03:49:15.160 | and certainly during today's podcast,

03:49:17.280 | is to do something to that effect.

03:49:20.200 | - And I think it's really good for people in the public

03:49:21.980 | to know this is how science progresses.

03:49:24.080 | This is, you know, someone says something,

03:49:26.140 | someone disagrees with it,

03:49:27.280 | you get an opportunity to clarify things.

03:49:29.120 | And I think that that's really good

03:49:31.480 | just to move things forward.

03:49:32.440 | So I think that was a good process that we've gone through.

03:49:36.080 | - Yeah, likewise.

03:49:36.960 | And it's certainly within the spirit of the podcast.

03:49:38.720 | In no way, shape or form do I purport

03:49:41.520 | to get everything right and where I've made mistakes,

03:49:43.760 | I really strive to correct them.

03:49:45.480 | And listen, it's been a real honor

03:49:47.640 | and privilege to have you out here.

03:49:49.060 | Thanks for coming all the way from Canada.

03:49:51.360 | And I do hope to have you back again

03:49:53.640 | as the research evolves

03:49:55.080 | and we can learn more about these topics and more.

03:49:57.640 | So thank you so much, Matt, appreciate you.

03:49:59.600 | - Great.

03:50:01.020 | - Thank you for joining me for today's discussion

03:50:02.840 | about cannabis with Dr. Matthew Hill.

03:50:05.160 | I hope you found the discussion

03:50:06.420 | to be as informative as I did.

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03:50:20.360 | you can leave us up to a five-star review.

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03:50:29.200 | If you have questions for me

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03:50:35.520 | please put those in the comment section on YouTube.

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03:50:39.880 | For those of you that haven't heard,

03:50:41.000 | I have a new book coming out.

03:50:42.200 | It's my very first book.

03:50:43.840 | It's entitled "Protocols,

03:50:45.240 | An Operating Manual for the Human Body."

03:50:47.360 | This is a book that I've been working on

03:50:48.560 | for more than five years,

03:50:49.700 | and that's based on more than 30 years

03:50:52.040 | of research and experience.

03:50:53.560 | And it covers protocols for everything from sleep

03:50:56.640 | to exercise, to stress control,

03:50:59.120 | protocols related to focus and motivation.

03:51:01.560 | And of course, I provide the scientific substantiation

03:51:04.960 | for the protocols that are included.

03:51:07.040 | The book is now available by presale at protocolsbook.com.

03:51:10.920 | There you can find links to various vendors.

03:51:13.280 | You can pick the one that you like best.

03:51:15.080 | Again, the book is called "Protocols,

03:51:16.840 | An Operating Manual for the Human Body."

03:51:19.420 | If you're not already following me on social media,

03:51:21.560 | I am @hubermanlab on all social media channels.

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03:51:29.680 | And on all those platforms,

03:51:31.120 | I discuss science and science-related tools,

03:51:33.320 | some of which overlap with the contents

03:51:34.800 | of the "Huberman Lab" podcast,

03:51:36.240 | but much of which is distinct from the contents

03:51:38.380 | of the "Huberman Lab" podcast.

03:51:39.880 | Again, that's @hubermanlab on all social media channels.

03:51:43.240 | If you haven't already subscribed

03:51:44.480 | to our Neural Network newsletter,

03:51:46.500 | our Neural Network newsletter

03:51:47.920 | is a zero-cost monthly newsletter

03:51:49.600 | that includes podcast summaries,

03:51:51.460 | as well as protocols in the form of brief PDFs

03:51:54.120 | of one to three pages,

03:51:55.520 | where I spell out the specific do's,

03:51:57.400 | and in some cases, do nots,

03:51:58.640 | but mostly do's related to things

03:52:00.160 | like how to optimize your sleep,

03:52:02.200 | how to regulate your dopamine levels.

03:52:04.240 | There's a protocol for neuroplasticity and learning,

03:52:07.200 | as well as protocols for fitness,

03:52:09.340 | which we call the foundational fitness protocol,

03:52:11.200 | includes everything sets, reps, cardiovascular training.

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03:52:25.000 | Thank you once again for joining me

03:52:26.340 | for today's discussion with Dr. Matthew Hill.

03:52:28.880 | And last, but certainly not least,

03:52:30.920 | thank you for your interest in science.

03:52:33.020 | (upbeat music)

03:52:35.600 | (upbeat music)

Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks

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