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

0:00:04 Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools
0:00:07 for everyday life.
0:00:13 I’m Andrew Huberman, and I’m a professor of neurobiology and ophthalmology at Stanford
0:00:15 School of Medicine.
0:00:17 My guest today is Dr. Matthew Hill.
0:00:23 Dr. Matthew Hill is a professor of cell biology and anatomy at the University of Calgary.
0:00:28 His laboratory studies cannabis and its effects on stress, its effects on feeding, and its
0:00:33 effects on the behavioral impacts of cannabis exposure at different stages of development.
0:00:37 The origin of today’s podcast episode is a bit unique, so I’d like to share a little
0:00:39 bit of that background with you.
0:00:44 Previously, I did a solo episode of the Huberman Lab Podcast about cannabis, the biology of
0:00:48 cannabis, some of its medical applications and uses, as well as some of its potential
0:00:49 harms.
0:00:53 That episode came out several years ago now, and remains a very popular episode.
0:00:57 It’s had millions of views and millions of listens.
0:01:03 A few months ago, we posted a clip of that episode to X formerly known as Twitter, and
0:01:08 Dr. Matthew Hill responded to that clip on X with criticism about the specific points
0:01:10 made within that clip.
0:01:15 Most notably, my discussion of the data that cannabis use can in some individuals cause
0:01:16 psychosis.
0:01:21 He also took issue with some of the specific points I made in that clip related to potential
0:01:26 differences in the biology of the effects of different strains of cannabis, most notably
0:01:29 indica versus sativa strains, and a few other points as well.
0:01:33 Now, as somebody who’s been in the field of science for several decades now, I’m very
0:01:38 familiar with the fact that every field, every single field within science, has debates
0:01:42 within it, controversies, and sometimes outright battles.
0:01:43 To me, that’s part of what makes science interesting.
0:01:45 It’s an evolving process.
0:01:49 It’s something for which we should all be very curious to try and understand what we
0:01:53 know, what we don’t know, and try and get to the real answers.
0:01:58 Right off the bat, on X, I invited Dr. Hill onto the podcast, and he accepted the invitation.
0:02:04 So today’s episode is really a unique one in that, first of all, we cover an enormous
0:02:10 amount of biology and clinical data as it relates to cannabis, meaning today’s discussion
0:02:11 is not a debate.
0:02:15 It is really an up-to-date discussion about how cannabis works.
0:02:17 So we talk about THC versus CBD.
0:02:22 We address the question of whether or not indicas versus sativas have different biological
0:02:25 and subjective effects or not.
0:02:29 We, of course, talk about the potential correlation, maybe even causation, between cannabis use
0:02:30 and psychosis.
0:02:32 I think you’ll find that discussion very interesting.
0:02:38 And we talk about how cannabis relates to hunger, to memory, to anxiety, and to the treatment
0:02:39 of anxiety.
0:02:43 I’m certain that given the widespread use of cannabis nowadays, that you’ll find the
0:02:48 discussion to be both an informative and potentially useful one that could help guide
0:02:53 decisions as to whether or not you or other should or should not use or avoid cannabis,
0:02:57 as well as one that can simply inform about this very interesting compound.
0:03:02 And, of course, you’ll learn a lot of neuroscience and biology along the way.
0:03:06 Before we begin, I’d like to emphasize that this podcast is separate from my teaching
0:03:07 and research roles at Stanford.
0:03:11 It is, however, part of my desire and effort to bring zero cost to consumer information
0:03:15 about science and science-related tools to the general public.
0:03:19 In keeping with that theme, I’d like to thank the sponsors of today’s podcast.
0:03:21 Our first sponsor is AteSleep.
0:03:25 AteSleep makes smart mattress covers with cooling, heating, and sleep tracking capacity.
0:03:30 I’ve spoken many times before on this podcast about the critical need to get sleep, both
0:03:32 enough sleep and enough quality sleep.
0:03:35 Now one of the key things to getting a great night’s sleep is that your body temperature
0:03:40 actually has to drop by about one to three degrees in order for you to fall and stay
0:03:41 deeply asleep.
0:03:45 And to wake up feeling refreshed, your body temperature actually has to increase by about
0:03:47 one to three degrees.
0:03:50 One of the best ways to ensure all of that happens is to control the temperature of your
0:03:52 sleeping environment.
0:03:54 And with AteSleep, it’s very easy to do that.
0:03:57 You program the temperature that you want at the beginning, middle, and the end of the
0:04:00 night, and that’s the temperature that you’re going to sleep at.
0:04:01 And it will track your sleep.
0:04:04 It tells you how much slow wave sleep you’re getting, how much rapid eye movement sleep
0:04:06 you’re getting, which is critical.
0:04:10 And all of that also helps you dial in the exact parameters you need in order to get
0:04:12 the best possible night’s sleep for you.
0:04:15 I’ve been sleeping on an AteSleep mattress cover for well over three years now, and it
0:04:19 has completely transformed my sleep for the better.
0:04:23 AteSleep recently launched their newest generation pod cover, the Pod 4 Ultra.
0:04:27 The Pod 4 Ultra cover has improved cooling and heating capacity, higher fidelity sleep
0:04:32 tracking technology, and the Pod 4 cover has snoring detection that will automatically
0:04:36 lift your head a few degrees to improve airflow and stop your snoring.
0:04:41 If you’d like to try an AteSleep mattress cover, you can go to atesleep.com/huberman
0:04:44 to save $350 off their Pod 4 Ultra.
0:04:50 AteSleep currently ships to the USA, Canada, UK, select countries in the EU, and Australia.
0:04:53 Again, that’s atesleep.com/huberman.
0:04:56 Today’s episode is also brought to us by Element.
0:05:00 Element is an electrolyte drink that has everything you need and nothing you don’t.
0:05:05 That means the electrolytes, sodium, magnesium, and potassium in the correct ratios, but no
0:05:06 sugar.
0:05:10 Now, I and others on the podcast have talked a lot about the critical importance of hydration
0:05:12 for proper brain and bodily function.
0:05:16 Research shows that even a slight degree of dehydration can really diminish cognitive
0:05:18 and physical performance.
0:05:21 It’s also important that you get adequate electrolytes in order for your body and brain
0:05:23 to function at their best.
0:05:27 The electrolytes, sodium, magnesium, and potassium are critical for the functioning of all the
0:05:30 cells in your body, especially your neurons or nerve cells.
0:05:33 To make sure that I’m getting proper amounts of hydration and electrolytes, I dissolve
0:05:38 one packet of element in about 16 to 32 ounces of water when I wake up in the morning, and
0:05:40 I drink that basically first thing in the morning.
0:05:44 I also drink element dissolved in water during any kind of physical exercise I’m doing,
0:05:48 especially on hot days if I’m sweating a lot and losing water and electrolytes.
0:05:56 If you’d like to try Element, you can go to drinkelement.com/huberman, spelled drinklmnt.com/huberman,
0:06:00 to claim a free Element sample pack with the purchase of any Element drink mix.
0:06:05 Again, that’s drinkelement.com/huberman to claim a free sample pack.
0:06:08 Today’s episode is also brought to us by BetterHelp.
0:06:12 BetterHelp offers professional therapy with a licensed therapist carried out entirely
0:06:13 online.
0:06:16 There are essentially three things that make up great therapy.
0:06:19 First of all, great therapy consists of having good rapport with somebody that you can really
0:06:22 trust and talk to about the issues that you’re dealing with.
0:06:27 Second of all, that therapist should provide support in the form of emotional support or
0:06:29 directed guidance.
0:06:33 And third, expert therapy should provide useful insights, insights that allow you to better
0:06:37 understand not just your emotional life and your relationship life, but of course also
0:06:42 your relationship to yourself and to career goals and school goals, meaning excellent
0:06:45 therapy should also inspire positive action.
0:06:49 BetterHelp makes it very easy for you to find an expert therapist with whom you really resonate
0:06:52 with and that can provide the benefits that I just described.
0:06:57 Also because BetterHelp therapy is done entirely online, it’s very time efficient and it’s
0:07:01 easy to fit into a busy schedule because it involves no commuting to a therapist’s office,
0:07:04 finding a parking spot, or sitting in a waiting room.
0:07:09 If you’d like to try BetterHelp, you can go to betterhelp.com/huberman to get 10% off
0:07:10 your first month.
0:07:14 Again, that’s betterhelp.com/huberman.
0:07:17 And now for my discussion with Dr. Matthew Hill.
0:07:18 Dr. Matt Hill, welcome.
0:07:20 Thanks for having me.
0:07:26 Delighted to have you here because you’re an expert in the biology of cannabis, a topic
0:07:32 that many, many people are curious about for a variety of reasons.
0:07:38 So just to kick things off, maybe we can get people up to speed on what cannabis is, a
0:07:42 little bit about how it works in the brain and body to produce the various effects that
0:07:45 it produces, and how some of that comes to be.
0:07:47 And then we can dig into some of the nuance.
0:07:52 I have a lot of questions about different types, if you will, of cannabis, the relationship
0:07:55 to mental health, potentially to mental illness.
0:07:57 We’re going to drill into all of that.
0:07:59 So just to kick things off, what is cannabis?
0:08:03 I mean, cannabis is a plant that has been around for some time.
0:08:09 It’s kind of got like a very rich history of use around the world for different cultures,
0:08:16 for both kind of medicinal and spiritual and recreational purposes over several centuries.
0:08:21 The plant has kind of become, I mean, in the West, it really wasn’t a thing mainstream-wise
0:08:26 until about the ’60s, and then it became kind of introduced as like a drug of choice that
0:08:30 a lot of people started using during the rise of the hippie era, and I think that was a
0:08:33 lot of the time that cannabis got popularized.
0:08:38 And then I’d say more recently cannabis has, into the ’90s and on, has become kind of a
0:08:44 very heavily used drug by a large swath of people ranging from teenagers on up.
0:08:48 In terms of what it is inside it, I mean, it’s a plant with a lot of very complex chemistry
0:08:49 and biology behind it.
0:08:52 So there’s a lot of molecules that it carries in it.
0:08:57 We call these cannabinoids, and they come in a lot of different flavors, but the main
0:09:02 one that’s the most important one when we talk about cannabis and what drives the kind
0:09:07 of intoxicating, and what I would refer to as psychoactive effects of cannabis is Delta
0:09:11 9 tetrahydrocanabinol, or what we call THC.
0:09:15 And that really is what dictates, you know, the psychoactive and intoxicating properties
0:09:16 of the plant.
0:09:22 The amount of THC that is within the cannabis plant will influence the, you know, how high
0:09:24 a person is going to get when they consume it.
0:09:30 There are probably 70 to 100 in some odd other cannabinoids that are within cannabis.
0:09:35 Most of them are pretty trace levels, like, and they vary from different types to cannabis
0:09:37 from one another.
0:09:40 But the other one that’s had a lot of attention is cannabidiol, or what we call CBD.
0:09:46 CBD is structurally looks pretty similar to THC, but doesn’t behave anything like THC.
0:09:49 It’s not intoxicating at all.
0:09:53 I’m not sure, I would probably say it’s not psychoactive in the sense that people can’t
0:09:55 tell if they’re on it or not.
0:10:00 But I would, some people still say it’s psychoactive because people claim, you know, it can affect
0:10:02 anxiety state or mood state or other things.
0:10:09 So in that context, maybe psychoactive is still somewhat appropriate of a word to use.
0:10:12 And then there’s a whole bunch of other things like cannabinol, cannabigerol, and these other
0:10:13 minor cannabinoids.
0:10:16 Most of which, we really don’t understand any of the biology.
0:10:18 We don’t know what they’re doing.
0:10:22 They may influence some of the effects of THC, they may not.
0:10:26 But they’re there, and they vary in their composition from, you know, different flavor
0:10:28 of different cannabis to different flavor.
0:10:32 And then there’s those other things called terpenes, which are kind of highly volatile
0:10:36 compounds, but they’re not specific to cannabis, they’re found in tons of other plants.
0:10:40 So this is a lot of which seems to contribute at least to some of the smell and the flavors
0:10:41 of cannabis.
0:10:46 There’s things like limonene, which, you know, gives some cannabis kind of a citrusy
0:10:51 odor or flavor to it, pineene, which gives things more of like a earthy tree kind of
0:10:58 smell, beta cariophiline, mersine, and these terpenes are also some of which do have known
0:11:00 biological activity, some don’t.
0:11:03 And they vary quite heavily across different kinds of cannabis as well.
0:11:08 And again, there’s some thought that they may be influencing some of the psychoactive
0:11:13 or intoxicating properties of cannabis, but the reality is we really don’t know a lot
0:11:14 about them at this point.
0:11:17 There’s kind of some emerging work that’s starting to come out now that kind of plays
0:11:24 with, you know, giving someone THC and adding in one other terpene or one other minor cannabinoid
0:11:25 and seeing how it influences things.
0:11:31 And so you can imagine with the plethora of molecules that exist in cannabis, doing this
0:11:36 in a piecewise manner could take decades to kind of really get to a point where we understand
0:11:41 all the interactive components of cannabis, but people tend to refer to this as like an
0:11:42 entourage effect.
0:11:46 That’s kind of a phrase that gets used quite widely in the cannabis world.
0:11:52 And the idea behind that is that if you took pure THC, and so there are some like distillate
0:11:56 pens and things that exist out there now in the product market, which are basically isolated
0:12:00 THC with trace levels of anything of other stuff, would be very different than if you
0:12:05 had THC in combination with some of these other molecules and how they might influence
0:12:08 how THC itself is working or not.
0:12:12 Fascinating plant.
0:12:15 You mentioned the psychoactive effects.
0:12:19 Some people listening to this and watching this presumably have experienced those psychoactive
0:12:20 effects.
0:12:22 Others perhaps have not.
0:12:28 How could we describe for both groups what the quote unquote psychoactive effects are?
0:12:34 You mentioned the higher the concentration of THC, the quote unquote higher someone will
0:12:35 get.
0:12:38 The higher the intensity of the high.
0:12:40 What is the high?
0:12:45 And I know people are probably chuckling saying does Heberman not know because he’s never
0:12:46 done it?
0:12:47 I mean, that’s my own business.
0:12:49 I just want people to understand what you mean by psychoactive effects.
0:12:54 So, I mean, the way that people would usually describe the intoxicating effects of cannabis
0:12:59 is they would, I mean, people often refer to it as they’re being some euphoria or some
0:13:00 positive mood.
0:13:04 Not on the same order as what people would describe with say cocaine or some other stimulants,
0:13:07 but there certainly is some kind of positive aspect.
0:13:09 I mean, if there wasn’t, people wouldn’t be using it.
0:13:13 If they didn’t feel positive about it afterwards.
0:13:19 There can be, you know, other aspects in terms of changes in feeding behavior.
0:13:21 People might find things funnier than they found things that might change the way they
0:13:25 perceive various environmental stimuli.
0:13:29 But it can also, for some people, create a bit of a dissociative state to some degree
0:13:32 where people might feel a little bit out of body.
0:13:38 So, it’s kind of a complicated intoxicating state to describe, I would say, because usually
0:13:41 if someone’s referring to something like a stimulant, they’re just like, oh, people feel
0:13:42 like they’re God.
0:13:44 They’re like, you know, jacked up.
0:13:45 Possibility everywhere.
0:13:46 Yeah, exactly.
0:13:48 Like they’re very happy and they’re kind of jacked up.
0:13:51 And I think with cannabis, the way people would describe it would be very different.
0:13:53 It’s like kind of an introspective state.
0:13:58 You might be more aware of your bodily feelings and states that are going on inside of you.
0:14:00 You’re kind of internal state.
0:14:03 But you also have a different perspective on external stimuli.
0:14:06 You might process information a bit differently, focus on things a bit differently.
0:14:10 So it’s kind of a complicated state to describe, I would say.
0:14:15 Usually when people are assessing, if someone’s intoxicated, the kind of lab work where people
0:14:19 get someone high, they just kind of use what we call a visual analog scale, which is like
0:14:24 a one to a hundred or something, or zero to a hundred and say, do you feel high?
0:14:25 Do you enjoy this?
0:14:27 Would you say you feel euphoric?
0:14:28 Is your mood elevated?
0:14:29 So they’re kind of scaling things like that.
0:14:33 So I think that’s more typically in a lab setting, how you would define if someone’s
0:14:35 high or not from it.
0:14:39 And this is why when people do studies with something like a placebo cannabis or a very
0:14:42 low THC cannabis, you’ll see kind of a scaling.
0:14:47 So even if you give someone a placebo cannabis, if they think that they’re getting cannabis,
0:14:49 a lot of people still respond by saying they feel a bit high.
0:14:50 That’s interesting.
0:14:54 Is that true even if they’ve never used cannabis before?
0:14:59 I’m not actually certain if you are allowed to have someone in a drug study if they’ve
0:15:01 never done something before.
0:15:04 I think they have to have had some previous experience with a drug.
0:15:05 And they pay you.
0:15:08 So now pot smokers everywhere are running to look at stuff.
0:15:11 Yeah, but I think, yeah, I don’t think you can use drug naive people.
0:15:15 I mean, I don’t run human clinical lab studies, so I can’t explicitly say it, but that’s my
0:15:19 understanding is that someone has to have had even limited, like, you know, not much,
0:15:20 but at least once or twice.
0:15:22 They have to have experienced the drug before.
0:15:26 So I don’t know if you would take someone who is completely blind because I don’t know
0:15:31 how they would replicate that state if they’re not expecting it.
0:15:36 What about the effects of cannabis on time perception?
0:15:42 You know, there’s this reputation that cannabis has for disrupting time perception that people
0:15:47 will think a long period of time has passed when in fact very little time has passed.
0:15:50 Maybe it’s sometimes even the reverse.
0:15:54 Is the mechanism by which cannabis can adjust time perception known?
0:15:57 I wouldn’t say it’s well worked out.
0:16:00 There definitely seems to be some, like, temporal dilation, like you’re saying, where people
0:16:04 think things have, you know, someone will be high and someone will ask them how long
0:16:05 do you think time has passed.
0:16:10 They would report usually longer periods of time have passed than I actually have.
0:16:14 I feel like there is some older work I could dig up to see if I could find that is either
0:16:18 in like it might even be in pigeons, but it might be in rodents that’s looking at like
0:16:22 temporal ordering and they give animals cannabinoids and that’s kind of a cleaner way of seeing
0:16:26 because they are very good at learning like if I wait 10 minutes and then I engage in
0:16:28 a behavior I get a reward.
0:16:32 And so you can really train animals to have this ordinal timing where they kind of know
0:16:34 distinct periods of time.
0:16:36 And if they give them cannabinoids, they respond differently.
0:16:42 So in that context, it does still seem to produce some state where there’s an altered perception
0:16:43 of time passing.
0:16:47 And so I think if we were going to really understand the mechanism of it, that would
0:16:48 probably be the way to go.
0:16:52 But I’m not super familiar with the work because no one’s, I mean, anything I can think of
0:16:53 is pretty old.
0:16:56 I can’t think of anything modern where people have actually looked at this.
0:16:57 Interesting.
0:17:00 You mentioned effects of cannabis on appetite.
0:17:05 And I know one of the medical uses of cannabis is in people that are undergoing treatment
0:17:11 for cancer in order to stimulate appetite because oftentimes they have very low or even
0:17:15 no appetite due to the cancer treatment.
0:17:18 Is the mechanism by which cannabis can stimulate appetite known?
0:17:22 And if so, what is the general trend of effect?
0:17:29 Makes people hungrier, obviously, but we hear again in kind of recreational terms of people
0:17:31 getting the munchies, you know, becoming exceedingly hungry.
0:17:37 Is that related to some cannabis induced effect on say blood sugar, like insulin or glucose
0:17:38 regulation?
0:17:39 Or is it happening at a different level?
0:17:42 I think we almost need to take a step back, actually, to talk about how cannabis works
0:17:45 in the brain before we kind of go into that.
0:17:50 So, THC as a molecule exerts almost all its effects are acting at this one receptor for
0:17:54 the most part that’s widely expressed through the brain called the cannabinoid type one
0:17:55 receptor.
0:17:56 CB1.
0:17:57 Yeah.
0:17:59 CB1 is the shorthand for it.
0:18:04 And I think, you know, as people tend to create analogies to describe what receptors are for
0:18:08 those that you don’t know, most people use like a lock and key analogy that like a receptor
0:18:11 would be a protein that sits on a cell and a molecule that binds to it like THC is the
0:18:13 key that fits in that lock.
0:18:17 When it activates it, it triggers some biological process in the cell, in this case, a neuron
0:18:21 that changes its activity in some capacity.
0:18:26 And so, THC acts on these CB1 receptors, which are very widely expressed, in fact, outside
0:18:29 of like kind of ion channels that are expressed in the brain.
0:18:33 The CB1 is, I think, one of the most, if not the most widely expressed receptor in the brain.
0:18:34 It’s everywhere.
0:18:37 So, it’s really important.
0:18:43 And I think, as kind of you had alluded to previously, it doesn’t exist in the, you know,
0:18:47 this didn’t evolve in humans in the hopes that one day humans would find cannabis.
0:18:48 This is just–
0:18:49 CB1.
0:18:50 Although cannabis users everywhere use that argument.
0:18:51 CB1.
0:18:52 Yeah.
0:18:53 I know people love to leverage things.
0:18:55 If it’s a plant, it’s, you know, it’s natural and safe.
0:18:58 And there’s obviously issues we’ll talk about with that.
0:19:00 But I mean, really, this is just biological redundancy.
0:19:04 I mean, you know, nature only has so many ways to create something.
0:19:08 And so, there’s going to be things that end up overlapping in the way that they function.
0:19:12 And so, the receptor that’s in the brain and throughout the body, the CB1, and there is
0:19:16 also a CB2 receptor, it’s not really expressed in the brain.
0:19:21 It’s in some of the immune cells in the brain and maybe some limited distribution in actual
0:19:23 brain cell neurons.
0:19:24 Where in the body is it expressed?
0:19:25 It’s mostly immune cells.
0:19:29 So, you’ll see CB2s mostly on like macrophages or other kind of immune cells.
0:19:30 Cells that gobble up debris.
0:19:31 Yeah.
0:19:34 And that basically, you know, regulate inflammatory processes.
0:19:39 And so, the main role of CB2 seems to be much more about like regulating inflammation.
0:19:43 So that’s kind of a separate role that can certainly impact the brain in different ways.
0:19:47 But when we talk about the effects on the central nervous system and the brain and behavior,
0:19:49 we’re talking almost entirely about CB1.
0:19:54 And so, both the CB1 and CB2 receptors, like I said, don’t exist because nature was like,
0:19:57 “Humans are going to find cannabis, though this will all work together now.”
0:20:02 So, there are molecules, our body produces, which we call endocannabinoids.
0:20:07 And they are kind of funny little molecules because they don’t really behave, like certainly
0:20:09 in the brain, they don’t behave like a normal neurotransmitter.
0:20:14 So, I mean, I assume most people who listen to your podcast are relatively adept with
0:20:16 the basic idea of how neurons work.
0:20:21 So you have neuron A, let’s call it the presynaptic neuron, because you have that gap between
0:20:23 the two cells where they communicate called the synapse.
0:20:28 So neuron A releases a transmitter, and it can be something that excites the neighboring
0:20:32 cell, neuron B, or it can inhibit it.
0:20:36 And so, the way that we always kind of talk about neurotransmission in the brain is neuron
0:20:42 A releases a chemical that crosses the synapse, acts on neuron B, and it can either jack that
0:20:44 neuron’s activity up or it can scale it down.
0:20:48 And that affects brain-wide patterns of activity.
0:20:52 And we call that anterograde because it moves from neuron A to neuron B, which is kind of
0:20:56 the general flow of things and how we usually think about it.
0:21:01 So, endocannabinoids are kind of this little bit of an oddity in the sense that they could
0:21:02 do the reverse.
0:21:06 And so, endocannabinoids are actually made in neuron B on the postsynaptic side, and
0:21:11 then they go backwards and act on neuron A to regulate how much transmitter is released.
0:21:15 And so, in many ways, this is like, I kind of liken it to a thermostat model for the
0:21:16 most part.
0:21:18 Certainly, we’re talking about some really excitability.
0:21:23 So if neuron A is dumping out something that excites neuron B, like glutamate, which is
0:21:28 an excitatory neurotransmitter, as neuron B gets too excited, it’s going to start releasing
0:21:32 endocannabinoids to go back and tell neuron A to stop driving it.
0:21:35 So sort of a homeostatic scale and trying to maintain a middle range.
0:21:36 Yeah.
0:21:39 I mean, at the end of the day, no matter how you discuss it and what system you discuss
0:21:44 it, I think the majority of people in the cannabinoid field would agree that the primary
0:21:47 physiological role of endocannabinoids is to maintain homeostasis.
0:21:48 That’s what they do.
0:21:51 They keep everything in its happy place, let’s say.
0:21:56 And that’s probably why the CB1 receptor is so widely distributed is that neurons can
0:22:01 excite or inhibit each other, that is, raise or reduce the amount of electrical activity
0:22:05 in the, let’s say, nearby neuron, because we’re talking about retrograde signaling.
0:22:10 But ultimately, you don’t want runaway excitation, because that looks like epilepsy.
0:22:16 And you don’t want runaway inhibition, because that looks like suppression of ability to
0:22:17 think, move, et cetera.
0:22:18 Exactly.
0:22:19 Okay.
0:22:20 So you want to keep things in where they should be.
0:22:23 And so you want neurons to get excited, but you don’t want them to get overexcited.
0:22:27 And so endocannabinoids in kind of a very prototypical sense act is this circuit breaker, essentially,
0:22:30 where they go back and gate how much is coming in.
0:22:35 And they do this by, through various mechanisms, essentially turning off the electrical activity
0:22:39 of that presynaptic neuron so that it stops releasing neurotransmitter.
0:22:44 They can also regulate, though, inhibitory neurotransmitter release as well.
0:22:48 And this is usually done through a little bit more of a complex process where it’s driven
0:22:51 by excitation, but then it regulates the inhibitory pathway.
0:22:54 So inhibiting the inhibitor leads to more excitation.
0:22:55 Exactly.
0:22:58 I usually liken it to basically taking the brakes off of a car while you’re going downhill
0:22:59 kind of thing.
0:23:02 Like you’re, you know, you use your braking system to keep things in check, but if you
0:23:05 want to go faster, you take the foot off the brakes and you let things accelerate.
0:23:12 And so this can be really important for things like forms of synaptic plasticity or neuroplasticity,
0:23:15 let’s say, where you want synaptic strengthening to happen.
0:23:20 So like under a learning event or something, you want that synapse to really hardwire better.
0:23:24 And so having endocannabinoids kind of turn off the inhibitory component is one of the
0:23:26 mechanisms to facilitate that.
0:23:31 But at the same time, if you want to have a bit more adaptive flexibility, endocannabinoids
0:23:36 can weaken that synapse at the same time by acting right at the excitatory terminal itself.
0:23:41 And so their ability to kind of play with the relative activity of a circuit is really
0:23:43 dependent on which neuron they’re acting on.
0:23:47 And so they can regulate excitation or inhibition differentially.
0:23:54 And I mean, CB1 receptors are found on virtually every single kind of neuron in the brain,
0:23:55 except one.
0:23:58 I think you’ll find this interesting because it’s dopamine.
0:24:03 And dopamine neurons are basically the only neurons in the brain that don’t really, at
0:24:07 least as far as we’ve been able to characterize the date, express cannabinoid receptors.
0:24:08 Interesting.
0:24:14 So if I may, earlier you mentioned one of the potential psychoactive effects of cannabis
0:24:15 is euphoria.
0:24:20 Does that mean that the euphoria associated with cannabis use is independent of dopamine
0:24:26 and is more reliant on something like perhaps the opioid receptor system or the serotonergic
0:24:27 receptor system?
0:24:32 So, yeah, I wouldn’t say that cannabinoids don’t affect dopamine because what we understand
0:24:37 in the ventral tegmental area, which is kind of a hotspot of dopamine neurons, or at least
0:24:43 the ones that are involved in motivation and stuff, those neurons are regulated by a lot
0:24:47 of inhibitory neurons that dump out inhibitory transmitter and keep those neurons kind of
0:24:48 quiet.
0:24:49 So there’s an opportunity for indirect.
0:24:50 Exactly.
0:24:53 So what you have is those neurons that regulate the dopamine neurons are very rich in cannabinoid
0:24:54 receptors.
0:24:58 This is actually kind of similar to how mu opioid receptors work for things like morphine
0:25:00 or heroin.
0:25:02 And essentially what the cannabinoid receptors will do is when they’re activated, they’ll
0:25:05 turn off that inhibitory control.
0:25:08 And that allows dopamine neurons to kind of move into a state where they’re more prone
0:25:11 to go into burst firing and have big dumps of dopamine.
0:25:16 Whether or not that relates to the positive affect or the euphoria, I don’t think anyone
0:25:18 has cleanly demonstrated that.
0:25:23 I mean, obviously, dopamine’s very complicated in terms of its relation to endpoints and
0:25:25 whether it’s reward or motivation.
0:25:28 But cannabinoids definitely do have an influence on dopamine transmission.
0:25:30 They just don’t tend to do it directly.
0:25:35 And I think that’s this very bizarre and interesting component of cannabinoid signaling
0:25:39 is why the brain would have evolved in a way to allow every other neurotransmitter system
0:25:44 to be actively and directly regulated by endocannabinoids, but dopamine is kind of spared from this.
0:25:46 So I don’t know.
0:25:49 And no one, I mean, obviously, you can always just theoretically guess as to why someone
0:25:50 would do that.
0:25:53 I don’t know what the reason for it would be, but it is something that has kind of intrigued
0:25:57 a lot of people because every other system in the brain is so tightly controlled to some
0:26:02 degree by endocannabinoids, and then this one circuit is kind of free of it.
0:26:07 But yeah, so the main role of endocannabinoids is really to regulate plasticity or homeostasis,
0:26:11 allow flexibility of circuits to either goose up their activity or ramp it down if they
0:26:15 need to, depending on the environment, depending on the experience of the organism.
0:26:19 So there’s a lot of kind of roles that endocannabinoids play in that domain.
0:26:24 But even within the endocannabinoids, I mean, there’s two primary endocannabinoids.
0:26:28 And again, this is one of the weird things about how endocannabinoids work, because if
0:26:34 you talk about things like serotonin or dopamine, you have a single molecule that gets released
0:26:38 in the typical anterograde way, and it diversifies at the level of a receptor.
0:26:43 So serotonin has like, I don’t know, like 15 receptors or 20 or something, no.
0:26:45 Dopamine has at least five.
0:26:49 And so the different actions that serotonin or dopamine will have is all driven by the
0:26:50 diversification of the receptors.
0:26:53 It’s one molecule, whereas cannabinoids are the reverse.
0:26:57 Not only do they work backwards across the synapse and work in this retrograde fashion,
0:27:00 but really you have one receptor that is regulated by two molecules.
0:27:05 So the diversification happens more at the level of the molecule then at the receptor,
0:27:07 which is, again, very unique.
0:27:11 And the two molecules that we know are kind of the bona fide endocannabinoids, there could
0:27:12 be more.
0:27:18 They’re called anandamide, which is actually kind of a funny name because it comes from
0:27:21 the Sanskrit word anand for bliss.
0:27:29 And so Rafi Mishulim, who was in Israel when he discovered the molecule 30 odd years ago,
0:27:31 wanted it to reflect inner bliss.
0:27:32 And so he named it anandamide.
0:27:35 So it’s like inner bliss with an amide bond is kind of the joke he had for it.
0:27:40 And so he discovered anandamide and decided to call it bliss because he had familiarity
0:27:45 with cannabis or because he took anandamide as a direct experience.
0:27:46 No, no, I mean–
0:27:49 He takes a lot for a scientist to discover a molecule, but then for a scientist to discover
0:27:55 a molecule and then name it bliss for a particular reason, you have to speculate that they had
0:27:56 some familiarity with the compound.
0:28:00 Rafi Mishulim was also the guy who isolated and discovered THC.
0:28:03 So I mean, he has a very– he’s kind of the grandfather of a whole cannabinoid field.
0:28:09 So he has a landmark paper from 1964, which ironically– and this is one of these weird
0:28:10 pop culture things.
0:28:11 I don’t know if this is true.
0:28:14 That paper was published on April 20, 1964.
0:28:17 And so the joke is, is this where 420 came from?
0:28:22 It was the original birth date of the first THC paper was 420, 1964.
0:28:28 Well, now that potential myth is definitely going to propagate.
0:28:32 But yeah, so he had been in the field for a while, and so he had studied cannabis on
0:28:33 that side.
0:28:38 And then in 1990, his lab isolated anandamide as being the first molecule that activated
0:28:39 the receptor endogenously.
0:28:44 And so it was kind of– yeah, I think it was a little tongue-in-cheek that he named it
0:28:45 the way he did.
0:28:49 A few years later, the second molecule, which is just called two-aractonal glycerol, or
0:28:53 what we call 2-AG, that was discovered kind of in tandem, both again by Michoulin, but
0:28:56 also by a Japanese group.
0:28:59 And so we understand these two molecules don’t do the same thing.
0:29:00 Like, they are a bit different.
0:29:06 So the way anandamide binds the receptor is– it’s what we would call a high affinity,
0:29:09 but low efficacy agonist, or molecule at least.
0:29:14 And what I mean by that is very low levels of anandamide are required to actually bind
0:29:15 to the receptor.
0:29:20 But once it binds, its ability to stimulate a biological response in that neuron kind
0:29:21 of caps out pretty fast.
0:29:29 So it doesn’t have like a sledgehammer effect, whereas 2-AG seems to require a bit more concentration
0:29:33 in the synapse to be able to bind to the receptor, so it has a lower affinity for the receptor.
0:29:37 But once it binds to the receptor, it’s like pretty heavy duty.
0:29:41 So it evokes a very robust intracellular signaling response.
0:29:46 And so why we have two endocannabinoids, we’re not totally sure.
0:29:47 Some of us have theories.
0:29:51 I’m of the camp that I think they may play somewhat differential roles, either based
0:29:56 on the synapse or the circuit that they’re working in, or this idea that maybe anandamide
0:29:58 might be more of a tonic molecule.
0:30:01 And what I mean by that is, we’ll say it’s like a stage setter.
0:30:06 So like anandamide might just be kind of made by neurons on an ongoing basis and just released.
0:30:12 And its job may be to kind of keep the steady state of a brain circuit and a desired range.
0:30:16 So that under resting conditions, it’s not too active or too quiet.
0:30:18 Your thermostat analogy is perfect here.
0:30:23 So in that context, it kind of is like just the thermostat of the house.
0:30:28 Whereas 2-AG is like, let’s say the pinch-hitter, who gets brought in to do the heavy lifting.
0:30:33 And so 2-AG, during a situation like, let’s say, something like even like a seizure is
0:30:37 an extreme example where you have a huge amount of neural activity, those neurons that are
0:30:42 getting heavily activated during massive amounts of neural activity start dumping out huge
0:30:47 amounts of 2-AG and that acts as the, okay, we really need to turn off this circuit very
0:30:49 quickly in this situation.
0:30:53 And in most of these forms of like synaptic plasticity, like I was saying earlier, where
0:30:58 you need to either strengthen or weaken a synapse in response to a change in the environment
0:31:03 or in response to an experience or something that’s going on, most of that is driven by
0:31:04 2-AG signaling.
0:31:10 And so, you know, all these forms of like turning things up or down in a kind of rapid
0:31:13 and on-demand manner, that’s mostly 2-AG.
0:31:19 So most people who study like neurophysiology and like record activity and neurons and look
0:31:24 at endocannabinoids, they’re almost entirely talking about 2-AG when they play with stuff.
0:31:26 So yeah, that’s kind of one of the ways we do it.
0:31:31 We say that anandamide may be more tonic and 2-AG might be more phasic and like brought
0:31:33 online when needed, but doesn’t do a lot.
0:31:37 There is some evidence that 2-AG may also have a role to regulate some circuits under
0:31:38 kind of resting conditions as well.
0:31:44 And there certainly are some situations where anandamide might get brought into play to affect
0:31:49 plasticity, but as kind of like an umbrella idea of how we look at it, that’s often how
0:31:50 we divide those two up.
0:31:54 So we kind of have these two molecules, they end of the day do the same thing.
0:31:59 They’re regulating or transmit a release through retrograde signaling, but what stimulation
0:32:04 brings them online or what drives their activity may differentiate and we don’t really understand
0:32:06 all the details behind that.
0:32:09 Outside of the fact that we very clearly know 2-AG is activity dependent.
0:32:15 So as that neuron becomes more active, it’s going to make 2-AG to regulate its inputs.
0:32:19 So yeah, you have this very complex system and it’s really widely distributed in, you
0:32:22 know, it’s everywhere as a cannabinoid receptors and the endocannabinoid molecules are in the
0:32:26 cortex, they’re in the hypothalamus, they’re in the striatum, the hippocampus, the cerebellum
0:32:27 all over the brain.
0:32:31 Except the one area where it’s really interesting actually, where you don’t really see much
0:32:37 receptor is in brainstem populations that regulate, you know, kind of unconscious cardiac and
0:32:38 respiratory function.
0:32:43 So this is one of the things that really differentiates cannabis from opiates because a lot of the
0:32:48 signaling mechanisms between opioid receptors and cannabinoid receptors are quite similar.
0:32:53 But as it’s been well established, people can overdose and fatally and die from opiates
0:32:54 relatively easily.
0:32:58 And the way that that tends to happen is when you activate the opiate receptors in the kind
0:33:02 of cardiorespiratory parts of the brainstem, it depresses neural activity.
0:33:08 So as the person loses consciousness, they also unconsciously will stop regulating their
0:33:11 own heart and breathing and it can be a fatal response.
0:33:15 Because cannabinoid receptors don’t really exist in those regions, you don’t get the
0:33:21 same kind of impact in terms of suppressing heart rate and breathing function.
0:33:25 And so that’s, I mean, you know, there’s always a saying like there’s never been an account
0:33:29 of someone actually dying from a cannabis overdose or a THC overdose.
0:33:32 I mean, certainly people can do stupid things while they’re intoxicated that result in their
0:33:33 death.
0:33:36 But in the same manner that someone can die from consuming too much opiates, that doesn’t
0:33:41 seem to be physically possible with cannabinoids as far as we’ve seen so far.
0:33:45 And a lot of that is just because of the localization, like for some reason, it’s just not the receptors
0:33:46 in that part of the brain.
0:33:49 So very interesting.
0:33:56 A lot of kind of aficionado questions about the receptor biology, I’ll just spare everyone
0:34:01 the details by just highlighting something that you already said far more eloquently
0:34:06 than I will, which is I think it is fascinating that this whole system has both a tonic, like
0:34:12 a steady release capability and a phasic, you know, so the ability to spike, forgive
0:34:16 the poem, the neuroscientists will know what I’m talking about, to spike more activity
0:34:20 of the system superimposed on that tonic activity, because this is something that you see in
0:34:21 the dopamine system.
0:34:27 This is something that you see in essentially every neuromodulator neurotransmitter system.
0:34:31 But it seems that the endocannabinoid system has accomplished this quite a bit differently.
0:34:38 So very interesting, unique system in a number of ways that raise a number of key questions.
0:34:41 So yeah, if you go back to the munchies question you had.
0:34:45 So if we tie into that, one of the, so there’s a few ways, I mean cannabinoids and feeding
0:34:51 are a really interesting thing, because proto, like if you ask people, like kind of the prototypical
0:34:55 responses to consuming cannabis, most people would usually say munchies is one of the things
0:34:58 that pops up pretty regularly.
0:35:05 And so, you know, the cannabinoid receptors are very, they are expressed in these feeding
0:35:10 circuits in the hypothalamus, and you know, there’s a lot of complex circuitry there that
0:35:12 can regulate food seeking behavior.
0:35:16 And yeah, we just had an episode with Zack Knight from HHMI and UCSF.
0:35:21 We talked about like the AGRP neurons and different neurons of the hypothalamus.
0:35:26 We can link to that in the show note captions nowadays, a rich understanding of the neurons
0:35:32 that stimulate food seeking craving and so we know that like cannabinoids, they regulate
0:35:36 again those inhibitory inputs around AGRP neurons, for example.
0:35:40 And so one thing they can do is disinhibit those AGRP neurons so they become more active
0:35:42 and that can drive food seeking behavior.
0:35:44 So that’s certainly one mechanism of it.
0:35:48 But there’s also a huge reward component to this in terms of the munchies.
0:35:53 And so, we know that like you can also just dump anandamide, for example.
0:35:56 This is, you know, Steve Mahler and Kent Baerge did this work years ago where they just put
0:36:00 anandamide into the nucleus accumbens and that can also stimulate palatable food intake.
0:36:04 So you also have this ability to integrate with the reward circuitry.
0:36:08 And then there was also this fascinating paper from a Japanese group in PNAS, I think
0:36:09 about 12 years ago.
0:36:14 And what they found was they would give a rodent a cannabinoid and then they would stimulate
0:36:16 different taste bud populations.
0:36:19 And then they would look at the gustatory cortical response to stimulating the populations.
0:36:25 And what they found is under the influence of a cannabinoid, if you stimulated sweet
0:36:28 taste buds, you got an enhanced response in the gustatory cortex.
0:36:32 But not if you did salty, bitter, sour, I don’t know if they did umami in that one,
0:36:35 but it was very explicit to sweet tasting.
0:36:41 And so you have this kind of ability to like jack up the way the brain is processing sweet
0:36:42 tasting foods.
0:36:43 You have this engagement of the reward circuitry.
0:36:48 And then you also have this ability to regulate AGRP neurons as well as the POMC neurons.
0:36:54 There’s kind of both sides to that in the, in the arcuate nucleus to regulate multiple
0:36:55 components of feeding.
0:37:00 But a big question is like my lab has become kind of interested in this as well because
0:37:03 we have a component of my lab that studies feeding behavior.
0:37:07 And one of my postdocs has been doing these projects for years now trying to understand
0:37:11 almost like at a behavioral mechanism level, what the munchies are.
0:37:15 And what she’s been looking at is we kind of started thinking about the idea that, you
0:37:20 know, what is it that, because it’s not just food seeking and it’s not just, you know,
0:37:24 like just want to consume something, there’s, there’s a maintenance of eating.
0:37:28 And so we know from humans and animals, you can satiate them, you can make someone full
0:37:31 and then get them high on cannabis and they’ll reinitiate eating.
0:37:36 So that’s an interesting thing in and of itself because that means you’re disrupting
0:37:40 either the ability of the brain to detect satiety or you’re messing with a process
0:37:42 we call reward devaluation.
0:37:46 And so reward devaluation is like, you know, if you haven’t eaten for a day and you see
0:37:50 like a picture of a pizza or someone brings a pizza in front of you, it just looks delicious.
0:37:52 And that first slice tastes amazing.
0:37:54 It’s salty, it’s fatty, it’s delicious.
0:37:56 You eat five of those slices, it feels greasy and nasty.
0:38:02 And so that process of how you perceive the food and its reward salience, the grades as
0:38:06 you eat and as your brain basically shifts into a thing of we don’t need to consume calories
0:38:09 and food anymore, we’re okay, we’re full now.
0:38:13 And so we’ve done a series of experiments in the lab where you’d get the animals and
0:38:18 either satiate it in advance where they have already devalued the food and under a normal
0:38:21 state they won’t eat it anymore, they won’t work to get access to it.
0:38:23 And you get them high on like a cannabis extract.
0:38:28 We have these vape chambers that are like, I don’t know how else to describe it outside
0:38:29 of like a little hot box.
0:38:35 It’s probably the best way to this because it’s essentially a kind of a locked airtight
0:38:40 box that the rack goes in and it gets like vapor puffs and it fills up and then they
0:38:43 inhale this and then it clears out and they get another puff and then it fills up and
0:38:48 we do this for like 15 minutes and we’ve titrated all this to get exactly blood levels
0:38:53 of THC that you would achieve in someone who’s consuming cannabis through smoking.
0:38:58 And so we get them to that point and then give them access to food and they will go
0:39:01 gangbusters, they eat food, doesn’t matter what you give them, you give them plain chow,
0:39:04 they go to town, you give them fatty, you give them sweet, they love it all, but you
0:39:09 pre-satiate them and they get them stoned, they will reinitiate eating again.
0:39:14 And you make them work for it where they have to like lever press and you get them stoned
0:39:18 and they will go to town on that and they will work and prove that even under the influence
0:39:22 of cannabis, animals will work hard.
0:39:26 Yeah, they, for food, I don’t know about other stuff, but for food they certainly will.
0:39:29 I mean, at least Weiritz and Cassie Moore have done this at Hopkins as well, they’ve
0:39:33 shown similarly using what we call progressive ratio, which is essentially a thing where
0:39:36 it’s like the first time you press a lever, you immediately get a sugar and next time
0:39:39 you got to hit it twice, they get a pellet, then you have to hit it four times, they get
0:39:45 six, then you got to hit it 16 and it kind of scales exponentially up.
0:39:48 I mean, we’ve had this one female we kind of joke about in the lab, this one female
0:39:52 rat and you get her high and she’ll do like 300 lever presses to get one sugar pellet,
0:39:53 she really wants it.
0:39:58 So you can really kind of goose up their motivation to eat and so there’s clearly a rewarding
0:40:02 aspect of this because they’re motivated to engage enough in working to get access to
0:40:07 the food, but you can also do another way of testing this question, which is you can
0:40:13 pair a food with something that will make the animal feel nauseous, like lithium chloride.
0:40:16 This is kind of the way that you would test condition taste aversion.
0:40:19 So you give them access to a food and then you give them something that makes them feel
0:40:22 nauseous and the animals will avoid that food.
0:40:27 And so that’s another way to kind of devalue a food is by pairing it with a nauseant so
0:40:28 the animal no longer likes it.
0:40:32 So again, same situation, you can get the animal stoned and it will re-engage in eating
0:40:36 that food that it had devalued through being paired with a nauseant.
0:40:42 So through either satiety or making it kind of a negative associated flavor because the
0:40:47 animal got nauseous before, you can kind of override these effects by giving THC.
0:40:53 And so that could be a complex process that either involves changes in the reward circuitry.
0:40:57 This could be something that’s like from the orbital frontal cortex, which is a very important
0:41:02 part of the brain that scales reward and kind of assesses how much someone wants to work
0:41:05 or an organism wants to work to achieve a reward at the end.
0:41:09 So we haven’t figured out the circuitry of this and where exactly it’s acting.
0:41:13 But I would say a lot of the stuff that we and others have done kind of supports this
0:41:18 idea that a lot of what the Munchies is, is this ability to kind of almost lock in the
0:41:23 reward value of food so that it doesn’t decay despite satiety, despite eating over time.
0:41:28 It just keeps it highly salient so that they want to work for it still.
0:41:32 And then similarly, we’ve also, we and others have also done work to show we can block satiety
0:41:33 signals.
0:41:37 So endocannabinoids, at least, are capable of overriding leptin.
0:41:43 So leptin is an anorectic molecule comes out from the fat and usually we release it when
0:41:47 we’ve eaten a lot and it’s one of these things that tells our brain stop eating.
0:41:52 It works through, again, populations in the arcute nucleus and changes the way those neurons
0:41:55 function to drive food seeking behavior.
0:41:59 And we and others have shown previously that if you elevate endocannabinoids, you can override
0:42:00 that.
0:42:04 One of the mechanisms by which leptin seems to suppress feeding is actually by turning
0:42:09 on the metabolism of endocannabinoids so that their levels decline.
0:42:13 And so as you lose that endocannabinoid function, the animal is less interested in eating.
0:42:18 And so you can prevent these anorectic effects of leptin by like gooseing up endocannabinoid
0:42:20 activity.
0:42:23 As many of you know, I’ve been taking AG1 for more than 10 years now.
0:42:26 So I’m delighted that they’re sponsoring this podcast.
0:42:30 To be clear, I don’t take AG1 because they’re a sponsor, rather they are a sponsor because
0:42:32 I take AG1.
0:42:36 In fact, I take AG1 once and often twice every single day and I’ve done that since
0:42:39 starting way back in 2012.
0:42:42 There is so much conflicting information out there nowadays about what proper nutrition
0:42:43 is.
0:42:46 But here’s what there seems to be a general consensus on.
0:42:51 Whether you’re an omnivore, a carnivore, a vegetarian or a vegan, I think it’s generally
0:42:56 agreed that you should get most of your food from unprocessed or minimally processed sources,
0:43:01 which allows you to eat enough but not overeat, get plenty of vitamins and minerals, probiotics
0:43:05 and micronutrients that we all need for physical and mental health.
0:43:09 Now I personally am an omnivore and I strive to get most of my food from unprocessed or
0:43:11 minimally processed sources.
0:43:16 But the reason I still take AG1 once and often twice every day is that it ensures I get all
0:43:19 of those vitamins, minerals, probiotics, etc.
0:43:22 But it also has adaptogens to help me cope with stress.
0:43:27 It’s basically a nutritional insurance policy meant to augment not replace quality food.
0:43:31 So by drinking a serving of AG1 in the morning and again in the afternoon or evening, I cover
0:43:34 all of my foundational nutritional needs.
0:43:38 And I, like so many other people that take AG1, report feeling much better in a number
0:43:43 of important ways, such as energy levels, digestion, sleep and more.
0:43:47 So while many supplements out there are really directed towards obtaining one specific outcome,
0:43:52 AG1 is foundational nutrition designed to support all aspects of well-being related to mental
0:43:54 health and physical health.
0:44:00 If you’d like to try AG1, you can go to drinkag1.com/huberman to claim a special offer.
0:44:05 They’ll give you five free travel packs with your order plus a year supply of vitamin D3K2.
0:44:09 Again, that’s drinkag1.com/huberman.
0:44:14 You’re talking about increasing endocannabinoid activity and we’ve said all this in the context
0:44:16 of cannabis.
0:44:20 So maybe we could talk a little bit about how the components in cannabis, THC mainly
0:44:27 but also CBD impact these receptors, the CB1 and let’s just leave CB2 out for the moment
0:44:30 because it sounds like it’s more of an immune system thing.
0:44:38 But just to make it very clear, is there a way to increase the activity of endocannabinoids
0:44:40 without ingesting THC?
0:44:41 Yes.
0:44:44 I mean, they dynamically change all the time.
0:44:48 But you’re talking about, you’re talking about experimentally or recreationally adjusting
0:44:52 their levels, but how does one do that without using THC?
0:44:55 So okay, few things there, we’ll take a step back.
0:45:02 So THC itself isn’t going to, it does its thing by acting directly on the cannabinoid
0:45:03 receptor, not-
0:45:07 So it sort of mimics the anandamide and 2AG?
0:45:08 Yes.
0:45:13 So THC, going back to kind of the pharmacology of this, so THC, if you look at how it interacts
0:45:18 with the receptor, it’s not a heavy-duty molecule.
0:45:21 So I mean, this was kind of one of the things that came up before as well.
0:45:25 Is this idea that THC is a sledgehammer and it overrides endocannabinoids?
0:45:28 By the way, Matt’s referring to the fact that I said that in a previous solo episode about
0:45:36 this and there I was nesting it in the concentrations of THC that can be found in high THC cannabis.
0:45:42 So essentially what I was saying is that at very high THC concentrations, the amount,
0:45:48 maybe not the binding affinity, but the amount of THC that is available to the CB1 receptors
0:45:53 is going to exceed what’s normally found in terms of the amount of anandamide that can
0:45:56 bind to CB1 receptors because what you’re talking about is a super physiological condition.
0:45:57 Yeah.
0:46:01 It’s, I mean, you don’t really actually need much THC in the brain to produce psychoactivity.
0:46:05 Like it’s a little bit of a mystery, to be honest, exactly how it works.
0:46:10 I mean, I think the main way that most people in the cannabinoid theory field would look
0:46:15 at this is that THC is not like a very strong agonist.
0:46:19 I mean, even if you look at its ability to trigger an intracellular response, it’s much
0:46:21 lower than 2 AG.
0:46:23 It’s actually more like anandamide.
0:46:25 So you said anandamide is high affinity, low efficacy.
0:46:26 Yeah.
0:46:27 So THC is the same.
0:46:29 THC is actually only a partial agonist.
0:46:31 It’s not even a full agonist at CB1.
0:46:32 But it is high affinity.
0:46:33 It’s high affinity.
0:46:40 So it has the ability, but the tricky thing with that is it can outcompete 2 AG, but because
0:46:45 it’s a lower efficacy agonist than 2 AG, in that sense, it’s almost blocking the effects,
0:46:48 not amplifying them.
0:46:52 Blocking the effects of 2 AG, but does it block the effects of anandamide?
0:46:57 THC and anandamide, the way I would visualize it is because they seem to have relatively
0:47:02 similar affinities and efficacies of the receptor, they might, let’s say, dance around.
0:47:04 So it would be somewhat interchangeable.
0:47:08 The difference there is, and this I think is the big point about what THC does versus
0:47:09 endocannabinoids.
0:47:14 Because we know now through the pharmaceutical development of drugs that can boost anandamide
0:47:15 levels, which exist.
0:47:17 We have inhibitors that prevent their metabolism.
0:47:18 We can elevate them.
0:47:22 There’s no intoxication and no psychoactivity associated with elevating anandamide.
0:47:24 That’s a very interesting point that we should highlight.
0:47:28 So there are drugs that now exist that can block the breakdown of anandamide, make more
0:47:34 available, presumably by disrupting some enzymatic breakdown, and therefore lead to more binding
0:47:40 of the now elevated levels of anandamide that are available to CB1, and you see no psychoactive
0:47:41 effects.
0:47:42 No psychoactive effects.
0:47:43 People are not aware that they’ve–
0:47:44 Yeah, you can do–
0:47:45 No one can guess.
0:47:46 Yeah, no one can guess.
0:47:47 What is it used for?
0:47:50 Well, I mean, it was developed– the first molecule really was developed by Pfizer to
0:47:53 look at if it could work on pain.
0:47:55 The first trial that was done did not work.
0:48:01 It was like a kind of strange osteoarthritic knee pain trial that was like– even in that
0:48:04 trial, the positive control of naproxen barely worked.
0:48:09 But because the fawn hibiter, which is– take a step back– fawns the enzyme that chews
0:48:10 up anandamide.
0:48:15 So the drug that is developed inhibits that enzyme, so you prevent the enzymatic breakdown
0:48:16 of anandamide.
0:48:18 So we just call them fawn hibiters.
0:48:23 So this drug will boost anandamide levels quite high, and an animal research showed
0:48:26 some efficacy in modulating pain.
0:48:30 And so they put it in a trial, and it didn’t work against the positive control of naproxen,
0:48:32 which is like an NSAID, just like Advil, basically.
0:48:33 A leave.
0:48:35 Yeah, essentially, yeah.
0:48:37 And that drug didn’t work that great to begin with.
0:48:40 So it was maybe some issues with the trial, but it essentially killed the development
0:48:43 of the drug from that point on, because everyone’s like, oh, it’s not going to work.
0:48:45 So it kind of shelved for a while.
0:48:52 A colleague of mine, Marcus Heilig and Leah Mayo, Leah is now a colleague of mine in Calgary.
0:48:57 But at the time, she was a postdoc with Marcus in Sweden, and they were able to get access
0:49:02 to this molecule right before COVID, essentially.
0:49:07 And they did a trial in just healthy controls with it, which, again, this is kind of jumping
0:49:09 the gun on some of the other stuff I’ll talk about, so I’ll tether back to that.
0:49:14 But what they did was they dosed people for 10 days on this drug, and then we looked at
0:49:18 stress and fear, because this is something that I study.
0:49:20 This is something that they were interested in.
0:49:26 And we did find that boosting anandamide with this drug over 10 days was sufficiently
0:49:29 capable of dampening stress-induced autonomic responses.
0:49:34 So looking at heart rate or skin conductance, I think skin conductance was the measure we
0:49:37 did in there, but it’s a proxy for adrenaline release.
0:49:40 So it blunted that, and it blunted subjective feelings of stress as well.
0:49:43 So people had lower levels of saying they actually felt stressed.
0:49:49 And it helped remove this conditioned fear memory that they had trained people to do.
0:49:53 And so I worked with them on doing the biochemistry of this to make sure the drug was working
0:49:54 properly.
0:49:58 But it was very interesting, because we did see in that situation where elevating anandamide
0:50:04 produced a reduction in stress perception, a reduction in stress physiology responses,
0:50:08 and helped reduce fear.
0:50:12 And so that is an interesting outcome, because it tracks with some of the stuff we know about
0:50:17 cannabis, and I’m sure we’ll talk about some of the PTSD stuff and anxiety later.
0:50:18 So that’s one of the things.
0:50:22 The drug has not really been used that widely yet.
0:50:26 It’s one of the frustrations I have as a scientist who does a lot of translational
0:50:31 work with clinical partners like Leah, is that getting access to these molecules is
0:50:36 not easy when they’re not out in the market, so you can just go and get them.
0:50:41 You really have to try and get access from the drug companies to be able to do trials
0:50:42 with them.
0:50:44 And so we are in the midst of trying to do that.
0:50:49 We did just complete a trial that Leah and Marcus ran that I worked with them on as well.
0:50:52 That was on PTSD.
0:50:55 And so there are various potential indications for this.
0:50:58 I mean, Johnson and Johnson developed one as well, and they looked at it in social anxiety
0:50:59 disorder.
0:51:04 They had some moderate efficacy in their trial, so I’d say the jury’s still out on exactly
0:51:08 what we’re going to do with these, but they have some potential.
0:51:11 I think in certain clinical settings, we just have to figure that out exactly.
0:51:15 But I think going back to where we started this from, they’re not psychoactive.
0:51:20 And so, I mean, when Pfizer first made the drug, they were actually initially concerned
0:51:23 that it wasn’t getting in the brain, because no one could tell they were on the drug.
0:51:25 I mean, this was the Wild West at this point.
0:51:28 No one had any idea what endocannabinoids were actually going to do.
0:51:32 People were basing it on what we knew about THC, so the assumption was people would have
0:51:35 psychoactivity, but they didn’t.
0:51:38 Pfizer then actually had to do, they had a sleep study to show that it did have some effects
0:51:41 on sleep cycle the same way THC does.
0:51:47 And then they also did an in vivo pet binding study to show that they could displace a radioactive
0:51:49 molecule that would bind to the enzyme in the brain.
0:51:54 It seems like a lot of gymnastics to basically confirm what they already knew, which is that
0:51:59 even greatly elevating the anandamide by blocking this enzymatic breakdown of anandamide leads
0:52:05 to, at least from what I’m understanding, vastly different subjective experience than
0:52:10 ingesting or smoking THC, which brings us back to THC.
0:52:11 So what’s it doing?
0:52:16 And cannabis, like, you know, so I think it seems that this thing that we call cannabis
0:52:23 and THC are overlapping with the endogenous effects of anandamide, but here you’re not
0:52:27 talking about endogenous normal levels, you’re talking about pharmacologically greatly increasing
0:52:32 anandamide, no psychoactive effect, no euphoria, no munchies, you know, et cetera.
0:52:40 Then people smoke or take an edible of THC or cannabis and you get a vastly different
0:52:41 set of effects.
0:52:45 So maybe we could talk about THC and the CB1 receptor.
0:52:50 And since we’re here, we might as well talk about CBD and the, I think you’re going to
0:52:54 tell us the lack of interaction with CB1 receptor, right?
0:52:59 And what is cannabis doing at the level of these receptors because it makes me wonder
0:53:04 whether or not these receptors are the whole story or whether or not cannabis is, you know,
0:53:09 as you mentioned, you know, 70 plus active molecules in there, terpenes and a bunch of
0:53:14 other things that may modify their action, but this thing we call cannabis has many
0:53:18 more actions than just mimicking the endogenous cannabinoid system.
0:53:19 Yeah.
0:53:23 I mean, I think I would say the main way that we think about this is the difference between
0:53:28 endocannabinoids and THC is endocannabinoids are going to be released in a very specific
0:53:30 spatial and temporal manner.
0:53:31 So they evolve to do that.
0:53:32 Yeah.
0:53:36 So there’s going to be, and I think like it’s very clear that like anandamide, for example,
0:53:39 is not active at every synapse that has CB1.
0:53:43 And so when we boost anandamide signaling by inhibiting its metabolism, all we’re doing
0:53:49 is amplifying anandamide signaling at the synapses that already exists, whereas THC,
0:53:54 when you consume it orally or inhalation-wise and it gets into your blood and into your
0:54:00 brain, it’s just blanket activation, you’re just carpet bombing the whole system indiscriminately.
0:54:03 And so you’re introducing the ligand, the thing that binds the receptor.
0:54:09 This is far and away different than say like the actions of amphetamines, which are disrupting
0:54:13 the normal biology in a way that’s giving you an amplification of an endogenous mechanism,
0:54:14 right?
0:54:17 If that was all just nerd speak for those listening.
0:54:21 It’s one, in the context of amphetamines, what you’re doing is you’re taking an endogenous
0:54:26 system, a naturally occurring system, and you’re greatly amplifying the amount of dopamine,
0:54:29 the amount of norepinephrine that’s available.
0:54:35 With what we’re discussing today, the endocannabinoid system seems to be producing a set of effects
0:54:42 that might overlap with the THC effects, but THC is doing a bunch of other things.
0:54:48 And that’s because THC, and we’ll talk about CBD, but at least THC is acting as the ligand.
0:54:52 In some sense, we don’t want to say replacing, but it’s masking the effects of anandamide.
0:54:57 I think the problem is when you just blanket activate all the CB1 receptors in the brain
0:55:02 indiscriminately, like you do when you consume cannabis with THC, the resulting effect is
0:55:04 the intoxicating state.
0:55:07 And it’s probably because there’s a lot of CB1 receptors in the cortex, and those are
0:55:12 going to be differentially regulated at different times by endocannabinoids, whereas when THC
0:55:15 hits them, all of them are going to get affected at once.
0:55:19 And if you think of the way that I had described how cannabinoid receptors work by essentially,
0:55:24 I mean, in its simplest form, what cannabinoid receptors do is they change the way that
0:55:26 two neurons talk to each other.
0:55:27 And so–
0:55:28 So you’re changing all the network simultaneously.
0:55:29 Yeah.
0:55:33 So if you hit a whole bunch of networks simultaneously, you’re just going to change the way that information
0:55:35 processing and perception occurs.
0:55:39 And I think as a consequence of that, that’s what produces the intoxicating state, not
0:55:47 that THC is like a super-duper version of an endocannabinoid or that it’s boosting endocannabinoids.
0:55:52 It’s kind of like just indiscriminately activating all the receptors as opposed to a system that’s
0:55:56 very finely tuned to do very specific things at very specific times.
0:55:57 That’s very helpful.
0:55:58 Yeah.
0:56:01 So the analogy that I was considering using coming in here, like the difference between
0:56:07 endogenous testosterone or estrogen versus pharmacologic testosterone or estrogen given
0:56:11 as a therapy is very different because that’s a level’s issue.
0:56:14 This is a level’s and an extent issue.
0:56:15 Yeah.
0:56:18 This is a lot more to do with just, yeah, the nature of how it hits everything.
0:56:22 Because like, so for example, if we talk about feeding, we know it’s been established at
0:56:25 this point that, for example, if an organism doesn’t eat for like a day.
0:56:28 So you fasted.
0:56:32 At that point, in those feeding circuits in your brain, like the arcuate area where these
0:56:36 AGRP neurons and stuff are, you’ll start seeing elevations in endocannabinoids.
0:56:42 So endocannabinoid levels start kind of going up and up following kind of fasting periods.
0:56:45 And part of this is because they’re trying to engage that feeding circuitry now and they’re
0:56:50 shifting the activity of those neurons to promote food-seeking behavior.
0:56:54 Because an organism is basically like energy detecting, it’s periphery and saying, “Oh,
0:56:56 we might be burning through our energy reserves.
0:56:58 We should probably eat more.”
0:57:03 And so there are obviously a few mechanisms that do this, NPY is another one and ghrelin
0:57:04 and things like that.
0:57:07 So there’s a lot of redundancy in these systems, but endocannabinoids are just one of the molecules
0:57:10 that seem to fine-tune like the feeding circuitry.
0:57:14 And so in states of fasting, endocannabinoids go up explicitly in that circuit.
0:57:18 And there’s some evidence they also go up in like the nucleus accumbens and affect some
0:57:19 of the reward circuitry.
0:57:22 So they’re probably driving food-seeking behavior and enhancing the rewarding aspects
0:57:24 of food at the same time.
0:57:30 And so that’s like a natural endogenous mechanism to regulate feeding based on nutritional state.
0:57:34 THC, on the other hand, it hits the brain, yes, some of it’s going to be the intoxication,
0:57:38 but in tandem, you’re going to hit the CB1 receptors that are in those feeding circuits
0:57:39 as well.
0:57:43 And the consequence of that is going to be, I mean, the way I kind of analogize it to
0:57:47 people is I say it’s almost like tricking the brain into thinking that you’ve been fasting.
0:57:51 Because you’re now activating receptors that are normally activated following kind of a
0:57:52 fasting state.
0:57:58 And as a consequence of that, it pushes someone or an organism or human or whatever into a
0:58:01 state of food-seeking behavior because now food also has high reward value in their kind
0:58:06 of the way that their food circuitry is responding in the brain at least seems to be similar
0:58:08 to what would happen if they’ve been fasted.
0:58:13 And the thought is that’s why when people, you know, when someone gets stoned, they’re
0:58:14 not like going to eat lettuce.
0:58:16 They want high-calorie food.
0:58:19 They tend to like things that are high carb, high fat.
0:58:23 That combo seems to be what people like when they’re intoxicated with cannabis.
0:58:24 And that comes with a lot of calories.
0:58:28 And the point of that would be you’re trying to replenish lost energy stores.
0:58:32 And so this at least is the kind of the theory that I have about what it is that it’s doing
0:58:36 is, you know, and I think you can make this analogy for multiple different things.
0:58:39 You know, if we talk about pain or stress, we can say similar kinds of things are going
0:58:43 on is that endocannabinoids normally do one thing.
0:58:47 But when THC hits the brain, it’s still activating these circuits in addition to everything else
0:58:48 it hits.
0:58:52 So you still drive that response that the endocannabinoid system normally physiologically
0:58:56 controls, but you’re almost like tricking the brain into thinking you’re in that state
0:58:57 now.
0:59:01 And so then you then, yeah, you go into food seeking behavior mode.
0:59:02 Super interesting.
0:59:07 Well, I have to imagine that there are many people who use cannabis not to stimulate appetite,
0:59:14 but for other reasons, they either like the euphoria or to adjust their anxiety.
0:59:21 What are some other known mechanisms by which cannabis can change people’s psychology?
0:59:27 Let me focus in on one particular aspect of subjective experience, which is focus.
0:59:32 Do you think that some people use cannabis because it allows them to focus better?
0:59:37 And I raised this specifically because I think that in the past, cannabis has had a bit of
0:59:40 a reputation for making people spacey.
0:59:43 Now, you use the word stoned, I’m kind of out of it.
0:59:46 And yet I’ve heard of some potential uses for enhancing focus.
0:59:50 I mean, honestly, this is a bit of a tricky one to speak to because I just don’t think
0:59:52 there’s good evidence for it.
0:59:57 Either way or I just don’t, I mean, as far as I’m aware, it hasn’t been studied in a
0:59:58 lot of depth.
1:00:01 I mean, there’s some things, you know, a lot of the stuff that’s been done is usually
1:00:06 more like kind of acute memory tasks, like a working memory or recall or something like
1:00:09 this as opposed to explicitly studying focus.
1:00:12 Anecdotally, there is certainly a lot of people that report that.
1:00:18 So my understanding is that people who use cannabis have poor certain forms of memory,
1:00:20 but not necessarily poor memory across the board.
1:00:21 Is that correct?
1:00:22 I don’t think I would say that.
1:00:24 I don’t think you could lump anything in that context.
1:00:28 I mean, I would say the only thing you can say confidently that I would be comfortable
1:00:34 saying is that acutely while someone’s intoxicated on cannabis, there is definitely short-term
1:00:35 effects on memory processing.
1:00:40 So people tend to negative effects or enhancements or decrements.
1:00:43 I would say most of it has to do with recall or consolidation.
1:00:47 So there does seem to be some, I mean, certainly the animal evidence is very compelling there,
1:00:51 but again, we can talk to what some of the limitations of that are.
1:00:55 But in humans, I would say most of the work that’s been done would suggest there is some
1:01:01 short-term memory deficits that are present during the intoxicated state.
1:01:06 I have not seen very much compelling evidence of long-term effects that emerge like when
1:01:09 someone’s not intoxicated, but they use cannabis somewhat regularly.
1:01:13 I don’t think there’s anything compelling for that.
1:01:17 And even in that case, like Carrie Cutler, who’s at Washington State, she’s done a lot
1:01:22 of this stuff looking at cognitive processing and different kinds of memory tasks in users
1:01:25 while they’re stoned often.
1:01:31 And within a person, either they have adapted to using it as much as they do, or they’ve
1:01:33 developed some form of tolerance to it.
1:01:40 But even in regular users, the impact on memory processing is usually not super robust.
1:01:41 It’s still there.
1:01:46 I mean, I think the effects that are more often seen in kind of, let’s say, smaller laboratory
1:01:49 studies where they’re using people who’ve used cannabis but aren’t regular users might
1:01:55 be a little bit more profound because they may not be used to that state, let’s say.
1:01:58 I mean, there’s certainly something we call state-dependent learning, which I’m sure you’re
1:02:00 familiar with.
1:02:04 And this is something people, I mean, I remember learning about this in undergrad through alcohol.
1:02:08 So like, someone, first time they get drunk tries doing something, they’re very bad at
1:02:09 the task.
1:02:12 But if every time they’re drunk, they do that task, they become better at doing it under
1:02:14 the influence.
1:02:18 And so then all of a sudden, they regularly do this task while they’re drunk and someone
1:02:21 tests them and they don’t look like they’re impaired at all because they’ve done it so
1:02:22 much.
1:02:26 And so I should just say this point has often been confused by undergraduates and others
1:02:33 to assume that just because one can gain proficiency at a task while under the influence of a substance
1:02:38 does not mean that you have higher proficiency at that particular task while under the influence.
1:02:44 In fact, the way it was presented to me when I was an undergraduate was incorrect.
1:02:49 I remember the lecturer said and later corrected it himself, I won’t call him out here because
1:02:50 that’s unfair.
1:02:56 He’s not here to defend himself, but it happens in lectures that people who studied drunk
1:02:58 would be better off coming to the exam drunk.
1:03:00 That is not true from what I understand.
1:03:01 I don’t think better off, no.
1:03:06 But they would probably score better than someone who had never studied drunk and came to the
1:03:10 test drunk just because they had had some state-dependent learning.
1:03:12 And so I think when we’re talking about, if you’re talking about someone who’s a chronic
1:03:17 cannabis user, they’re going to have done a lot of cognitive tasks while they’re under
1:03:18 the influence.
1:03:23 And so if you acutely test them, the impairment you might see in them is probably less than
1:03:27 you would see in someone who’s relatively naive or a much less experienced user.
1:03:30 That being said, I think it’s relatively well-established.
1:03:35 Most people would agree that acutely intoxication with cannabis does impair memory processes
1:03:36 in some capacity.
1:03:38 What explicit form of memory?
1:03:42 I don’t think I could speak to comfortably just because I’m not a memory researcher and
1:03:46 I know there’s very specific things like episodic and declarative and whatnot.
1:03:50 I can’t say that, but I’d say it’s kind of generally, and I mean, again, you can replicate
1:03:54 this in animals where if you’ve trained them on a task while they’re under the influence,
1:03:58 they don’t seem to have consolidated that information as well.
1:04:02 But again, I don’t really think there’s super compelling evidence that there’s kind of long-term
1:04:07 permanent effects on cognitive function in individuals who use cannabis.
1:04:13 At least I’ve never seen anything that’s replicable or reliable or stable in any way, so yeah.
1:04:18 Thanks for clarifying that, and also thank you for clarifying the discrepancy between
1:04:23 endogenous cannabinoid binding and affinity for CB1 versus THC.
1:04:26 I really appreciate that because that’s something that you and I discussed in light of the solo
1:04:32 episode I did about cannabis, and now you’ve made it clear that THC does not bind with
1:04:33 much higher affinity.
1:04:39 It’s just as I think your words were, assuming high THC levels in the cannabis, carpet bombs,
1:04:44 all the networks, as opposed to binding more with higher affinity at particular receptors.
1:04:45 Yeah.
1:04:47 I mean, I don’t actually even think it matters if it’s high THC in the cannabis.
1:04:51 I think like some people can get very intoxicated off of very, very low doses of cannabis.
1:04:52 Is that right?
1:04:57 I mean, you look at edibles, for example, I mean, this may be an interesting segue into
1:05:00 root of administration stuff because I think it’s an important point that a lot of people
1:05:05 don’t recognize is the difference between someone inhaling cannabis versus someone
1:05:08 orally consuming cannabis is like a different game.
1:05:09 Yeah.
1:05:13 Let’s talk about this because I know that you and I arrived at different understanding
1:05:24 of the fastest, typical, and slowest routes of entry for THC into the system to get to
1:05:26 arrive at the brain.
1:05:30 The numbers I gave in the previous discussion about this were related to how quickly inhaled
1:05:34 smoke moves from the lungs to the bloodstream and crosses the blood brain barrier.
1:05:35 Which is very fast.
1:05:36 Right.
1:05:37 Which is very fast.
1:05:38 Yeah.
1:05:39 I don’t know if it’s different than nicotine.
1:05:42 I’m not sure, again, I don’t know if I would say that, but yeah.
1:05:43 It’s very fast.
1:05:44 Okay.
1:05:50 So there may be, it may be that it is the same as nicotine, it may be that it’s faster,
1:05:53 but importantly, it can be fast.
1:06:00 But typically, how fast is the onset of the subjective experience of, okay, somebody takes
1:06:07 a hit off a joint or a bong hit, and they start to experience the subjective effects
1:06:08 of euphoria, et cetera.
1:06:09 How quickly after?
1:06:11 Two to five minutes, I would say.
1:06:12 Two to five minutes.
1:06:13 It’s pretty fast.
1:06:18 I mean, so this is one of the things with cannabis is, and again, this will kind of go into this
1:06:23 idea of the change in potency of the plant as well.
1:06:27 It’s pretty quick, and people titrate cannabis pretty well, like at least people who’ve used
1:06:29 it a couple of times and understand this.
1:06:32 I’ve seen some people not titrate it very well.
1:06:34 Depending again on how you, so again, this can vary.
1:06:42 So cannabis from the ’70s was like, I don’t know, 5% THC, let’s say, it was pretty low.
1:06:46 And nowadays cannabis is, a lot of the commercial stuff is between 20 and 30, although whether
1:06:51 those are super accurate numbers, not entirely clear, but so it’s gone up a fair amount.
1:06:52 Yeah.
1:06:53 But that’s not just a fair amount.
1:06:56 That’s, I mean, if we were talking about alcohol concentration.
1:06:57 It’s beer and vodka.
1:06:58 Yeah.
1:07:01 Basically, you’re talking about a beer or wine to a spirit.
1:07:04 And there are a variety, so to speak.
1:07:10 By the way, I think when people hear me talk about any kind of drug that can be used recreationally
1:07:14 or alcohol, I think some people assume that, you know, I’m ultra anti all these things.
1:07:15 I’m actually not, right?
1:07:21 I’m non-alcoholic, so I can drink a little bit and I have, I just don’t tend to.
1:07:23 And we could discuss cannabis in a different venue.
1:07:28 But the point here is, we’re not trying to frame this as what people should or shouldn’t
1:07:29 do.
1:07:30 We’re just trying to inform people.
1:07:32 I want to be very clear about that.
1:07:38 So, but when I hear about, you know, 20 to 30% concentration as opposed to, you know,
1:07:41 5% concentration, it’s significant.
1:07:44 So I would say this is what’s super interesting.
1:07:49 And this was something that came out of the way that cannabis research is done, certainly
1:07:50 in the States.
1:07:53 And Canada has been quite behind on this, even with legalization.
1:07:55 We haven’t caught up.
1:08:00 But they have been doing lab-based studies of cannabis, you know, Meg Haney, Harriet DeWitt,
1:08:04 this cluster of researchers around the country, Zeva Cooper at UCLA here, have all done this
1:08:08 where, you know, you have people come into the lab, you give them cannabis, you measure
1:08:11 subjective outcomes or neuro-imaging outcomes or whatnot.
1:08:16 So to do this, you can’t use commercial cannabis.
1:08:20 And even like the state-by-state legalizations hasn’t changed this.
1:08:23 So, if you are doing cannabis research in humans and you’re funded by, like, NIDA, which
1:08:29 is National Institute of Drug Abuse, you get all your cannabis sourced, I mean, this may
1:08:30 be changing.
1:08:31 I think there are some shifts that are happening.
1:08:35 But historically, and all the literature that we would talk about that’s kind of pre-the
1:08:40 last couple of years, all that cannabis came from one source, which was, I believe, a farm
1:08:44 in, like, Mississippi that was essentially funded by NIDA to produce cannabis.
1:08:45 Lucky farm.
1:08:49 And, well, the cannabis that came out of it, though, and this is one of the reasons a lot
1:08:52 of the clinical stuff people have kind of been like, “Oh, I don’t know how representative
1:08:56 this is,” because it reflects cannabis that I would say is more from, like, the ’70s or
1:08:57 ’80s.
1:09:01 So it would be, like, 5% to 9% kind of THC cannabis.
1:09:08 Now, when you put someone in a lab setting and you get them to smoke to level of intoxication,
1:09:13 people would take, you know, whatever, eight toaks, let’s say, something like that.
1:09:14 And that’s where they would stop.
1:09:18 And so, you know, a lot of the labs that use this have always been, like, are people who
1:09:20 are regular cannabis users are getting high off of it.
1:09:24 It’s not as potent as the stuff that’s on the street, but they’re clearly getting intoxicated
1:09:27 from it, and it’s giving us reliable data.
1:09:32 So when they started looking at the blood levels of THC that you achieve, it was around
1:09:35 100 nanograms per mil of THC, give or take.
1:09:37 That seemed to be where it was.
1:09:45 Now, because of the way that you can legally study cannabis in the States, you couldn’t
1:09:48 just go down to a dispensary and buy the products that everyone on the street are using, which
1:09:51 is kind of like, it’s been a weird thing for a lot of people because they’re like, “Why
1:09:53 wouldn’t you study what we’re using?”
1:09:56 But because of the legal aspects of this, you couldn’t bring those products into the
1:09:57 lab.
1:09:58 They’d never been standardized.
1:10:02 No one knew exactly what was in them, pesticides, all this other stuff that could influence it.
1:10:07 So from a safety perspective, it was always like, “No, you used the cannabis that’s sourced
1:10:10 from NIDA.”
1:10:15 So there’s a group in Colorado, Kent Hutchinson and Angela Bryan and Cinnamon Bidwell have
1:10:21 kind of, I would say, became very creative actually to figure out how to study cannabis
1:10:26 that’s being used, I call it, in the wild, in kind of an ecological setting, let’s say.
1:10:29 And so they created what was called the Canavan.
1:10:35 And the Canavan was a way to study people using products on the street, but not have
1:10:37 them come into a laboratory setting where it was complicated.
1:10:42 And so what they would do is they would drive the Canavan to someone’s house, but they’d
1:10:47 be parked on the street, and someone would use the product, whatever it was, in their
1:10:53 own property, in their own time, and then come into the Canavan to have blood taken to
1:10:55 look at what their THC levels are and to undergo testing.
1:10:59 And so it was actually like, I think this was a great advance in the field because it
1:11:03 was this huge innovative approach that allowed us to start comparing what we’ve learned from
1:11:09 lab-based settings with this kind of old-school weed that was coming from NIDA with what is
1:11:10 being used on the street.
1:11:11 I love this.
1:11:18 I mean, as somebody whose lab has done an in-laboratory VR-based experiment on human anxiety and fear
1:11:25 and then compared that to, you know, a clinical study that we did sort of en masse where people
1:11:28 were at home doing specific respiration practices.
1:11:32 You have many more subjects, but of course, they’re reporting back their effects where
1:11:37 you can monitor them by device, you know, look at HRV, look at hardware, et cetera.
1:11:42 I think having the ability to compare and contrast in-laboratory and ex-laboratory data
1:11:43 is extremely valuable.
1:11:44 Yeah.
1:11:47 And I mean, my view is you need both because you need the in-laboratory for the control
1:11:52 because we all need control over various things, but you also need the ecological validity
1:11:55 to see how it shakes out and make sure it looks the same.
1:11:56 Yeah.
1:12:00 For people that have never been to a laboratory or tried to find a parking spot at a university,
1:12:02 that’s an anxiety inducing experience in and of itself.
1:12:06 A novel experience while someone’s intoxicated with cannabis can also create a very different
1:12:07 altered state.
1:12:08 I would want to be stoned in a laboratory.
1:12:10 I’ll tell you that much.
1:12:13 I feel like there’s pluses and minuses to both sides, but I think the data together
1:12:16 is very compelling and that’s where we get a lot of advance in the field.
1:12:21 So what Kent and Angela and Cinnamon did with the Canavan was kind of create the situation
1:12:24 that allowed this research to occur.
1:12:28 And what we found fascinating, I remember talking to Meg Haney about this because all
1:12:32 the people in her lab said he’s tended to always hit around 100 nanograms per mil using
1:12:35 this relatively lower potency cannabis.
1:12:39 When Kent and Angela and Cinnamon started studying this in the people and taking blood,
1:12:43 despite the fact that these people are now using cannabis that’s 20 to 30%, their blood
1:12:45 levels are the same.
1:12:49 So they’re still coming in around 100 nanograms per mil because people are really good at
1:12:50 self-titrating.
1:12:54 Now where things fall apart is with the concentrates.
1:13:00 So then you go into things like dabs or these high potency products that are now like, because
1:13:04 cannabis itself realistically, from what I understand from the botanist that I’ve talked
1:13:09 to, you can’t really grow a plant that’s going to exceed more than 25 to 30% THC just
1:13:11 by sheer biology.
1:13:12 So it taps out there.
1:13:14 That’s about as high as it’s going to go.
1:13:16 Concentrates can go up to like 90, 98%.
1:13:17 So you can get really, really–
1:13:19 These are tinctures.
1:13:27 Distillates, like, yeah, various just in oil-based forms that are very, very high potency products.
1:13:29 Those are incredibly challenging to titrate.
1:13:33 They cannot be titrated because the sheer volume of THC that hits the system even from
1:13:36 a single hit is so overwhelming.
1:13:41 And so when the Colorado group looked at those, their blood levels were closer to 200 to 300
1:13:42 nanograms per mil.
1:13:48 So with cannabis planned, there does seem to be this ability for people to relatively
1:13:49 self-titrate.
1:13:53 And then my buddy, Ryan McLaughlin, who’s also at Washington State, he was really one
1:13:57 of the ones that pioneered these vape chambers and rats and created this really cool model
1:14:02 of self-administration, which was a very important thing to actually establish because it was
1:14:07 very challenging to get rodents to self-administer cannabis if you’re doing like an IV approach
1:14:09 or something else because they found it quite aversive.
1:14:15 But when you let rodents actually tighter their ability to get vape hits, they will work
1:14:16 for this.
1:14:18 The same way they will other reinforcing drugs.
1:14:21 So it was a really important finding that you could do this.
1:14:26 And what Ryan found was he actually did one study where he gave them access to a low potency
1:14:30 product, we’ll call it medium and then a high.
1:14:33 And what you ended up, if you look at the data, is the one the rats liked the best was
1:14:35 the medium potency product.
1:14:39 And if you gave them the high potency product, they would actually take less vape hits off
1:14:41 that than they would off the lower ones.
1:14:47 And again, all their blood levels tended to cluster in the same range because they titrated,
1:14:52 like even at the rodent level, they’re able to titrate because of the lag between inhalation
1:14:56 and feeling the effects is only on the order of a couple of minutes.
1:15:01 People can titrate better, I mean, not just people, it seems like the rodents can as well.
1:15:06 So the higher potency cannabis, where it becomes a problem is if someone’s highly inexperienced
1:15:10 and they consume a whole bunch of it without allowing that time lag to occur.
1:15:14 And then they can probably exceed the levels they intended to and consume too much and then
1:15:16 have a probably an adverse response.
1:15:21 So does that mean that cannabis use rarely leads to tolerance of cannabis use?
1:15:22 I wouldn’t say that.
1:15:24 There’s definitely some degree of tolerance.
1:15:28 The tolerance is definitely more prominent when people start using concentrates.
1:15:29 There’s no question about that.
1:15:32 I mean, we can talk about the concentrates, I guess, separately after, because I would
1:15:36 say if we’re talking about a harm reduction thing, that’s more where we need to focus
1:15:38 a lot more is this idea of these high potency products.
1:15:43 Yeah, it sounds like those are precarious that somebody who thinks they have a lot of experience
1:15:50 or God forbid, no experience takes a concentrate and is what, no longer getting the euphoric
1:15:55 experience that they anticipated, but instead are getting what, a paranoid anxiety attack.
1:15:59 I think you’re far more likely to go overboard and have an adverse response.
1:16:04 But also, I think the problem is if you’re using a product of that potency and that much
1:16:09 THC-fledger system on a regular basis, the biological changes from that are going to
1:16:10 be very different.
1:16:17 Then what you get if, again, you’re titrating your THC from inhaling plant at roughly the
1:16:23 same level, whether that’s a 10%, 5% or 25%, people generally tend to scale.
1:16:28 This is a very important point and I’m going to highlight it because I think it’s very,
1:16:32 very important, although you’re making it very clearly already, which is these days
1:16:39 we hear a lot about the “problems” with high THC-containing cannabis as relative to what
1:16:44 was present in the 70s and 80s and presumably 90s as well.
1:16:48 I was a teen in the 90s, so maybe I’m alluding to something there, but what you’re saying
1:16:55 is that unless one is talking about concentrates that people and animals in the laboratory
1:17:01 will self-regulate the amount of intake in a way that leads to approximately the same
1:17:07 blood levels of THC, so it may not be as much of a concern, at least in light of the concerns
1:17:11 about, “Oh, these levels are so high that people are overwhelming their system with
1:17:12 THC.”
1:17:18 Basically, this could be stated in real-world terms as people are taking fewer totes of
1:17:23 the higher concentration stuff that allow them to match blood levels that were present
1:17:26 in the person taking many more totes in the 70s.
1:17:30 The joke I always make to people is they say, “Go watch a Cheech and Chong movie from the
1:17:31 late 70s.
1:17:35 Look at the size of the joints that they smoke in movies like that relative to what you would
1:17:39 see someone on the street consuming nowadays.”
1:17:45 The advantage that existed from a titration perspective was with 70s weed, there’s a large
1:17:46 window to titrate.
1:17:52 People could take small amounts and not over-consume, let’s say, because there was a much lower
1:17:57 concentration of THC in the plant, so they’re able to consume even if they were doing it
1:18:01 relatively fast because of how little THC was coming into the system, it was a little
1:18:03 easier to scale that.
1:18:08 There certainly is the propensity for people to over-consume higher potency cannabis, even
1:18:12 independent of concentrates, if they’re not allowing that titration to occur.
1:18:18 Also, if you have someone who is just exquisitely sensitive to THC for various reasons, even
1:18:22 one or two totes could be too much for them because at the higher potency, they may not
1:18:25 have that ability to titrate quite as well.
1:18:30 A lot of people, anecdotally, you talk to people about cannabis and a lot of people
1:18:34 who don’t like cannabis have said, “Oh, I’ve tried, the new stuff’s too strong.”
1:18:38 If there’s someone who’s more in our age range, who grew up in an earlier decade where things
1:18:42 were a bit different, they may be referencing their own experience from when they were younger
1:18:45 and what they were able to consume and now they try doing the same and it hits them like
1:18:46 a sledgehammer.
1:18:47 Got it.
1:18:52 It’s a little different in that sense, but I don’t think it’s to say it’s not concerning
1:18:57 that cannabis is as high as THC as it is, I just think if I’m going to put my efforts
1:19:03 into public health perspectives of this, I would be digging my feet in much more about
1:19:07 the access to concentrates and the issues and the potential harms that are going to
1:19:10 come with them than I would about the cannabis flower, myself.
1:19:15 That’s just my opinion based on what I see with the concerns and what we’ve seen from
1:19:16 the data in humans.
1:19:20 I think the real world, the ecological studies that the Colorado group have done have been
1:19:25 very informative in this sense because if the blood levels of THC you achieve from concentrates
1:19:30 are double to triple of what you get even from higher potency flower, that’s a concern.
1:19:33 I think that’s where problems are arising because then you’re going to start seeing
1:19:35 a lot higher degree of tolerance.
1:19:39 I mean, there used to be more of a debate in the field as to whether people develop tolerance
1:19:43 because one of the things with cannabis that I do find very interesting is with a lot of
1:19:47 chronic users, they don’t escalate the way you would see with cocaine or alcohol where
1:19:51 there’s very profound tolerance that develops.
1:19:56 People definitely see this in cocaine where people can become tolerant almost immediately,
1:19:58 and so dosing starts scaling up very fast.
1:20:03 Yeah, usually it’s the life destruction that thwarts their progressive increase.
1:20:04 Yeah, or the cost.
1:20:05 I mean, the sheer cost.
1:20:08 Another form of life deterioration.
1:20:13 Yeah, that is required to be able to maintain that, but with cannabis, it seems like there
1:20:20 is some degree of tolerance that people exhibit, it varies from person to person, but as Meg
1:20:25 has said to me many times, the guys that come in, her studies, these are very heavy users,
1:20:29 and then they will use this relatively low potency product and still get high off of
1:20:30 it.
1:20:34 And so it’s not to say that there’s no tolerance, it’s just it’s not as profound as I think
1:20:36 we see with a lot of other drugs.
1:20:42 And this is probably due to the fact of just like, we definitely see, if we look at some
1:20:45 pet imaging studies, chronic cannabis users do have some downward reaction.
1:20:46 Sorry, I have to interrupt.
1:20:47 Pet.
1:20:49 A positron emission tomography, not pets.
1:20:53 So people get their pets high, and we don’t know what those pets think about that.
1:20:54 Not good.
1:20:55 Don’t get dogs high.
1:20:58 If also high, one can assume a lot of things about what your pet is thinking while also
1:20:59 high.
1:21:01 Sort of half joke there.
1:21:07 But yes, positron emission tomography is one way to assess the binding of drugs within
1:21:15 the brain, as well as activity of endogenous neurotransmitters, neuromodulators, such as
1:21:17 anandamide, dopamine, et cetera.
1:21:18 Yeah.
1:21:23 A typical pet study in a human looking at this, they’d give a molecule that’s radiolabeled
1:21:25 that will bind to CB1 receptors.
1:21:29 You can scan them and then look at the emission rates of the radiation to get an idea of the
1:21:32 density of receptors that are in the brain.
1:21:35 Chronic cannabis users tend to have less.
1:21:41 What that means in terms of the functional outcome is unclear.
1:21:45 I mean, there could be some, I think there’s a lot of evidence that there’s some degree
1:21:49 of a reservoir of CB1 receptors that there might be a lot more receptors there than we
1:21:53 necessarily always need or are always using, let’s say.
1:21:57 So we might be down-regulating a component of this, but maybe not all of the ones that
1:22:00 are required to produce the psychoactive effects because there’s clearly some maintenance
1:22:05 of the system that allows someone to continue to get intoxicated.
1:22:07 And so with cannabis users, we do see that.
1:22:12 But you do see much more profound tolerance with people using high potency extracts and
1:22:13 concentrates and things like this.
1:22:19 And again, surely, I think as a response to the biology of hitting the system that heavily
1:22:24 with that much THC as it comes in because they can’t titrate it the same way.
1:22:25 That makes sense.
1:22:30 Yeah, these concentrates sound like something to at least pay attention to as a potential
1:22:31 problem.
1:22:35 I’d like to take a quick break and acknowledge our sponsor, Inside Tracker.
1:22:39 Inside Tracker is a personalized nutrition platform that analyzes data from your blood
1:22:43 and DNA to help you better understand your body and help you reach your health goals.
1:22:47 Now, I’ve long been a believer in getting regular blood work done for the simple reason
1:22:51 that many of the factors that impact your immediate and long-term health can only be
1:22:53 analyzed from a quality blood test.
1:22:58 Now, a major problem with a lot of blood tests out there is that you get information back
1:23:02 about metabolic factors and hormones and lipids and so forth, but you don’t know what to
1:23:04 do with that information.
1:23:08 With Inside Tracker, they make it very easy to know what to do with those numbers because
1:23:12 they have a personalized platform that allows you to see the levels of those metabolic factors,
1:23:16 lipids, hormones, et cetera, and they give you specific directives that you can follow
1:23:20 related to nutrition, behavioral modification, supplementation, and more that can help you
1:23:24 bring those numbers into the ranges that are optimal for you.
1:23:29 If you’d like to try Inside Tracker, you can go to insidetracker.com/huberman to get 10%
1:23:31 off their new membership program.
1:23:36 Inside Tracker membership offers significantly reduced prices on Inside Tracker’s comprehensive
1:23:37 blood panels.
1:23:42 Again, that’s insidetracker.com/huberman to get 10% off.
1:23:50 Along the lines of use, tolerance, et cetera, is cannabis addictive and/or habit forming?
1:23:52 I think it’s probably important that we distinguish between the two.
1:23:57 I may have made this joke in the previous episode on cannabis.
1:24:05 I’ve known a lot of chronic cannabis users and none of them admit to being addicted.
1:24:08 That’s not my place to challenge them on that.
1:24:13 They do seem, in my experience, this is not an experiment, but in my experience, more
1:24:21 irritable when they don’t have access to what they call their “medicine.”
1:24:26 That speaks to dependence or something, but then we need to be careful because in the
1:24:32 classic sense, addiction, I’ve defined in others in the field of addiction, have defined
1:24:38 it as a progressive narrowing of the things that bring you pleasure such that it causes
1:24:42 disruption to other areas of life and your life becomes maladaptive.
1:24:43 Yeah.
1:24:45 I’m not going to play with the definition of addiction.
1:24:51 I feel like I have enough friends in the addiction space that it’s a very contentious field.
1:24:57 I will try and not use that word although I understand that talking to the general public,
1:25:01 if you say someone has a use disorder versus an addiction, that may not make sense to them.
1:25:02 Right.
1:25:06 But that’s the nomenclature now that people are using, alcohol use disorder at cannabis
1:25:07 use disorder.
1:25:10 This is what you start to see now instead of saying being addicted to pot or being addicted
1:25:11 to alcohol.
1:25:12 Yeah.
1:25:16 And so, I mean, an addiction is obviously a very complex thing that, again, I don’t want
1:25:20 to touch it simply because it’s not my space.
1:25:24 But that being said, there’s no question that people can develop cannabis use disorder.
1:25:27 I mean, it’s definitely a thing.
1:25:31 So if we say is cannabis addictive and kind of a normal lay speak, I would say, yes, it
1:25:33 is addictive.
1:25:34 What does that look like?
1:25:36 How does that relate to other substances of abuse?
1:25:43 I mean, certainly, the outcomes associated with it are going to be slightly different
1:25:48 than something like opiates or alcohol because that’s a totally different beast because you
1:25:52 have fatality potential, there’s a whole bunch of other health consequences.
1:25:56 But if we look at how we would define a use disorder, the criteria for someone hitting
1:26:00 cannabis use disorder is really no different than how someone would hit alcohol use disorder
1:26:04 or opiate use disorder in the sense that it can consume their life.
1:26:06 It can shift the way that they behave.
1:26:09 They can put themselves in risky positions to get access to a drug.
1:26:12 It can consume their time and their energy to have it.
1:26:17 Like you said, if they don’t have access to it, it can trigger an assembly of behaviors
1:26:21 that looks like irritability, anger, frustration, things like that.
1:26:28 So I mean, the numbers in terms of the conversion rate of use to developing use disorder, I
1:26:30 would say are not entirely clear.
1:26:35 The kind of old numbers that used to get tossed around were like 9% to 11% of people that would
1:26:40 start initiating cannabis use would probably transition to develop use disorder.
1:26:45 The more modern numbers, I would say, if we’re looking at people who are already using weekly,
1:26:47 we’re talking probably closer to 30%.
1:26:48 So it’s much higher.
1:26:51 I mean, when you’re using that frequently, then the rates of people who would qualify
1:26:54 as having cannabis use disorder probably go higher.
1:26:56 So I just want to make sure I’m understanding clearly.
1:27:03 For people that use cannabis weekly, the propensity for developing cannabis use disorder
1:27:05 is on the order of about 30%.
1:27:10 Yeah, I’d say in that neighborhood, they would probably qualify as meeting criteria for cannabis
1:27:11 use disorder.
1:27:13 Because weekly doesn’t seem like that often.
1:27:14 No.
1:27:16 I mean, it depends, again, on how you vary this.
1:27:20 Again, I’ve had a lot of conversations with the public, and I think depending on someone’s
1:27:24 experience in their own or in their own inner circles, life with cannabis, the way they
1:27:26 would view it is very differently.
1:27:31 Because I think a lot of people, again, regardless of anyone’s opinion of alcohol, if someone
1:27:35 told you they had a glass of wine with dinner every night, I don’t think people would say
1:27:37 you have an alcohol use disorder.
1:27:38 I think that’s not uncommon.
1:27:39 I don’t think they would.
1:27:45 Similarly, if someone had a brandy at the end of the night or a nightcap to go to bed
1:27:48 and they did that on a nightly basis, I don’t think anyone would say that they have a use
1:27:49 disorder.
1:27:54 And I think with cannabis, there are a lot of people that fall into that bracket that
1:28:00 would use it even daily, but relatively infrequently and kind of as an end of the day thing.
1:28:04 I think some of them certainly would fall into the criteria of cannabis use disorder.
1:28:09 Because if you start looking and say, well, if you travel to Egypt, are you going to go
1:28:13 put yourself at risk of going to jail to get access to cannabis because you can’t function
1:28:14 without it?
1:28:17 If you do, then yeah, you’ve got cannabis use disorder.
1:28:19 Are you going to burn relationships?
1:28:23 Are you going to start failing at meeting responsibilities or getting things done on
1:28:26 time because you’re preoccupied with cannabis?
1:28:30 Yes, you’re going to hit the criteria for cannabis use disorder.
1:28:34 If it’s someone who’s kind of just intermittently using it the same way that a lot of people
1:28:39 casually use alcohol, I would say a lot of them probably wouldn’t hit criteria.
1:28:45 But I think to someone who has never had cannabis in their inner circle or in their life, they
1:28:49 look at it like a drug like cocaine, whereas they’re like, wow, if you’re using cocaine
1:28:52 on a daily basis, we’d be super concerned about you.
1:28:58 And so I think that’s this like, it’s just as you go, I mean, cannabis is in this really
1:29:03 weird transitionary period, I would say, of going from illicit to not just because of
1:29:05 the changes in the legal regulatory framework.
1:29:09 I mean, in Canada now, we’re like five and a half years into legalization.
1:29:14 So in many ways, I would say the transition has happened where a lot of people view cannabis
1:29:18 very similarly to alcohol, whereas you go to some states and the perspective is still
1:29:19 very different.
1:29:21 And certainly if you’re still in one of the states where there’s no legal access, people
1:29:26 still look at cannabis the same way they look at a lot of other illicit drugs like cocaine
1:29:27 or amphetamines or things.
1:29:28 That’s interesting.
1:29:33 I was under the impression this has really changed over the last five, 10 years.
1:29:39 Coming up, I mean, I think there are still people in jail now because of possession
1:29:42 and sale of cannabis.
1:29:46 And then of course, there are stores not far from here where people are selling cannabis.
1:29:47 It’s ironic.
1:29:48 Yeah, sadly.
1:29:54 It’s very, I mean, obviously a big push for legalization is not endorsement of the safety
1:29:55 of cannabis.
1:30:00 It’s more the harms associated with prohibition outweigh the harms associated with legalization.
1:30:03 I think that’s generally the public health perspective.
1:30:05 That’s certainly what motivated it in Canada.
1:30:09 And there was some attempts, let’s say, at restorative justice in terms of removing criminal
1:30:13 records and things may not have been entirely as successful as people had hoped it would
1:30:15 be, but it certainly has changed things.
1:30:19 I mean, we can look at our federal data and see that arrest rates related to cannabis are
1:30:22 obviously very low compared to what they were.
1:30:26 That obviously becomes very important because there are clearly minoritized communities.
1:30:29 They get hit more with this than other communities.
1:30:35 And so the kind of perpetual disenfranchisement that happens with a prohibition model in
1:30:40 communities that are already suffering from various other things that affect them just
1:30:42 potentiates all that.
1:30:46 So I can understand the legal framework behind why there would be a move to a legalization
1:30:52 state over a prohibition state, which again, a lot of people confuse legality with safety,
1:30:55 which is a weird, I mean, alcohol is the perfect example of this.
1:30:59 I mean, you look at the scale of harms on a public health level.
1:31:02 I mean, alcohol stacks at the top.
1:31:06 Across the board in terms of harms to the individual, harms to society, it’s a lot.
1:31:07 Cannabis has harms.
1:31:08 There’s no question on that.
1:31:11 It just would fall lower than alcohol.
1:31:14 But the way that people view it, a lot of people are like alcohol is legal, therefore
1:31:17 it’s safe and it’s not something to judge people on.
1:31:20 Cannabis at least historically was illegal and in some states still is.
1:31:22 So people view it very differently.
1:31:28 And I think it’s an interesting thing because I feel like, you know, despite the fact that
1:31:31 some people hate the government and hate the way that it regulates their life, there’s
1:31:34 this weird passive belief that like, if the government dictates something as legal, that
1:31:36 means it’s safe.
1:31:46 Is the legalization of cannabis leading to more cannabis users or fewer and/or incidents
1:31:51 of people going into the emergency room suffering from cannabis-induced psychosis, something
1:31:55 that I hope we can also talk about?
1:31:57 So it depends on how you break this down.
1:32:02 So what we’ve seen in Canada is, I would say there’s like demographic differences.
1:32:07 Proportionately, when we look at the biggest change in use, it’s actually elderly communities.
1:32:13 It’s like 55 plus, especially women over 55 tend to be more cannabis users.
1:32:16 Now granted, their baseline was quite low, pre-legalization.
1:32:21 So if you look at a fold change, it looks like a very dramatic increase.
1:32:24 Raw numbers, it’s probably not that high.
1:32:28 But I mean, it was like one to 2% or something before, and now it’s gone up to like 8% or
1:32:29 something.
1:32:31 So it’s a four-fold increase kind of thing.
1:32:34 So we do see the magnitude of that seems to be the biggest in terms of where the use
1:32:36 has come from.
1:32:42 Definitely the young adult population, like 20, 24, that group has definitely seen increased
1:32:43 use as well.
1:32:45 Does it split male/female?
1:32:48 Historically cannabis tended to be more male biased.
1:32:54 I’d say the gender separation there has kind of narrowed quite a bit, where you do see
1:32:58 a lot more females used than historically had.
1:33:00 There is a little bit of difference.
1:33:02 Females tend to prefer edibles over males.
1:33:05 So males tend to like inhalation over females.
1:33:13 So roots of administration vary a little bit based on who someone is, but yeah, interestingly,
1:33:18 we don’t have a lot of actual indication that teenagers have used more.
1:33:20 So you look at 14 to 18-year-olds.
1:33:25 That has been — now, granted, our baseline going in was pretty high, as is down here
1:33:26 in the States.
1:33:27 I mean, Canada and the States both hover.
1:33:32 You look at like grade 12ers, and it’s somewhere between 35% and 40% of them have used cannabis.
1:33:37 Now, I mean, you even have some that are like probably around 5% or probably almost daily
1:33:38 users.
1:33:43 So you do have a pretty high baseline to begin with in that group, but that has remained relatively
1:33:45 unchanged.
1:33:49 If anything, some of the states when they legalized saw slight dips in teenage use of cannabis.
1:33:54 So I think that’s obviously an important demographic to have tracked.
1:33:59 This was one of the concerns with legalization was you’d prove increased access.
1:34:03 Teenagers would get it from their parents and whatnot or had just other siblings and
1:34:07 stuff, and so you’d get this big boost in consumption, but we don’t seem to see that
1:34:11 in terms of raw numbers of teenagers who are using cannabis.
1:34:12 So that’s good.
1:34:14 ER visits.
1:34:16 So we did an interesting roll out in Canada.
1:34:20 We legalized flour for a year before edibles came online.
1:34:24 So we have kind of a before and after.
1:34:31 Once edibles became available, there was a notable increase in unintentional pediatric
1:34:36 consumption that resulted in ER visits because kids would, you know, a lot of these look
1:34:38 like gummies and candies.
1:34:41 People are buying them, not, you know, storing them properly.
1:34:46 Kids would find them and eat them and like become very intoxicated.
1:34:49 I want to make mention of something along those lines.
1:34:58 Actually know somebody whose child accidentally ate THC containing gummies.
1:35:03 Fortunately, the child was fine, but there are actually pretty serious ramifications
1:35:05 for this.
1:35:11 The parents actually are quite susceptible to legal action if this happens, right?
1:35:13 So this is something to like really keep in mind.
1:35:17 And there are a million other health related reasons why this is probably.
1:35:21 I don’t know if that’s true in Canada the same way, but in the states.
1:35:27 If your kid gets into a stash of THC containing gummies and ends up in the emergency room,
1:35:32 there will also be, most likely, there’ll be a police visit to that emergency room also,
1:35:34 and it doesn’t bode well for the parents.
1:35:35 It’s a very serious issue.
1:35:41 And again, this was highlighted to me by someone that I know who didn’t anticipate any of this,
1:35:43 but you know, kids are good at finding candy.
1:35:47 And if that candy contains THC and they end up in the emergency room, serious issues.
1:35:50 Nonetheless, if your kid is acting strange because you think they ingested THC containing
1:35:53 anything, take them to the emergency room anyway.
1:35:58 Well, so this was one of the things that also was influenced by legalization is in Canada,
1:36:04 like some of the increase in the ER visits was because of the shift in legalization and
1:36:06 the change in policy.
1:36:12 And so, you know, if your kid ends up drunk underage, it’s not the same ramifications as
1:36:14 if your kid used an illegal substance underage.
1:36:21 And so, once cannabis was legal, people were more likely to actually go into the ER because
1:36:24 the consequences were different.
1:36:29 And so, sure, some of this is availability, and some of it is just like, okay, I’m not
1:36:33 as concerned now about something happening because I’ve taken my kid in, like I’m not
1:36:36 going to have my kid taken away from me or whatnot.
1:36:39 So there is, I mean, both those factors, I think, have contributed to it, but we definitely
1:36:44 see the majority, at least, of kids ending up in the ER is almost all based on edibles.
1:36:50 That’s, I can’t imagine a situation where that would happen from inhalation.
1:36:51 It would be very rare, if it would.
1:36:53 It’s almost always edibles because kids find them.
1:37:00 So as long as we’re talking about edibles, is there any fundamental difference between
1:37:04 the dose regulation that you talked about earlier of inhalants versus, excuse me, versus
1:37:10 edibles, meaning earlier, you said that even if it’s high THC-containing cannabis, people
1:37:14 will self-regulate to achieve the same, approximately the same blood concentrations.
1:37:19 But with edibles, I imagine you eat half a cookie, a quarter of a cookie, and you can
1:37:21 end up in a vastly different place than you expected.
1:37:26 So edibles, so this throws a wrench in the whole system.
1:37:30 And I’ll say this in the context of blood levels, and then what that means from a regulatory
1:37:33 capacity as well because of the impact this has.
1:37:37 Edibles are very low doses, for the most part.
1:37:41 I mean, in Canada, at least, you cannot buy a pack of edibles, and I think this law might
1:37:42 be changing.
1:37:45 At least when they first brought it in, no pack could have more than 10 milligrams of
1:37:46 THC in it.
1:37:51 So that either meant one 10-meg gummy or two five-meg gummies or four 2.5-meg gummies,
1:37:52 you get it.
1:37:55 So you couldn’t, in one package, have more than 10 milligrams of THC.
1:38:02 Now, for people who are, I would say, relatively naive to cannabis or THC, even people who
1:38:08 might use it intermittently, most people will feel five milligrams, like they’ll feel some
1:38:11 form of intoxication.
1:38:13 Some will even feel it at 2.5-megs.
1:38:17 Most people will feel it at five, virtually everyone will feel it at 10.
1:38:22 Now, if you look at the blood levels these produce, we’re now talking blood levels of
1:38:24 two to five nanograms per mil.
1:38:27 So folds lower than what you get from inhalation.
1:38:28 Before you said 100.
1:38:29 Yeah.
1:38:30 So this is dramatically lower.
1:38:36 And so also the time course of this is fundamentally different.
1:38:44 And oral consumption, you’re looking at a minimum of 30 to 45 minutes for onset of intoxication
1:38:46 for some people up to 90 minutes after they’ve eaten.
1:38:51 Now this is also the reason why the majority of adverse events that happen with cannabis
1:38:54 happen with edibles, because people don’t understand this.
1:38:58 And so they eat a cookie or a gummy, they wait half an hour, like, “I’m not feeling
1:38:59 anything.
1:39:00 I clearly didn’t take enough.”
1:39:03 They double their dose, and then 15 minutes later it starts hitting them.
1:39:07 And then once it fully kicks in, it’s just like a steamroller.
1:39:08 I’ve heard of this happening.
1:39:09 Yeah.
1:39:11 I mean, there was that New York, I think it was Maureen Doud or someone, went down to
1:39:18 Colorado and she ate an insane amount of THC and a chocolate bar, some 50 or 100 milligrams,
1:39:21 and spent the weekend on the floor of a hotel room, being like, “This was the most
1:39:22 aversive experience.
1:39:25 Why would anyone do this?”
1:39:27 And again, I think people just don’t understand the dosing around this.
1:39:30 And so this is one of the things we’re trying to do in Canada, and I was create this idea
1:39:34 of standardized dosing units, so that people have, like we do with alcohol, we always say,
1:39:38 one beer is the equivalent of one glass of wine versus, you know, like a shot of tequila
1:39:42 or something, so that there’s some comparator that people understand how many drinks are,
1:39:45 you know, you say two drinks you do, you’re going to hit legal limit kind of thing.
1:39:46 Yeah, it seems very important.
1:39:47 Yeah.
1:39:52 And so this is very difficult to do with cannabis, because the dosing with oral consumption is
1:39:55 just a different ball game than it is with inhalation.
1:39:59 But what happens with oral consumption is, like, it kind of very slowly leaks out of
1:40:03 the GI tract, and it also goes through first-past metabolism in the liver.
1:40:10 And what happens there is you get a metabolite called 11-hydroxy-THC, which seems to be a
1:40:13 bit more potent than THC is in terms of its ability to activate the receptor.
1:40:20 So it’s efficacy, at least, at driving a response through CB1 receptors seems to be higher than
1:40:25 what you would get with just the parent molecule of THC itself.
1:40:29 And so, and it seems to accumulate a lot more as well.
1:40:34 So at any given time, you know, you’ve got THC kind of leaking out of the gut, going
1:40:38 through the liver, making 11-hydroxy, and it progressively accumulates in the brain.
1:40:43 And that’s one of the reasons why it takes, you know, 45 to 90 minutes to kick in.
1:40:47 But then the high itself also lasts, like, six hours, four to six, sometimes eight, depending
1:40:52 on the person, what they’ve eaten, versus inhalation is just this, like, spike.
1:40:56 So you get this very rapid, because it goes right through the lungs into the blood, goes
1:40:58 into the brain, but it also clears out.
1:41:02 And so, yeah, people will start feeling intoxicated two to five minutes.
1:41:07 They, the peak high is, like, 15 to 30 minutes maybe from consumption, and then they’ll start
1:41:08 to come back down.
1:41:12 And you will still see some indications of intoxication that can go on for three to four
1:41:17 hours, but the bulk of the intoxication from inhalation is done by two hours for the most
1:41:18 part.
1:41:25 As long as we’re on the topic of time course, you know, based on what I was able to find,
1:41:30 I believed, and tell me if I was wrong, that cannabis can stay in one system for as long
1:41:31 as 80 days.
1:41:35 The reason I brought this up previously was there are a number of people who have used
1:41:40 cannabis are going to take a drug test and want to know how fast it can clear from their
1:41:42 system.
1:41:48 But based on conversations we had offline, sounds like that 80 days might be a bit too
1:41:49 long.
1:41:51 I mean, you could still fail a drug test at 80s.
1:41:55 I would say, I feel like, I think the way it was worded more, it was like that, you
1:41:56 made it sound like that was the standard.
1:41:58 I wouldn’t say that was the standard at all.
1:42:05 I would say, for the majority of people, 30 days probably after that, they would not pass,
1:42:09 or they would be able to pass a drug test, but that’d be abstinence for 30 days.
1:42:13 After abstaining for 30 days, and it’s going to be highly variable depending on how much
1:42:14 you consume.
1:42:17 I mean, if you’re talking about someone who’s used it once, I don’t imagine it would be
1:42:18 in your system out long.
1:42:19 That’d be surprising.
1:42:23 The thing is, THC is a lipophilic molecule.
1:42:24 It’s fat soluble.
1:42:25 Yeah.
1:42:26 So it’s fat soluble.
1:42:27 It likes the Stortza.
1:42:28 It doesn’t like the blood.
1:42:29 The blood is aqueous and watery.
1:42:30 It likes fat.
1:42:34 So it goes into the brain, it goes into the fat, and it kind of resides there.
1:42:42 And it can essentially kind of slowly leak back as it, as, you know, THC concentrations
1:42:46 in the blood would reduce, THC that’s in the fat will start kind of leaking back into the
1:42:47 blood still.
1:42:51 So detectably, you will still have THC for quite some time.
1:42:54 I mean, some of this, again, it’s going to be depending on how much cannabis someone’s
1:42:58 used, how much THC they’ve consumed, how long it’s been in their system for.
1:43:03 I would have thought this was going to be somewhat reflective of people’s body fat content,
1:43:06 although talking to colleagues who do this, they say not always.
1:43:13 But we do know, you know, certain things like exercise, for example, anything that’s going
1:43:15 to trigger adrenaline because adrenaline is lipolytic.
1:43:20 So adrenaline causes fat to metabolize and release stuff that’s inside it.
1:43:24 So there are plenty of cases I’ve heard from people where they were testing themselves
1:43:29 and were negative and then went for a run or went to the gym and then tested positive.
1:43:30 Or lost weight.
1:43:31 Yeah.
1:43:32 Or they’ve lost weight.
1:43:40 But anything that’s going to cause the lipolysis to occur so that it releases that THC, you
1:43:44 can certainly all of a sudden test positive again when someone had tested negative previously
1:43:48 just because of the fact that there still is some in the fat.
1:43:51 And so this is where something like, and this is what I mean by standardization of regulatory
1:43:55 issues become very complicated, was I remember right when legalization happened in Canada,
1:43:59 all these kind of chemists were like talking to me about they’re going to create like a
1:44:02 breathalyzer for cannabis because this way they’ll be able to do roadside detection the
1:44:05 same way they could do with alcohol.
1:44:10 And I kept trying to say to them, I’m like, the rate limiting step here is not the science
1:44:12 of detection thresholds.
1:44:17 It’s the biology of how the body processes cannabis and you’re never going to get a test
1:44:23 that works because you can take someone who has eaten an edible and is profoundly intoxicated
1:44:28 and they will have possibly under five nanograms per mil of THC in their blood.
1:44:33 But you were talking about this metabolite that can come from the edibles that doesn’t
1:44:35 come from inhalants that can have a much more potent effect.
1:44:38 You get a bit of it from inhalant, but not nearly as much as you get from edibles.
1:44:41 So it’s sort of a different situation altogether.
1:44:44 It is, but it’s also the timeline because of the fact that with inhalation, it’s like
1:44:50 a bolus that hits you at once, you get a high blood level.
1:44:52 With edibles, it’s like the time course.
1:44:56 So I mean, it’s going to be like five nanograms per mil, let’s say, but it would be like that
1:44:57 for a long time.
1:45:01 Because the hundred nanogram per mil from smoking is like for 20 minutes and then it
1:45:03 starts dropping.
1:45:07 But the problem is with the way that you detect it is you can take someone who’s a chronic
1:45:12 cannabis user and is completely sober and hasn’t consumed in a day or two.
1:45:17 And their basal levels of THC in their blood may be higher than someone who’s profoundly
1:45:19 intoxicated by an edible.
1:45:22 Just by the sheer nature of the fact that it would reside in their fat tissue or their
1:45:24 brain, it would leak back into the blood.
1:45:30 And so you have this issue where, let’s say your cutoff was five nanograms per mil, which
1:45:34 is for some of the stuff detection thresholds would hover around that area.
1:45:38 So you’re going to have someone who’s dead sober that tests positive and someone who’s
1:45:40 profoundly intoxicated who tests negative.
1:45:43 So it’s like, what’s the value in this?
1:45:44 It’s not telling us anything.
1:45:48 Well, I guess it sounds like the drug tests either have to be revised or discarded.
1:45:52 And it also sounds like if somebody is going to take a drug test for cannabis and they have
1:45:58 used cannabis in any form in the previous 90 days, let’s say, going for a run right
1:46:04 before your test is going to liberate whatever THC resides in the fat stores.
1:46:05 Potentially, yeah.
1:46:06 So I mean, it is complicated.
1:46:10 A lot of people are writing this down.
1:46:14 Along the lines of what’s known and not known, I’m curious what is known and not known about
1:46:20 the effects of cannabis THC in particular on hormones.
1:46:26 I’ve seen studies that site increases in testosterone from cannabis use.
1:46:30 I’ve seen studies that site increases in estrogen from cannabis use.
1:46:35 And they argue for increased aromatization of testosterone into estrogen as the mechanism.
1:46:39 I’ve also seen studies that say the exact opposite.
1:46:46 So is there any global takeaway message yet or is it just highly variable or depends too
1:46:49 much on dose and individual age, et cetera, that we just really can’t say?
1:46:53 I would say there’s nothing that’s super clean cut.
1:46:57 I mean, I know in the previous podcast, you talked about a prolactin thing.
1:46:58 Right.
1:46:59 Well, there’s…
1:47:03 And this is where I think it’s important that people understand that on this podcast,
1:47:08 we cover science and studies, but we also pull from common experience that people want
1:47:10 explained if we can.
1:47:15 And one of the experiences that is talked about a lot in certain, let’s just say online
1:47:20 communities is the experience of people who had no pre-existing gynecomastia, male breast
1:47:21 development.
1:47:22 Yeah.
1:47:23 Will smoke marijuana…
1:47:25 Do we call it marijuana these days?
1:47:27 We’ll go with cannabis.
1:47:31 I actually got a lot of comments that said marijuana is an inappropriate term.
1:47:32 It is.
1:47:33 Okay.
1:47:34 Smoke…
1:47:35 We’ll go back to that.
1:47:36 That was new to me.
1:47:37 I didn’t know.
1:47:38 So forgive me if I didn’t know.
1:47:39 No, no, no.
1:47:40 I mean, I understand it, but yeah, a lot of people don’t know that.
1:47:41 Okay.
1:47:49 So a lot of people think that it’s an inappropriate term, but it’s not an inappropriate term.
1:47:50 It’s not.
1:47:51 It’s not an inappropriate term.
1:47:52 It’s not.
1:47:53 It’s not.
1:47:54 It’s not.
1:47:55 It’s not.
1:47:56 It’s not.
1:47:57 It’s not.
1:47:58 It’s not.
1:47:59 It’s not.
1:48:00 It’s not.
1:48:01 It’s not.
1:48:02 It’s not.
1:48:03 It’s not.
1:48:04 It’s not.
1:48:05 It’s not.
1:48:06 It’s not.
1:48:07 It’s not.
1:48:08 It’s not.
1:48:09 It’s not.
1:48:10 There’s a lot of comments about that.
1:48:17 A lot of that discussion around does cannabis impact aromatization of testosterone and
1:48:20 estrogen, and you can find a little bit of evidence for that, but you can also find evidence
1:48:22 to the contrary in the scientific literature.
1:48:23 So I’m just curious your thoughts on this.
1:48:24 It’s super mixed.
1:48:27 So I mean, you’re talking about something like prolactin, for example.
1:48:31 That is another one that’s obviously involved in this whole cascade stuff.
1:48:36 Generally, I would say the bulk of the literature actually says that cannabis would suppress
1:48:37 prolactin, not increase it.
1:48:39 That’s the majority of the literature that’s out there.
1:48:42 Dopamine is one of the main ways that prolactin is suppressed.
1:48:43 They’re kind of in a seesaw.
1:48:46 They work in somewhat seesaw fashion.
1:48:49 And probably, I mean, the rodent work would suggest it’s through dopamine that’s turning
1:48:53 off prolactin, because you can reverse some of these effects by playing with dopamine signaling.
1:48:55 So I don’t doubt that’s the mechanism.
1:49:00 So typically, I would say more often, I mean, there’s studies with inhalation and IV that
1:49:04 have generally found reduced prolactin.
1:49:08 And in chronic cannabis users, they find somewhat lower resting states of prolactin.
1:49:09 That’s been found in one study.
1:49:10 It came out of Yale.
1:49:11 Interesting.
1:49:17 Testosterone gets a little bit more complicated, because there are a lot of studies that find
1:49:20 A to begin with.
1:49:24 Cannabis users may have higher levels of testosterone just at rest.
1:49:25 Now whether that’s a pre-existing thing–
1:49:26 Is there any reason to think that would be the case?
1:49:28 I don’t know.
1:49:29 Yeah.
1:49:35 I mean, that being said, a lot of the stuff– now granted, this was mostly done in the ’70s.
1:49:40 And this is from my previous life, because my undergrad and graduate supervisor, he was
1:49:44 a neuroendocrinologist, focused much more on sex hormones and reproductive hormones.
1:49:48 So we’ve written a few reviews, so I’ve done reviews on this area.
1:49:50 And I know the literature somewhat.
1:49:51 It’s mixed.
1:49:57 But generally, from the ’70s studies, what they would often see is that if they would
1:50:02 look– serially look at testosterone after someone consumed, they would have little dips.
1:50:03 That wasn’t uncommon for them to find it.
1:50:06 Not every study found it.
1:50:11 That being said, the kind of range that testosterone stayed in was always the normative range.
1:50:15 Like it was never that it went so low that someone would have classified as being hypergonadal
1:50:20 or would lead to something like gynecomastia, at least from a testosterone deficiency side
1:50:25 in terms of the balance between testosterone and estradiol.
1:50:28 I don’t know as much about the aromatization side of it.
1:50:29 Again, I’d say it’s pretty mixed.
1:50:35 I mean, I don’t think the gynecomastia stuff is– I mean, certainly people online might
1:50:36 be talking about it.
1:50:37 And there might be some other components to this.
1:50:40 I’ve also heard– and again, this isn’t like science.
1:50:44 This is just the same kind of stuff you see on random internet communities.
1:50:46 People talking about, oh, well, you know, it has plant estrogens.
1:50:49 So maybe they’re subbing in and having estrogenic effects.
1:50:50 I don’t know how valid any of this is.
1:50:54 Yeah, it seems to be– I mean, there are phytoestrogens and tons of different plants.
1:51:01 The sort of attacks on soy and the attacks on– this, I think, grew out of the soy versus
1:51:04 meat communities and plant-based versus carnivore.
1:51:09 This podcast has always been agnostic with respect to nutrition and is really– if we
1:51:15 encourage anything, it’s that people consume unprocessed and minimally processed foods
1:51:16 as the bulk of their food intake.
1:51:17 There seems to be enough data on that.
1:51:22 But whether or not people choose to be vegan and eat a lot of plants or carnivore and just
1:51:28 meet– we’ve essentially stepped out of that debate because let’s just say it’s as futile
1:51:31 as about any other debate.
1:51:33 You’re just never going to– it’s completely circular.
1:51:34 You end up right back in Twitter.
1:51:35 Yeah.
1:51:39 And I think that– I mean, when it comes to something like this, I’ve not seen any compelling
1:51:40 evidence for it.
1:51:44 So I can’t– I certainly wouldn’t say that it’s a typical side effect that men would
1:51:47 experience as developing breast tissue in response to cannabis.
1:51:51 I feel like if that was the case, it would be very known in the scientific community
1:51:53 as something that comes out.
1:52:00 So this seems to be something that purportedly occurs on a backdrop of elevated androgens,
1:52:06 meaning impuberty or a backdrop of some other form of androgen increase.
1:52:08 Like someone who’s on steroids or something.
1:52:09 Yeah.
1:52:10 But that’s not the community I’m referring to.
1:52:15 It seems that– because transient gynecomastia during puberty is actually fairly common because
1:52:19 of there’s just so much androgen being produced in puberty that some gets aromatized.
1:52:24 And that the idea– I’m not stating this as fact– is that it may exacerbate that.
1:52:28 In any case, it sounds like the takeaway from this is that there aren’t a lot of conclusive
1:52:33 studies about the effects of cannabis on testosterone or estrogen or aromatization
1:52:34 in any direction.
1:52:35 Yeah.
1:52:40 I don’t– I mean, I’d say like, yeah, enough studies to suggest that you might see transient
1:52:45 drops in testosterone from cannabis, and it seems to be relatively short-lived.
1:52:50 It doesn’t seem to– but again, a lot of these studies also find that the basal testosterone
1:52:52 is already kind of high to begin with.
1:52:54 So you’re staying in a normal dynamic range.
1:52:55 There it is again.
1:52:56 It’s homeostatic.
1:52:57 Just like the endocannabinoids.
1:52:58 Yeah.
1:52:59 And that’s the thing.
1:53:01 I mean, testosterone fluctuates across the day anyway.
1:53:02 Sure.
1:53:03 I mean, there’s other things that fluctuate.
1:53:04 It’s like cortisol.
1:53:05 These hormones have cycles.
1:53:11 So as long as you’re in this normal range, there really shouldn’t be any kind of behavioral,
1:53:17 like in terms of sex drive for testosterone or like physiological like gynecomastia or
1:53:22 some change in– I mean, now, there are potentially effects of THD directly on the testes that
1:53:23 could affect sperm.
1:53:26 That could happen independent of changes in testosterone.
1:53:28 Are those positive or negative changes?
1:53:34 I’m assuming that the studies you’re referring to saw disrupted what they call sperm quality,
1:53:36 which has to do with motility, et cetera.
1:53:37 Yeah.
1:53:41 I mean, a lot of the kind of in vitro stuff definitely would suggest that some of the animal
1:53:42 stuff as well.
1:53:44 The human stuff is definitely a bit mixed, I mean.
1:53:48 But again, if anything, it would be like, yeah, it could have some effect on sperm.
1:53:49 So I have like–
1:53:53 As we say this, I’m just chuckling to myself because anytime this conversation comes up
1:53:58 about a substance and sperm quality or egg quality, I always get a barrage of comments
1:54:02 of people telling me how many children they conceived while under the influence.
1:54:04 No one is saying that you’re going to be infertile.
1:54:09 But if people are having challenges conceiving, it might be something to think about.
1:54:10 I would say that.
1:54:11 I would agree on that.
1:54:16 So I would say if someone was asking me this and they were trying to get pregnant and struggling,
1:54:21 I would say, well, definitely cut cannabis because some people may be more impacted by
1:54:22 it than others.
1:54:26 So for some various biological reasons that we don’t have a biomarker for, there may be
1:54:30 some men that use cannabis and it has a profound effect on their sperm quality, their sperm
1:54:33 capacitance, their ability to maintain fertility.
1:54:36 And for the bulk majority of men, I’d say it’s probably not the case.
1:54:40 But again, if you’re someone who is struggling and you use cannabis, male or female, I would
1:54:45 say cut that out and see if that has an effect for you along those lines.
1:54:52 I saw it kind of a jaw dropping statistic and I’m not sure I still believe it.
1:55:00 But you tell me what you know about this, which is that up to 15% of pregnant women
1:55:04 in the U.S. have used cannabis during pregnancy.
1:55:08 That just seems that number just seems too high and yet, you know, it exists out there.
1:55:11 It’s very, I mean, I’ve heard higher numbers in the match.
1:55:12 In the research literature.
1:55:13 No, I’ve heard higher numbers in that as well.
1:55:14 Okay, so I’m on the low end of this.
1:55:17 Well, I mean, so I’ve heard as low as two and I’ve heard as high as 20.
1:55:23 Okay, two sounds like, okay, that I could imagine, but as high as 20.
1:55:27 And do we know what the effects on the developing fetus are?
1:55:29 There’s lots of unpack there.
1:55:35 So first thing, going back to the levels, that’s challenging because, again, this depends
1:55:38 on are you talking about self-report or are you talking about verified blood levels because
1:55:39 those are varied.
1:55:43 So some of the higher numbers actually come from blood levels where they’ve taken blood
1:55:47 samples and found THC, but the women have reported not using cannabis.
1:55:52 And so the idea that it’s like the self-report numbers tend to come in around two or three.
1:55:57 My guess is the real number is probably somewhere around 10%, but that also is going to vary
1:56:01 depending on what you’re talking about because there are a proportion of people who are using
1:56:06 cannabis and become pregnant and are unaware they’re pregnant and are still using cannabis
1:56:12 and that would still qualify under the way that it’s defined that someone used cannabis
1:56:13 while pregnant.
1:56:18 So the majority, I would say the overwhelming majority of people, once they learn they’re
1:56:23 pregnant, now that can be all the way up to almost the end of the first trimester, typically
1:56:25 stop using cannabis.
1:56:27 That seems to be the norm, I would say.
1:56:28 Important point there.
1:56:33 Yeah, and I think also the number that carry on through the entire gestational period is
1:56:36 going to be a lot less, I would guess.
1:56:44 Now the motivations for this quite often are more in the capacity of the kind of anti-nausean
1:56:48 qualities that cannabis can have for some people and for women struggling with morning
1:56:49 sickness.
1:56:55 Now anecdotally, I have heard women say with the history of things like thalidomide and
1:57:00 other anti-nausean drugs that had profound ratogenic effects on the fetuses, women have
1:57:04 said that they would rather use cannabis than one of these other compounds because they’re
1:57:10 less concerned about the impacts of cannabis than they are because of the thalidomide
1:57:11 effects that happened.
1:57:16 The thalidomide effects are malformation of the limbs and other bodily structures in
1:57:17 the fetuses.
1:57:24 It was an absolute tragedy of medicine that this occurred in even one birth.
1:57:30 But yeah, the reason why thalidomide is now, I believe, banned as a drug for use during
1:57:31 pregnancy.
1:57:33 Yeah, I actually have no idea, but I would imagine.
1:57:37 I think it would be one of those hard things to sell, given its history especially.
1:57:43 But so I think there is a reticence of a lot of people to consider using pharmaceuticals
1:57:48 to regulate nausea because they’re uncertain of the consequences of it and they feel that
1:57:50 cannabis may be safer.
1:57:56 Now that in and of itself could present some problems in terms of that thought process.
1:58:02 Now there was also a study that I thought was like, some of these things just frustrate
1:58:03 you.
1:58:06 It’s where they actually decided to call, this was done in Colorado where they called
1:58:10 dispensaries and just acted naive and asked what their recommendations were.
1:58:15 And it was something like 80 to 85% of them were actually recommending that people would
1:58:18 use cannabis to manage morning sickness.
1:58:21 And I thought that was like, it’s just one of these disappointing things where you’re
1:58:25 like, why are you being so wildly irresponsible to kind of promote these things?
1:58:29 You’re talking about that irresponsible that the dispensaries would say that or irresponsible
1:58:32 that the study was carried out that way, because it’s a little bit of —
1:58:33 Entrapment.
1:58:36 You said it, not me.
1:58:37 Could be.
1:58:40 I mean, you can bulk at either side of this.
1:58:47 I think it’s, I mean, I have a lot of frustration in general with the information that bud tenders
1:58:48 put out into the world.
1:58:50 Is that what they’re called bud tenders?
1:58:51 Yeah, bud tenders.
1:58:53 That’s kind of like the colloquial term that people will use for someone who sells cannabis
1:58:54 at a dispensary.
1:58:58 We see this in Canada and I’ve heard this throughout the States as well.
1:59:04 I personally have been a huge advocate for the fact that I think, so, you know, I worked
1:59:07 in restaurants and bars and stuff when I was younger.
1:59:11 And for me to serve alcohol, I had to undergo, I don’t know if you do this in the States.
1:59:14 In Canada, you have to do like a, it’s like a weekend course essentially called like serving
1:59:19 it right or some other terminology where you learn the basics of alcohol, harms, blah,
1:59:23 blah, blah, how to tell if someone’s intoxicated, when you have to cut them off, all these things
1:59:24 that you have to do to be able to serve alcohol.
1:59:29 I have no idea if this exists in the States, but it was a thing in Canada.
1:59:33 Bar tenders in the US put in the comments on YouTube, do you have to undergo training
1:59:35 about alcohol to be a bartender?
1:59:42 Even if it’s just like an online quiz, but like, so my perspective is because pre legalization,
1:59:45 at least in Canada, there was somewhat of, I think of a misguided thought that people
1:59:48 would leverage their physicians for knowledge about cannabis.
1:59:52 And what’s become very apparent is that the overwhelming majority of people talk to the
1:59:54 people selling them the cannabis.
2:00:00 And yet those people selling cannabis don’t need to have undergone any form of education.
2:00:05 And so like this kind of kills me because we’ve worked very hard to try and create educational
2:00:09 platforms that are like agnostic in terms of our position on cannabis that are just based
2:00:10 on the science.
2:00:13 I’m an executive director of an organization called the Canadian consortium for the investigation
2:00:18 of cannabinoids, the CCIC and it’s, we’ve done CME courses for physicians to try and
2:00:21 train them about cannabis because I think it’s important that physicians understand this.
2:00:27 But I’ve tried suggesting that I think that anyone selling cannabis should undergo a course
2:00:33 like this just so that there’s some consensus in the informed level that someone who comes
2:00:36 in because a lot of people going to buy cannabis are quite naive about it.
2:00:38 And they just, I mean, even when we’re talking about dosing and what we’ve talked about with
2:00:43 edibles or smoking or how people consume it, like you need to have a reliable source of
2:00:47 information at the front line that is able to relay that to people.
2:00:52 And it becomes very frustrating to me that they have become the main source of information
2:00:56 that people go and I’m uncertain of what their level of training is.
2:01:00 You’re certainly doing your part to provide the public education about cannabis now.
2:01:05 So we all appreciate your highly informed and broad distribution of this information.
2:01:09 Because this is also an issue with psychedelics which currently don’t have legal status in
2:01:13 the U.S. This is an ongoing process of whether or not it will.
2:01:17 Right now, things are really on the teeter-totter with MDMA where we await the decision from
2:01:18 the FDA.
2:01:25 But the early recommendation to the FDA was to not approve MDMA as a treatment for PTSD.
2:01:29 That’s today and mid to late June 2024, we’ll see what happens.
2:01:35 But this is also the case for ketamine which has legal status, but many people are accessing
2:01:39 ketamine not through a physician but through online sources.
2:01:45 So what you’re speaking to here is a much larger issue and I absolutely agree with you.
2:01:50 I think most people are probably not aware except by experience, positive or negative
2:01:55 in some cases about the differences in blood concentration as it relates to number of toks
2:01:58 versus concentration versus edible.
2:02:02 These are critical themes especially for where we’re going to go next which is all the discussion
2:02:04 about high THC and psychosis.
2:02:05 Yeah.
2:02:06 Yeah, exactly.
2:02:10 I just wish, I mean, again, even if this was just like an online course that wasn’t that
2:02:17 much but at least had some consensus of information that was the basics about how to have conversations.
2:02:22 I mean, some of the, our system at least is somewhat provincially regulated.
2:02:28 So our organization has worked with the Ontario group that deals with cannabis distribution,
2:02:33 the OCS which is Ontario Cannabis Stores and helped to create some information pamphlets
2:02:34 and stuff.
2:02:39 It’s not the same as a teaching course but at least it’s like these little infographics
2:02:45 stuff that gives people rough breakdowns of things and gives you a little bit of information
2:02:49 about dosing and understanding things, especially with some edibles, how long you should wait.
2:02:50 Just stuff like this.
2:02:55 It sounds like the take-home message is proceed with caution low and slow.
2:02:57 I mean, that’s the, yeah.
2:02:59 Don’t ingest too much too quickly.
2:03:04 If one is going to explore this legally, of course, take a little bit.
2:03:05 Wait.
2:03:06 Take a little bit.
2:03:07 Wait.
2:03:09 Because otherwise you’re going to get the, who was the reporter?
2:03:11 Oh, I think it was Maureen Dowd.
2:03:12 Right.
2:03:13 You’re going to, I don’t know.
2:03:14 Actually, when I say that-
2:03:16 Is she still on the floor in a Colorado herself?
2:03:17 She may have recovered right now.
2:03:19 Reporting from the floor in Colorado.
2:03:24 But like, it can become very frustrating.
2:03:28 It’s just the kind of lack of understanding that exists in this space.
2:03:31 And so I think this is one of the reasons why we’ve really kind of tried to push the
2:03:34 public health side of this a lot more.
2:03:38 And we have, I mean, there was the Center for Addiction and Mental Health in Canada,
2:03:40 which does a lot of the organization of these things.
2:03:44 They did kind of put together what I found to be really useful, which again, could be
2:03:45 leveraged in the States.
2:03:46 These are all accessible on lines.
2:03:48 It’s called the lower risk cannabis use guidelines.
2:03:52 They kind of tried to create a framework that is similar to how people have done stuff with
2:03:53 alcohol.
2:03:56 That just kind of goes through and a lot of it is this low and slow approach, but it’s
2:03:59 like, obviously you want no risk, you abstain.
2:04:03 If you’re going to use, these are the different ways to engage in harm reduction.
2:04:08 You know, like obviously oral consumption has, you know, you avoid the issue of lung damage
2:04:11 that you could get from smoking.
2:04:13 But then, you know, with oral consumption, you have to be aware of dosing and timing
2:04:14 and all these other considerations.
2:04:17 What about vaping?
2:04:21 Can people self-regulate their THC concentration in the blood by vaping as well as they can
2:04:24 by joint or bong or other form of smoking?
2:04:25 I think that will depend on exactly what you’re vaping.
2:04:29 So in the States, I’ve noticed when people say vaping, they almost exclusively refer to
2:04:32 some kind of oil-based product that’s in a pen.
2:04:37 So in those situations, that’s going to really heavily depend on what the concentration of
2:04:39 THC in that product is.
2:04:44 Now the other form of vaping that I think is a little bit more common in Canada maybe
2:04:46 is vaping of the plant matter itself.
2:04:50 And so this is where they have like a vaporizer device that heats the cannabis to a point
2:04:55 that will essentially hit the lift point to vaporize THC in the cannabinoids.
2:04:56 A little big bag.
2:04:57 Yeah.
2:04:58 Like a volcano.
2:04:59 I’ve seen it.
2:05:00 Yeah.
2:05:01 But it doesn’t create any plant combustion.
2:05:05 So there are studies that have been run on that that have shown that you avoid the combustion
2:05:06 byproducts.
2:05:09 So people don’t like exhale carbon monoxide or these other things that we know can be
2:05:13 damaging if they’re vaping plant matter.
2:05:16 That was actually somewhat approved as like a medical device.
2:05:21 Pre-legalization in cannabis in Canada was only under medical authorization because of
2:05:27 the reduced harm associated with vaporizing the plant matter versus smoking it.
2:05:31 That is, I would say, a safe guideline for harm reduction that if you’re going to try
2:05:34 to avoid, you know, there’s still going to be some issues that happen with vaporization
2:05:36 of plant matter, but it’s not the same as combustion.
2:05:39 So you avoid like some of the other issues that come out.
2:05:43 When we’re talking about oil-based vapor products or whatever they’re in, they’re
2:05:47 usually in some kind of oil-based solution.
2:05:48 Who know?
2:05:49 I mean, we don’t have the research on this.
2:05:50 Like we just don’t know.
2:05:55 I mean, we certainly know like there have been some pretty big errors of like the things
2:05:56 that happen in the states.
2:06:00 Like there was that problem where all those people developed kind of, I don’t know, popcorn
2:06:04 lung or that lung inflammation where several people died from vaping products, which seemed
2:06:08 to be like a byproduct, I believe, of them adding like vitamin E acetate or something
2:06:12 into the, because again, everyone just assumes it’s inert.
2:06:17 But then when it combusts through the vaporization process, it creates a massive irritant on
2:06:18 lung tissue.
2:06:23 And so that was just, you know, again, in my mind, this is a problem with a lack of
2:06:28 a federal regulatory framework because stuff like this happens.
2:06:32 You would not see that on a federal landscape because you’d have to go through testing.
2:06:34 Like people, it’s kind of the wild west you get down here.
2:06:36 Every state has its own rules.
2:06:39 People is not really a lot of like regulation of things.
2:06:41 But if you go overseas, it’s even more wild.
2:06:42 I mean,
2:06:45 Then there’s, I mean, then you have no idea what you’re consuming anywhere, I would say.
2:06:50 Just because outside, I mean, again, Netherlands is a little bit of a different situation.
2:06:51 They’re not legal.
2:06:52 They’re decriminalized.
2:06:55 They don’t know how well the regulation over there, the product is, you know, we’re going
2:06:58 to be doing episodes on stem cells and you get people flying out of country to do some
2:06:59 cell injections.
2:07:02 People are getting them down in Florida who went blind from the injections of stem cells
2:07:06 into the eye and an attempt to save what little vision they already had.
2:07:09 Probably don’t want to get me started on that one.
2:07:12 I’m in total agreement with you, by the way.
2:07:17 I want to make sure that I ask about psychosis and paranoia.
2:07:18 Yeah.
2:07:22 I’ve previously said, and I was sort of, I wasn’t joking.
2:07:31 But I have observed in my history that when people started to experience some degree of
2:07:38 anxiety or paranoia when smoking cannabis, that sometimes the message they would receive
2:07:42 back is to take more, to just adjust the subjective experience.
2:07:44 I think that’s a terrible idea.
2:07:45 Terrible idea.
2:07:46 I am baffled that you heard that.
2:07:47 I have no idea.
2:07:49 Let’s just say I did more than hear it.
2:07:50 Yeah.
2:07:51 See, I’ve observed it.
2:07:53 I cannot even understand that.
2:07:55 That is the strangest thing I’ve ever heard, but okay, yeah.
2:08:02 Well, usually the advice of people in terms of, that was recreational drug taking is rarely
2:08:03 excellent advice.
2:08:04 Yeah.
2:08:05 No, no.
2:08:06 That’s so, yeah.
2:08:10 I mean, I agree with you on that point for sure that you should not be consuming more
2:08:14 if you’re having a bad reaction to it because that will just grease the wheels going downhill
2:08:17 for sure.
2:08:22 I also am aware that there are some very high profile papers that have been published in
2:08:29 the last, really five years or so, pointing to potential increased risk for psychosis
2:08:36 of lasting duration even after the effects of cannabis have worn off in high THC cannabis
2:08:42 users, in particular high THC cannabis users that initiate that cannabis use young and
2:08:45 this might be preferentially impacting males.
2:08:49 I want to make clear that what I just said is not a statement of absolute fact.
2:08:54 It’s my understanding of the conclusions of these papers.
2:08:59 There are other conclusions in these papers also, but that particular conclusion seems
2:09:03 to be important enough that they place it in the abstract and it’s reached major press
2:09:04 headlines.
2:09:11 So I guess the simple question, which probably doesn’t have a simple answer, is does THC
2:09:12 cause psychosis?
2:09:17 So yeah, there’s not a simple answer to that and I think that also is a question over whether
2:09:22 you’re talking about acute drug induced psychotic episode versus the development of a chronic
2:09:25 psychotic disease like schizophrenia.
2:09:30 So the first arm of that is just can people acutely have a psychotic episode to THC or
2:09:31 cannabis?
2:09:32 And the answer to that is yes, it’s not common.
2:09:36 I would say in terms of adverse events that happen with people consuming cannabis, it’s
2:09:40 on the rarer side, but it definitely can happen.
2:09:41 So less than 5% of people that–
2:09:42 Oh, much less than that.
2:09:46 I mean, certainly, I mean, if something like this was happening at a regular frequency,
2:09:49 it would be very well known.
2:09:50 What about anxiety attack?
2:09:54 Yeah, anxiety attack is, I’d say, more of a standard indication that someone’s kind
2:09:55 of gone overboard.
2:09:56 Like that’s not–
2:10:03 Dostage overboard, or does it carry the same setting considerations that psychedelics like
2:10:04 psilocybin–
2:10:05 Both.
2:10:08 So I think there’s some contextual component to it.
2:10:13 There was like, I mean, back in the ’70s when they did more, let’s say, interesting studies,
2:10:18 there’s one where basically they dosed people on THC and then had them undergo oral surgery,
2:10:20 which seems like, in hindsight, a very bad idea.
2:10:23 And I think virtually everyone in that study had a panic attack.
2:10:27 So it really potentiated the stress of what they were undergoing.
2:10:30 And had they been given that same dose in a different setting, I’m not sure it would
2:10:32 have evoked that kind of response.
2:10:40 But there is definitely a dose effect to this in terms of the kind of classic low dose aspects
2:10:47 of THC or cannabis that are usually considered more the positive, pleasurable responses that
2:10:48 are why people use.
2:10:52 Like it reduces anxiety, it relaxes, blah, blah, blah.
2:10:57 That is more of like a low to normalish dose, let’s say, of what someone consumes to produce
2:10:58 those responses.
2:11:03 If they start going upwards though, it’s not like it’s graded, it’s like a full flip.
2:11:04 It’s not linear at all.
2:11:06 It’s almost like it goes in the opposite direction.
2:11:10 So someone can use cannabis to reduce anxiety, but then cannabis can also trigger anxiety
2:11:14 in other people and even in the same person if they consume too much.
2:11:19 And a lot of this, at least we think, has to do with the ability of it to regulate both
2:11:22 excitatory neurotransmission and inhibitory.
2:11:27 And so for reasons that we don’t totally understand, there’s like way more cannabinoid receptors
2:11:31 on inhibitory neurons than there is on excitatory neurons.
2:11:37 But in the early days of creating the genetic lines, Giovanni Marsicano and Beat Lutz were
2:11:42 over in Europe created like deletion of CB1 only from excitatory neurons or only from
2:11:43 inhibitory neurons.
2:11:44 Okay.
2:11:49 So to just clarify for people, these are laboratory mice that are genetically modified so that
2:11:56 they contain or lack specific receptors on particular neuron types so that researchers
2:12:02 can parse the effects of THC on what we’re referring to as inhibitory neurons, which quiet
2:12:06 other neurons versus excitatory neurons, which excite other neurons and so forth.
2:12:12 And in doing so to understand some of the network biology, which is basically impossible
2:12:19 to do in a typical mouse, what’s called a wild type mouse or a human because when one
2:12:23 ingests the drug or when the mouse is given the drug, it affects any site in the brain,
2:12:26 potentially any site in the brain where the CB1 express.
2:12:27 Yeah.
2:12:31 So if you do like a full body deletion of CB1 and you give a mouse THC, doesn’t respond
2:12:32 to it at all.
2:12:33 Not surprisingly.
2:12:34 That’s a comforting experiment.
2:12:35 Yeah.
2:12:36 You want to see that result.
2:12:37 Yeah, exactly.
2:12:40 So that’s how we know CB1 drives all the kind of psychoactive effects of THC.
2:12:47 So if you delete CB1 off of inhibitory GABA neurons, even though that removes like 70%
2:12:51 of the CB1 receptors in the brain, those animals look just like wild type.
2:12:55 They still get like they still exhibit all the classic signs of intoxication in terms
2:13:01 of how that would respond to like pain sensitivity or locomotion or these other like assays we
2:13:03 use in mice that tell if they’re high.
2:13:08 If you delete the CB1 only off of excitatory neurons, the glutamate neurons, then you
2:13:12 see what looks like the full knockout.
2:13:13 So now the animals don’t seem to get high.
2:13:19 So even though the majority of CB1 receptors seem to be on these inhibitory GABA neurons,
2:13:23 it’s the CB1 on the glutamatergic excitatory neurons that mediate most of the classic
2:13:27 signs of what we would consider intoxication from THC or cannabis.
2:13:33 But what’s interesting is, Beat worked with the Spanish group 10, 12 years ago, then they
2:13:39 showed they’re looking at anxiety that if you delete CB1 only off of excitatory neurons,
2:13:47 you lose the anti-anxiety, anxiolytic effects of THC, but you still have the panicky angiogenic
2:13:48 effects of high dose.
2:13:53 If you delete CB1 off of only the inhibitory GABA neurons, you still have the low dose
2:13:59 anti-anxiety effect, but now you don’t have the high dose angiogenic panicky effect.
2:14:07 So what that was suggesting was that for some reason, CB1 like THC will initially hit CB1
2:14:09 on kind of glutamatergic neurons.
2:14:15 And essentially the thought is this will reduce excitatory transmission and probably quiet
2:14:16 down circuits.
2:14:20 Talking about something like the amygdala, this is probably how it’s reducing anxiety.
2:14:25 Whereas as dosing starts to increase and you start to saturate the CB1 on the GABA neurons
2:14:30 and turn off inhibition, then the network effect is more of an amplification and that
2:14:35 seems to result in the development of kind of an angiogenic pro-anxiety response that’s
2:14:37 obviously undesirable.
2:14:39 Why there’s this differential shift?
2:14:41 It’s not exactly clear.
2:14:45 I mean, it’s probably either due to some of the like biology of exactly where the CB1
2:14:50 receptors sit on excitatory or inhibitory neurons relative to all the machinery that
2:14:52 regulates transmitter release.
2:14:56 I mean, B. atloots has definitely done some stuff looking at the ability of cannabinoid
2:14:59 receptors to evoke signaling responses in a cell.
2:15:02 And on glutamate neurons, they’re much more sensitive than they are in GABA neurons.
2:15:04 So there’s probably a dose threshold.
2:15:09 So it does look like this kind of, you know, low dosing, what most people are trying to
2:15:13 achieve I would assume when they consume cannabis is probably these effects mediated by quieting
2:15:15 down excitatory transmission.
2:15:18 And then the adverse effects when someone consumes too much and they have a negative
2:15:23 response that’s probably due to the higher dose starting to saturate on the inhibitory
2:15:24 neurons.
2:15:27 Now, we obviously can never test something like that in humans because we can’t know.
2:15:31 But based on what we see in animals, that’s my theory of kind of how this is working and
2:15:34 why we see these kind of classic biphasic effects.
2:15:39 So yeah, too much THC, not a good thing because then you start maybe disinhibiting things like
2:15:45 the amygdala and producing these kind of panicky angziogenic like outcomes.
2:15:48 On that scale though, I mean, paranoia obviously, that’s a hard, I don’t know how you study
2:15:49 that in a rodent.
2:15:52 I mean, that’s just a strange thing.
2:15:56 But I mean, that’s kind of the precedent of when you start going into the psychosis because
2:16:00 obviously paranoia would be a big component of that.
2:16:06 Someone wants to ask me a question about, you know, what happens in the brain like imaging
2:16:09 wise when someone’s having like a psychotic episode from cannabis and I was kind of thinking
2:16:11 like, how would that study get done?
2:16:17 Probably on accident because somebody takes cannabis is in the scanner and then starts
2:16:19 having a psychotic episode.
2:16:21 But chances are they’re going to try and get out.
2:16:25 For those that don’t know these, I don’t want to scare people out of doing MRI or fMRI.
2:16:28 But you know, you’re typically told to stay extremely still.
2:16:32 There’s sometimes even a bite bar, you know, like this is a very controlled environment,
2:16:35 not an environment that you would want to be in during a psychotic episode.
2:16:38 I can’t actually even imagine how that would go down.
2:16:41 So I’m like, this is something I don’t think we’re ever going to have an answer to because
2:16:43 I don’t think you can actually ever test it.
2:16:48 But in terms of people having this kind of psychotic response, it is pretty rare.
2:16:53 I mean, and I say this because I can think of in Canada kind of whenever it’s happened
2:16:58 and someone has actually done something wildly unpredictable because they’ve had a psychotic
2:17:00 response to cannabis, it tends to make headlines.
2:17:02 So it’s not, it’s not common.
2:17:07 I could not give you an actual number, but it’s certainly not a frequent thing because
2:17:09 we would hear about this a lot more if we did.
2:17:13 And there’s also the issue of polypharmacology, which is simply when people take one drug,
2:17:17 then there’s often the tendency to take another drug either because it’s available in those
2:17:23 conditions or because they’re threshold to saying yes is a little bit lower.
2:17:29 Do most people who take cannabis and achieve the high have a tendency to do other drugs?
2:17:33 It doesn’t seem like a drug that people combine with a lot of other drugs.
2:17:34 I wouldn’t say parts.
2:17:39 I mean, there’s certainly cannabis is used in tandem with other drugs, alcohol, psychedelics
2:17:40 at times for sure.
2:17:47 But that being said, I mean, there is clearly a population of people that use cannabis as
2:17:48 their only drug that they use.
2:17:51 I don’t think that’s that uncommon.
2:17:56 But in the context of the psychosis stuff, I would definitely say, sure, if someone mixed
2:18:00 it with amphetamine or something, you could have a very unpredictable response.
2:18:03 But I mean, I think the psychotic responses that have been documented that are usually
2:18:05 purely due to cannabis.
2:18:08 It’s not necessarily due to some kind of drug interaction there.
2:18:12 There is something about the way that cannabis is changing, the way the brain functions in
2:18:17 a way that for people who seem to be prone to this, they can have a psychotic response.
2:18:19 Again, I don’t think it’s a very typical thing.
2:18:24 But when we’re talking about what that means in the context of an actual disorder, like
2:18:29 a chronic disorder like schizophrenia, which is characterized by psychosis, I think we’re
2:18:30 talking about a whole different ballgame here.
2:18:35 And this is an area that is, I mean, I think it’s an important thing to discuss in the
2:18:41 context of science because you can’t establish causality.
2:18:45 In my view, it’s virtually impossible because there’s just no way to control all the variables
2:18:46 that play into this.
2:18:53 What we can say definitively is individuals who have schizophrenia, first of all, they
2:18:56 use cannabis at a higher rate than the general population.
2:18:57 That’s very clear.
2:19:01 They definitely use cannabis at a higher rate than the general population.
2:19:09 There is definitely a relationship between using cannabis and having the initiation of
2:19:11 the development of schizophrenia.
2:19:16 And this is where a lot of the statistics that have been used to develop the risk assessment,
2:19:18 essentially, so that you have a greater risk.
2:19:22 If you were saying, if you’ve used cannabis as a teenager, you use high potency as a lot
2:19:26 of the research has shown, though they’ve done these studies and they say it relates
2:19:33 to a greater risk of schizophrenia, essentially, this is just a statistical association that
2:19:37 they found that people who use cannabis, the conversion into schizophrenia happens at a
2:19:41 higher rate and there’s more people with schizophrenia who are using cannabis.
2:19:44 Is there a bias towards males developing psychosis?
2:19:50 I know there may be a bias initially toward males in schizophrenia that could confound
2:19:52 this, so we want to be careful.
2:19:57 To be honest, in all the literature I’ve read on this, I don’t ever remember there
2:20:01 being clear-sex descriptions of the differences of males and females.
2:20:06 Again, historically, cannabis was more used by males and females, so that could lean towards
2:20:13 any bias that may be out there in the media or the popular, just in general, what people
2:20:14 talk about.
2:20:18 I can’t think of any study that I’ve ever read that explicitly said this was male bias,
2:20:19 per se.
2:20:26 It’s just report numbers or proportions of people.
2:20:32 The issue is, so yes, there’s this relationship that exists and yes, we know that cannabis
2:20:36 can trigger psychotic episodes, so if there’s an individual who has schizophrenia, we know
2:20:42 for certain that cannabis can lead to the onset of increases in positive symptoms like
2:20:47 hallucinations and delusions and a full-blown psychotic episode.
2:20:52 I think the first thing to say, which is very clear, is in my view, if someone has schizophrenia,
2:20:53 cannabis is contraindicated.
2:20:54 You shouldn’t be using cannabis.
2:20:57 If you have schizophrenia, I think that’s a risk across the board.
2:21:01 What about a first relative who has schizophrenia, because there’s a strong genetic component
2:21:02 to schizophrenia?
2:21:06 I was going to say the next question is, knowing who’s going to develop schizophrenia, obviously
2:21:07 we don’t know this.
2:21:12 As you say, the only real predictive variable that we know of is a first-degree family member
2:21:17 that has schizophrenia, means that you have a higher risk of developing schizophrenia.
2:21:19 Again, same with bipolar.
2:21:22 I would say if there’s bipolar or schizophrenia in a family, to me those are the people who
2:21:25 should avoid cannabis.
2:21:29 Just in terms of the likelihood, there’s a much greater likelihood that they’d have.
2:21:34 It would relate to the onset of a disease or could accelerate its presentation in some
2:21:35 capacity.
2:21:40 I think where things get really complicated in this whole cannabis schizophrenia story
2:21:43 is the causality.
2:21:47 There is a camp of people who have looked at this literature and definitively believe
2:21:51 that cannabis causes schizophrenia.
2:21:56 They attribute a proportion of people who have schizophrenia to only having that schizophrenia
2:21:59 because of the fact that they used cannabis.
2:22:01 I think you’d had some discussion about this in the last podcast.
2:22:04 I can’t remember exactly the way that you described it.
2:22:05 Yeah.
2:22:11 I was looking toward some of the recent studies in Lancet, JAMA psychiatry.
2:22:14 We can provide links to these again.
2:22:18 Now more recently, there’s been a lot of, let’s just call it mainstream media coverage
2:22:29 of this potential linkage between adolescent teen and young adult use of high THC cannabis
2:22:33 and lasting psychosis.
2:22:39 The more I hear you talk about this, the more I’m wondering if that idea is being amplified
2:22:44 more than perhaps we ought to let it be amplified.
2:22:48 I mean, I think this is what happens when you have, I mean, obviously you’re familiar
2:22:52 with this in science, there’s different, some things that we can be a little bit more definitive
2:22:55 about and then there’s some things that we just can’t know for certain.
2:22:59 It’s just the way it is because of the way that we gather data and because of the way
2:23:00 humans are.
2:23:03 And this isn’t a question I believe we can ask from an animal model perspective in the
2:23:05 same capacity.
2:23:08 So I don’t think anyone would deny, at least anyone who’s read the literature, that this
2:23:13 relationship between cannabis use, especially in adolescence and the development of schizophrenia.
2:23:18 Now my perspective on this is, and I’ll explain why I have this perspective and how I justify
2:23:21 it, is to me cannabis is fuel on a fire.
2:23:26 So if someone is prone to developing schizophrenia, adding cannabis into the mix, I think we’ll
2:23:28 make it kick in faster and harder.
2:23:34 So if there is a genetic vulnerability for developing schizophrenia or some biological
2:23:40 predisposition that’s there, I would say in that situation cannabis can trigger an initial
2:23:45 onset of the first episode and it can make the prognosis of the disease in the long-term
2:23:46 a lot worse, let’s say.
2:23:53 As I recall, and I may have this incorrectly, but as I recall from my undergraduate years,
2:23:59 what you just said is also true for military service, for people that have a predisposition
2:24:04 to develop schizophrenia, that active military duty can exacerbate it as well.
2:24:08 I mean, I’ve never heard that, but that would be a stressor and stressors are other ways.
2:24:14 I mean, a lot of the situations where, I mean, some of it’s the age, but like, for example,
2:24:17 if someone is prone to develop schizophrenia, they move away to college.
2:24:22 Even that stressor can be some of that brings on an episode, but cannabis very specifically,
2:24:27 like different than any other drugs, like alcohol or cigarettes, as far as I understand
2:24:31 it at least, the temporal relationship between cannabis use and the development of a first
2:24:35 episode can be pretty linked.
2:24:39 But the arguments that I’ve always had with people in this area who are very definitive
2:24:47 on their end of the spectrum that this is a causal relationship is, first of all, we
2:24:52 have a few things that I would leverage as real world evidence that makes this questionable.
2:24:55 The first one is, like I was saying earlier in the episode, I mean, we really didn’t have
2:25:00 cannabis use in the West as a normal thing, as one of the drugs that was part of the repertoire
2:25:04 of what people use recreationally until the 60s.
2:25:09 So unlike alcohol, which has been there for centuries, we have a little bit of a before
2:25:11 and after what we can look at.
2:25:13 The Grateful Dead.
2:25:14 Yeah.
2:25:18 So, now granted, we don’t have really good prevalence data of what schizophrenia was
2:25:19 in the era prior.
2:25:25 I mean, even nowadays, our prevalence data is not perfect, but if cannabis is a solitary
2:25:31 variable was driving the genesis of schizophrenia, de novo, in the absence of any kind of biological
2:25:35 predisposition or genetic predisposition, I find it very hard to believe that we wouldn’t
2:25:39 have seen a shift in the prevalence of the disease as cannabis became more mainstream
2:25:41 and more widely used.
2:25:46 And generally, schizophrenia rates have remained largely stable.
2:25:49 People can make arguments about that, better care, other things that to challenge that
2:25:50 argument, sure.
2:25:54 So another modern perspective would be, okay, well, let’s look at Canada and the States,
2:25:58 let’s say, where we have, as I said earlier, teenagers in Canada and the States, by grade
2:26:04 12, 35 to 40% of teenagers have at least used cannabis, somewhat sporadically, and somewhere
2:26:07 around 5%-ish are probably using almost daily.
2:26:12 So we have a concentrated group of what would be the high-risk population here that are
2:26:14 using at a pretty high rate.
2:26:17 And then we compare that to somewhere like, let’s say, Norway or Sweden or any of the
2:26:22 Scandinavian countries where cannabis is like not a thing, certainly not at a recreational
2:26:23 level and not teenagers.
2:26:29 And I mean, the rate use rates there are probably under 5% globally for teenagers, like probably
2:26:30 closer to 2% or 3%.
2:26:36 So you have two countries that have pretty similar social structures and other capacities
2:26:37 of things.
2:26:41 We’re both Western countries, and yet our schizophrenia rates, prevalence-wise, are
2:26:43 relatively comparable.
2:26:48 And yet in Canada and the States, our cannabis use rates and adolescents are wildly amplified
2:26:50 compared to those countries.
2:26:56 So again, if this was causing schizophrenia to develop as a disease out of nowhere, how
2:26:57 would that not track?
2:27:01 How would that not be seen when you just look at individual variances across countries and
2:27:02 prevalence rates?
2:27:03 Yeah.
2:27:06 I hear your point loud and clear.
2:27:11 I seem to recall that there is a higher incidence of schizophrenia, independent of cannabis
2:27:16 use, closer to the polls and less so at the equator.
2:27:19 I don’t know if those statistics still hold up.
2:27:20 I have no idea.
2:27:21 Okay.
2:27:22 I don’t know yet.
2:27:26 It’d be interesting for us to look into that, because then it would argue that since we’re
2:27:31 comparing very northern locations to less northern locations, that perhaps cannabis
2:27:33 was sort of exacerbating the answer.
2:27:34 Yeah.
2:27:35 I mean, you could probably use Greece or Italy.
2:27:38 I mean, they’re going to have cannabis use higher than Scandinavian countries, but it’s
2:27:41 going to be way lower than North America still, because it’s just…
2:27:44 What is it about North Americans and cannabis use?
2:27:45 I have no idea.
2:27:47 I mean, I think it’s just part of the culture here.
2:27:48 It’s just evolved totally differently.
2:27:49 I mean…
2:27:50 The Grateful Dead.
2:27:51 No, I’m just kidding.
2:27:52 I’m not picking on the Grateful Dead.
2:27:53 I like the Grateful Dead.
2:27:56 Rick Rubin convinced me to start listening to them again, because my sister used to listen
2:28:00 to them and there’s some great songs and they’re from Menlo Park Palo Alto, so I’ve done my
2:28:01 duty to listen to them.
2:28:03 There’s some great songs, so I’m not picking on them.
2:28:10 But I mean, like in Europe though, alcohol is also much more normalized in general.
2:28:11 Kids will drink…
2:28:13 It’s not abnormal for kids who are teenagers to drink out.
2:28:16 Alcohol is just much more of a cultural thing as well.
2:28:17 There are just differences.
2:28:18 I mean, it’s the same thing.
2:28:20 You look at like the opioid crisis that we’re going through.
2:28:23 It’s sure it’s there to some degree in Europe, but it’s nothing like it is in North America.
2:28:27 We are just a different beast for a lot of drug use.
2:28:31 Do you see differences between United States and Canada with respect to either cannabis
2:28:32 or opioid use?
2:28:33 I don’t think dramatically.
2:28:35 I think we’re pretty comparable.
2:28:38 I mean, for cannabis rates, I would say they’re almost the same.
2:28:39 I’ve not seen…
2:28:41 Sure, you might get some regional differences.
2:28:42 Like we…
2:28:45 I think Quebec has much lower rates of cannabis use than some other parts of Canada and you
2:28:49 guys probably in some southern states maybe are a bit different than other states.
2:28:54 I don’t know about that, but again, overall at a federal level, I think the…
2:28:58 Which is where most of the data aggregates, I would say that they’re pretty comparable
2:28:59 with each other.
2:29:00 They’re not wildly different at all.
2:29:04 Again, even if you talk about climate, a lot of the US is a lot warmer than Canada.
2:29:08 You guys are certainly closer to the equator than we are.
2:29:12 We know you do see higher rates of schizophrenia in urban settings than you do in rural settings.
2:29:13 And so, I mean…
2:29:14 It’s a stress or argument.
2:29:15 Yeah.
2:29:16 There’s other…
2:29:17 I mean, you also have more…
2:29:18 There’s just…
2:29:21 Yeah, there’s a lot of transitory populations that come in and out of cities that you don’t
2:29:23 see as much in rural communities.
2:29:24 There’s a lot more mental health services.
2:29:26 There’s other variables that can influence that.
2:29:32 No one’s really, I think, sussed out a mechanism to explain why you see that, but…
2:29:36 So there are things that shift across places, but I don’t think it has anything to do with
2:29:38 the rates of cannabis use.
2:29:42 I mean, the other thing that became very interesting in this whole debate over the last 15-odd
2:29:47 years that people have really been talking about this a lot more is the fact that there’s
2:29:51 also been several studies now that have done genetics, either at the GWAS level or just
2:29:54 even just looking at polygenic risk scores.
2:29:58 And there’s at least three papers I can think of off the top of my head that I could put
2:30:05 the citations down for, for sure, after this, that do look at this from a somewhat, let’s
2:30:09 say, unbiased perspective where they see, you know, there’s certainly some genetic architecture
2:30:14 that relates to people either initiating cannabis use or people developing cannabis
2:30:15 use disorder.
2:30:20 And there’s clearly some genetic architecture that relates to risk for schizophrenia.
2:30:24 And what these studies have found, kind of across the three of them, was quite similar,
2:30:31 which was, from their analysis, the directionality suggested much more that having genetic risk
2:30:37 for schizophrenia predicted cannabis use, more so than cannabis use predicted the development
2:30:38 of schizophrenia.
2:30:39 Interesting.
2:30:44 What that would mean is that there is some underlying biology that might be shared between
2:30:51 a biological vulnerability to develop schizophrenia and some factor that relates to people using
2:30:54 and or liking and or excessively using cannabis.
2:31:01 I’ve spoken to many psychiatrists in an effort to find someone expert in ADHD.
2:31:05 We’ve done two episodes on ADHD focusing on everything from behavioral to nutritional
2:31:08 but also prescription drug treatments for ADHD.
2:31:13 And what’s interesting is that all of them have relayed the fact that many people, not
2:31:20 just young people, but adults with ADHD will often use, not necessarily abuse, but will
2:31:24 use stimulants like coffee and other forms of stimulants to a high degree.
2:31:29 And then of course you can say, well, perhaps the stimulants are causing ADHD, but they
2:31:33 actually argue for the opposite, which is that people are attempting to self-medicate.
2:31:39 And then it’s perhaps no surprise that most, not all, but most of the medications that are
2:31:43 approved for the treatment of ADHD are variants of amphetamine or similar.
2:31:47 So it’s another case where depending on whether or not you look through the lens of the drug
2:31:51 leading to the condition or the condition leading or through the lens of the condition
2:31:57 leading to the use of the drug, you can end up in two very different places, but it looks
2:32:01 exactly the same through each lens, so to speak.
2:32:06 So I mean, and this is, you know, I’ve debated with other researchers in the area in print
2:32:10 and in person about the different interpretations of this.
2:32:14 And one of the possibilities is, again, this idea of self-medication, I mean, independent
2:32:19 of there being some underlying biological thing that just is a third variable that explains
2:32:25 the relationship between cannabis and schizophrenia, the other possibility is self-medication.
2:32:30 And there are some studies that suggest this and others that don’t support it, anecdotally
2:32:34 from having done work in the community and talked to individuals who have schizophrenia,
2:32:37 who use cannabis, what their perspective on it is.
2:32:41 What I’ve heard from a few of them is, you know, the medications that they’re provided
2:32:47 to manage the disease are relatively effective at managing, let’s say, the positive symptoms
2:32:52 like hallucinations, delusions, that aspect of the disease is somewhat well managed.
2:32:55 But then there’s another component, which is the negative symptoms, which is kind of
2:33:00 like things that, you know, avalitions, they don’t like engaging in stuff.
2:33:05 There’s some anxiety, some depression, some social withdrawal, and a lot of the medications
2:33:07 don’t manage that component of the disease.
2:33:11 And they have said that they find cannabis helps that side of it, or it helps them de-arouse
2:33:16 a little bit, even though a lot of them recognize it may trigger the development of some of the
2:33:18 positive symptoms.
2:33:21 They feel that they don’t have any tool in their kit to manage the negative symptoms.
2:33:26 And so it could be, in my mind, when I look at that, it could be a bit of a vicious cycle,
2:33:29 where someone’s using it to kind of bandaid one aspect, but making other aspects of the
2:33:31 disease worse at the same time.
2:33:33 So it can get very complicated.
2:33:38 But so, I mean, there are various ways of looking at this in terms of, you know, so
2:33:42 it’s either you could say there’s a causal argument, which is made by many saying cannabis
2:33:47 causes schizophrenia, and therefore, if we eradicated it, I think you had alluded to
2:33:49 something like that in the last podcast, that if you removed it, it would have this
2:33:52 big effect in terms of reducing schizophrenia rates.
2:33:55 And that’s similar to the argument that a lot of the researchers in Britain have made,
2:33:58 and I’m not personally convinced of that.
2:34:01 And I say that simply because I look at the data from Scandinavia, and I’m like, well,
2:34:05 there you have a population that barely uses any cannabis, and yet their schizophrenia rates
2:34:06 are the same.
2:34:11 So the only way in my mind, if I look at this kind of scientifically from a data perspective,
2:34:16 that cannabis could be causing schizophrenia de novo in a subset of people, is that there
2:34:22 must be an equal proportion of people for whom for some reason and somehow cannabis is preventing
2:34:26 them from developing schizophrenia, so that it’s a zero sum game at the end of the day,
2:34:27 and there’s no change in rates.
2:34:31 Like, I can’t actually understand any other model that could explain this.
2:34:32 Yeah.
2:34:35 No, the way you’re explaining it now makes perfect sense.
2:34:41 I do want to make sure that we distinguish between schizophrenia-like psychosis or schizophrenia
2:34:47 itself induced by cannabis and manic bipolar episodes.
2:34:52 So people who have a predisposition or full-blown manic bipolar, sometimes called manic depression,
2:34:54 but there’s still a lot of nuance there.
2:34:59 We did an episode about this that people can also find linked in the show note captions.
2:35:04 But in any case, is there any evidence for the fact that people who suffer from or have
2:35:11 a predisposition to manic bipolar conditions like bipolar depression, for instance, should
2:35:17 avoid high THC cannabis?
2:35:23 So well, first of all, I mean, in heredity family trees, for example, where you look
2:35:27 at something like bipolar schizophrenia, the two do kind of track together.
2:35:34 So I think it’s hard to separate these in some capacity because I remember years ago
2:35:37 at Society for Neuroscience, Glenn Close was one of the, I don’t know if you were at
2:35:42 that meeting, but Glenn Close was one of the public speakers and she had talked about schizophrenia
2:35:48 in her family tree and she kind of put up this family tree of her family and the previous
2:35:54 relatives in her family and showed the individuals who had schizophrenia and bipolar as well.
2:35:59 And this is something I think that’s been seen a fair amount is there is some co-relationship
2:36:02 in the way that these track at a heredity ability level.
2:36:05 And so I don’t know that area really well enough to be able to comment on it.
2:36:12 And I’m from the cannabis perspective, bipolar is definitely much less studied and focused
2:36:13 on than schizophrenia is.
2:36:17 But I think also to the comment about the high THC thing, I think this is the other part
2:36:20 of the argument that’s emerged out of this.
2:36:25 And this is the other part where I see a lot of the causality arguments kind of crumble
2:36:26 onto themselves to some degree.
2:36:29 And there’s been others who’ve made these very similar arguments to what I’m making
2:36:35 here, which is the push that came out of this out of the UK at least was much more that
2:36:39 it’s this high potency kind of skunk cannabis they referred to, which first of all was based
2:36:42 on a smell, which they didn’t really hadn’t done a lot of analytics on.
2:36:46 So it was people make the assumption if it smells stronger, it’s more potent cannabis.
2:36:48 That’s not really true because THC doesn’t dictate the odor.
2:36:53 That’s so I was saying more of a terpene thing, but certainly I’m sure some of the skunk cannabis
2:36:55 they were referring to is high potency cannabis.
2:36:58 And so the analysis on this, if you actually go back to those papers and read is they often
2:37:03 use like hash or low potency cannabis is their control where they show no association with
2:37:04 cannabis.
2:37:09 And so that’s what’s used this argument that it’s the high potency cannabis that has driven
2:37:10 this.
2:37:17 So now the problem with this argument in my view, again, I look for what is the answer
2:37:22 that fits in with the data, like what’s the most parsimonious explanation here that everything
2:37:23 can be explained by.
2:37:27 And so the problem with that argument is if you look at the cannabis schizophrenia literature,
2:37:33 one goes back to this one 1987 Lancet paper out of Sweden, where in that paper they essentially
2:37:39 looked at, they have really detailed life records and health records, and this was Swedish conscripts.
2:37:43 And they essentially found that if someone had used cannabis, the rate, the risk of developing
2:37:45 schizophrenia had gone up and up.
2:37:50 And so this was based on a cohort of people when it was published in ’87 that the data
2:37:53 would have been collected through like the 60s, 70s, early ’80s.
2:37:57 So we’re talking about Sweden and cannabis, which is not a country that has high cannabis
2:38:02 use rates, and in an era when cannabis was hovering in a two to five percent THC range.
2:38:06 That was the initial finding that provided this association between it.
2:38:10 And yet the cannabis in that study that they would have been referring to would have been
2:38:15 incredibly low potency compared to what has happened or like what it is today.
2:38:20 So if the argument is that it’s only related to high potency, how would that initial finding
2:38:23 have ever been found?
2:38:26 Because that doesn’t make any sense, whereas the alternate explanation that others have
2:38:32 put forward, which I agree with and is far more sound, is that there is some biological
2:38:37 reason why individuals who are either prone to develop or who have schizophrenia like
2:38:42 cannabis, and they will tend to seek out the highest potency product they can get access
2:38:43 to.
2:38:47 So in the ’70s in Sweden, that would have been two to five percent THC cannabis.
2:38:50 Nowadays, it’s higher potency cannabis.
2:38:54 Or maybe they seek out lots of different forms of recreational drugs, and cannabis just happens
2:38:59 to be one that they land on, which raises the other question, which is, it’s hard to
2:39:05 imagine that these people who develop psychosis, who happen to be using cannabis, are only
2:39:06 using cannabis.
2:39:07 It could be, but-
2:39:11 I mean, they also, there’s no question there’s a lot of nicotine consumption.
2:39:14 I mean, individuals with schizophrenia use, they smoke a lot of cigarettes.
2:39:15 I mean, that’s also-
2:39:16 That’s well established.
2:39:18 It’s higher than the general population rates as well.
2:39:21 Which is known to stimulate dopamine, and other pathways.
2:39:25 And there could be other reasons, you know, again, there may be some reason why they like
2:39:26 it.
2:39:29 And I think this is something that I think we just don’t understand.
2:39:31 It’s a very challenging thing to figure out.
2:39:35 Why it is that individuals that have certain diseases may like certain substances.
2:39:37 Is it helping them?
2:39:42 I mean, some people have argued that perhaps nicotine, for example, might enhance cognition
2:39:45 in individuals with schizophrenia, and that may be why they like it.
2:39:47 I think it enhances cognition in everybody.
2:39:49 It just carries certain health concerns.
2:39:51 And by the way, it doesn’t enhance all forms of cognition.
2:39:58 But there is a nice body of work to support the idea that nicotine delivered in any number
2:40:02 of different forms can improve cognitive function, to some extent.
2:40:03 But I don’t suggest people run out and do it.
2:40:12 And in fact, it’s one of the more quickly abused drugs nowadays because of the non-smoking
2:40:17 delivery routes that are becoming really popular pouches and things that, in fact, I was chewing
2:40:20 a little bit of Nicaragum to kind of do an experiment.
2:40:21 I liked it a lot.
2:40:26 And then I decided to stop completely recently because it just, it wasn’t having the same
2:40:27 effect.
2:40:28 And I found myself reaching for more.
2:40:30 And that’s the time when I usually back out.
2:40:35 Well, yeah, nicotine’s a whole other thing, which I, yeah.
2:40:37 We’ll have you back to talk about nicotine.
2:40:41 I would definitely do not know enough about that to have any kind of informed conversation.
2:40:44 But so I don’t know.
2:40:48 I would say to me, at the end of the day, if I put all the data together, what I would
2:40:55 kind of, the perspective that I have on this is, for some reason, be it genetic architecture,
2:40:59 biological predisposition, individuals who are prone to develop schizophrenia also seem
2:41:05 to be prone to use cannabis and use it, possibly at excessive levels or possibly at higher
2:41:08 potency products they seek out.
2:41:13 Using cannabis, if someone is prone to develop it, may initiate or trigger the onset of the
2:41:14 disease.
2:41:18 And I think in the long term it will likely make the prognosis of the disease worse.
2:41:27 So if you were a psychiatrist in a clinic and you consistently see patients presenting
2:41:34 saying, I didn’t have psychosis, I used cannabis, now I have psychosis and it converts into schizophrenia,
2:41:40 I can understand why the association would be made regularly that there’s kind of a
2:41:45 domino effect here and causality becomes attributed.
2:41:51 But I think when we take a step back and look at the larger data in its kind of entirety,
2:41:54 to me it’s a very tricky argument to make because there’s a lot of things that you just
2:41:56 can’t explain from that perspective.
2:42:01 And this is also one of the things that I find absolutely bizarre about cannabis in general
2:42:07 is it’s a wildly polarizing topic of conversation.
2:42:12 And people have incredibly deep-rooted opinions on both sides of the spectrum.
2:42:17 And for some reason, if I don’t say cannabis is the devil and causes disease, that means
2:42:19 I’m an advocate.
2:42:22 And then on the other side of the coin, if I don’t say cannabis cures everything, I’m
2:42:23 a prohibitionist.
2:42:27 So I’m in this fun position where I get hate mail from both sides.
2:42:30 And everyone just generally, depending on their perspective, thinks that I have a bias
2:42:33 kind of going in one way or the other, and I’m very, you know, want it this way or want
2:42:34 it this way.
2:42:36 And at the end of the day, I’m just like, no, I just like data.
2:42:39 So I’m like, I’m going to try and answer things as best I can with that.
2:42:42 And to me, that’s the perspective I’ve maintained.
2:42:48 And I do think that, like, these aren’t trivial questions because when we went through the
2:42:51 legalization process in Canada, this was something that came up again and again and
2:42:52 again.
2:42:55 Was this association with schizophrenia?
2:42:59 And in the UK, this is something that comes up again and again and again because whenever
2:43:03 there’s any discussion about the UK moving forward to legalization, these ideas come
2:43:04 back.
2:43:09 And so the public health kind of consequence of this is not intangible.
2:43:14 And so for people to be making these very strong causality arguments and having this
2:43:21 kind of opinion that a lot of people just take up, I think can have a lot of influence.
2:43:24 And so that’s why, like, there’s literally no reason I should have a dog in this fight.
2:43:28 I don’t study schizophrenia in any capacity.
2:43:30 And it’s not my area of research.
2:43:35 But because I’m in the cannabis field, I always feel very strongly that we need to maintain
2:43:39 clarity over what the data says and not get caught in these opinion-based arguments.
2:43:43 And I feel like this is one of these areas that has just kind of the amount of people
2:43:47 I talk to that regularly tell me that they know that cannabis causes schizophrenia and
2:43:51 they’re terrified of someone uses it because it’s going to cause them to become schizophrenic.
2:43:53 I am just kind of shocked by.
2:43:58 So this has clearly permeated the general population that there’s a widespread belief
2:43:59 of this.
2:44:03 I think it’s because of these very high profile papers and the way those were picked up by
2:44:05 traditional media.
2:44:11 And this seems to be something that every couple of years there’s a resurgence of this idea.
2:44:12 Clearly people are curious about it.
2:44:19 And so I just want to say thank you for clarifying what is now to me obvious that it could be
2:44:21 that there’s a relationship there.
2:44:24 It’s clearly not the case yet.
2:44:27 And it may never be the case that there’s a causal relationship there.
2:44:31 And it could just as well be that people who have a predisposition to schizophrenia are
2:44:33 seeking out cannabis use and engaging in cannabis use.
2:44:37 And I think that’s a very important principle for our listeners and viewers to just hear
2:44:41 and understand any time we’re talking about a substance and a condition.
2:44:42 Yeah.
2:44:45 And I mean, I think again, this is, again, no endorsement that that doesn’t mean that
2:44:47 it’s safe and that that’s without harm.
2:44:51 I’m just strong of the opinion that I don’t think individuals with schizophrenia who are
2:44:55 or who have first degree relatives should use cannabis because I think there’s a high
2:45:00 degree of risk there, but that’s a very different argument than making saying cannabis causes
2:45:01 schizophrenia.
2:45:03 And if we remove it from society, we’ll see drops in rates of schizophrenia.
2:45:07 I don’t believe there’s any evidence that actually could support that.
2:45:10 So it’s just a nuanced argument.
2:45:14 And this is a good thing about more of a long form podcast is it allows for nuance.
2:45:15 Yeah.
2:45:16 Absolutely.
2:45:19 Let’s talk about strains of cannabis.
2:45:25 I’ve spoken before about the sativa versus the indica strains.
2:45:32 And certainly there is a lot, a lot, a lot of subjective anecdotal descriptions about
2:45:37 differences in the, quote, unquote, effects of those as reported by users.
2:45:42 When I talked about this before in the cannabis episode, I leaned on a paper that took those
2:45:49 subjective reports of arguably many, many people push those subjective reports through
2:45:51 what was known about the strains they claim to have used.
2:45:54 So this is, you know, people are reporting their use.
2:45:57 We assume honestly, but you always have to assume that there’s, I guess, people could
2:46:04 be lying about which strains were misinformed, but, and then using machine learning to couple
2:46:10 their subjective experiences as they report them to indica versus sativa strains.
2:46:15 And then by looking at the chemical composition of those different products, because these
2:46:20 were products that they had consumed, trying to tap chemical composition to strain in this
2:46:27 case that mainly the indica sativa discrepancy to subjective experience.
2:46:32 And I know that you and presumably others in the field of cannabis research take real
2:46:35 issue to that sort of approach.
2:46:42 And perhaps I have the feeling this is what you’re going to say.
2:46:47 Rest on the idea that we, at least at this point in time, really can’t say anything about
2:46:51 the different biological effects of sativas versus indicas.
2:46:55 And yet at the beginning of the episode, you said that there are many, many different cannabinoid
2:46:57 compounds in cannabis.
2:47:01 So three questions, and I’ll keep these very short.
2:47:06 One, do you think that there are different subjective effects of different strains of
2:47:10 cannabis that can be attributed to the different strains, right?
2:47:13 Not just to individual differences in experience.
2:47:18 And then the second is, do you think that there will ever be a time in which we can understand
2:47:20 this plant flower, right?
2:47:26 To the extent that we can engineer it to provide specific subjective experiences, perhaps more
2:47:28 positive than negative, et cetera.
2:47:30 And then there’s a third question, but I’ll hold off.
2:47:31 Okay.
2:47:39 So yes, so going back to just the idea with the indica sativa thing.
2:47:46 So the indica sativa names, at least from everything I’ve understood from everyone that I talked
2:47:53 to and being in this field, is those are botanical terms that largely refer to shape of the plant,
2:47:55 the way the bud grows, blah, blah, blah.
2:47:59 They do not track with chemical composition in any way.
2:48:05 In fact, Nick Jacomas has done like a lot of analysis of like thousands and thousands
2:48:11 of different kinds of cannabis that have been submitted for kind of biochemical analysis
2:48:16 to understand THC, CBD, terpenes, minor cannabinoid content.
2:48:21 And essentially his work, as well as from all the people that have done the genetics
2:48:29 on this is the variability that exists within what someone calls an indica or a sativa is
2:48:33 greater than the variability that there is between them.
2:48:38 And there’s no, there is no such thing as a chemical profile that exists in something
2:48:40 that’s a sativa versus something that’s an indica.
2:48:45 Is it possible that there’s a chemical profile that relates to the most common indicas or
2:48:46 most common sativas?
2:48:51 I mean, I think in Nick’s analysis, there was like a couple of terpenes that may have
2:48:56 loaded on a little bit onto things that were sativas, but there was tons of sativas that
2:48:57 didn’t fall into that bracket.
2:48:58 Okay.
2:49:03 Well, then that immediately to me negates the sort of premise of this paper that I was
2:49:06 referring to that divides according to indica sativa.
2:49:11 And yet the paper is also trying to distinguish among all the different types or products
2:49:12 of cannabis.
2:49:13 Yeah.
2:49:18 Meaning, is there some other feature of the cannabis plant that does relate to these different
2:49:19 subjective effects?
2:49:25 Because people do seem to get different subjective effects from different products that relate
2:49:28 in some way to things other than the concentration of THC.
2:49:29 Yeah.
2:49:32 I would, my honest opinion is this is expectancy bias.
2:49:33 This is all expectancy bias.
2:49:34 I mean…
2:49:35 I see.
2:49:36 So they purchase something that they think is going to make them calm and it makes them
2:49:37 feel calm.
2:49:42 If 20 people tell you that taking this makes you calm, you cannot remove your expectation
2:49:45 bias from the fact that when you consume it, you feel calm.
2:49:50 And this has been, I think one of the most common things with cannabis is like this whole
2:49:57 area is so ripe with these expectancy biases that people have about what they assume.
2:50:01 If you go, someone goes into, you know, and a bud tender tells them, “This is a sativa.
2:50:03 It’s going to energize you.”
2:50:07 There’s no way to remove that expectancy bias from what you get.
2:50:11 And I mean, like, from talking to a lot of people that kind of study this more explicitly,
2:50:15 they always say the biggest predictor of what someone feels when they consume cannabis is
2:50:17 what they’re told on the label it’s going to do to them.
2:50:18 I mean…
2:50:19 That’s pretty wild.
2:50:23 And it speaks to, you know, I did an episode on the placebo effect and a lot of people
2:50:27 hear placebo effect and they go, “Okay, well, then everything’s a placebo effect is amazing.”
2:50:31 There’s dose response and placebo effect of nicotine on cognition, dose response.
2:50:35 If you’re told you got a high dose, when you actually got a low dose, you will exhibit
2:50:39 the high dose neurocognitive enhancement effect.
2:50:44 And by brain imaging, it shows a high dose like enhancement of the relevant brain areas.
2:50:47 In other words, the expectancy drives changes in brain activity.
2:50:48 It’s across the board.
2:50:51 I mean, it’s, again, this is not unique to cannabis in any way.
2:50:57 It’s just cannabis is so ripe for this because of the myth, like the lore that it just exists.
2:50:58 Like, people say this.
2:51:03 I mean, the issue has been, and I just asked Ryan Vandery this.
2:51:07 As far as I know, I don’t believe there’s actually ever been a clinical trial that has
2:51:12 blinded people and given them sativas or indicas and actually had them predict what
2:51:16 they are or been able to characterize any kind of phenotymic description of what that
2:51:19 intoxicated state feels like.
2:51:25 And because all the, like the paper that you were referring to where it was users who had
2:51:32 got the product, they can’t remove their own inherent biases from their own experience.
2:51:33 It’s going to influence it.
2:51:35 There’s no way around it.
2:51:41 And so people kind of lean into this, and probably not consciously, but they, I mean,
2:51:46 the amount of people I’ve talked to that really genuinely believe this to their core that
2:51:52 sativa does this and indica does this is fascinating to me because, again, like you
2:51:55 have these two, like THC is what drives the high.
2:51:57 That’s very clear.
2:52:02 And you can take a sativan and indica that have virtually identical levels of THC.
2:52:06 And yet people will report very different intoxicating states that come out of that.
2:52:13 Do you think this also explains the lower or perhaps it’s real that different alcohols
2:52:16 produce different drunks?
2:52:19 You know, I mean, I’ve heard of, you know, I’ve got friends who will swear that whiskey
2:52:26 makes them feel aggressive and vodka is mellow and white tequila’s feel different than the
2:52:27 other tequila’s.
2:52:30 And, you know, for people listening to this, they go, okay, well, that’s not science.
2:52:31 I agree.
2:52:32 That’s not science.
2:52:33 That’s just anecdote.
2:52:39 And yet, you know, the chemical composition of these different drinks is different, but
2:52:41 ultimately we’re talking about alcohol, right?
2:52:44 Different sugar contents, you know, different hangover propensity.
2:52:47 I mean, I have to believe the majority that’s an expectancy bias.
2:52:51 I have a hard time believing that these things are really driven by fundamental biological
2:52:55 differences within, because anything else that’s, I mean, that’s the thing like, sure,
2:53:00 some of the labs now there is a movement to start looking at can certain compositions
2:53:04 of other things in cannabis start to maybe modulate or influence.
2:53:07 This is called, like I think I’ve said this before, the entourage effect, this idea that
2:53:13 THC alone might do one thing, but then layering in other terpenes or minor cannabinoids may
2:53:14 influence that effect.
2:53:15 That is a theory.
2:53:18 That’s not a thing that we know definitively in any way.
2:53:21 And in fact, there’s virtually no research that’s ever been done to test this.
2:53:26 There’s some stuff that’s starting to come out now, like Ryan Vandery at Hopkins recently
2:53:30 published a paper where they kind of in a dose dependent manner added limonene, which
2:53:31 is one of these terpenes.
2:53:36 Like I said, I think gives it like a citrus yoder into the THC and did find that a really
2:53:41 high dose, probably a dose that I don’t think you could actually find in cannabis.
2:53:44 It’s a little bit higher than what you would have gotten there, but limonene did seem to
2:53:48 be able to curb the ability of high dose THC to make someone feel anxious.
2:53:49 And this was done in a blinded manner.
2:53:56 So there’s I think some validity to the interaction, whether that’s occurring in cannabis naturally,
2:53:57 because of the levels of THC to limonene.
2:54:02 I don’t know, but it really was one of the first demonstrations that adding in a terpene
2:54:09 could actually influence a component of the intoxicated state in a blinded manner, I think
2:54:10 is interesting.
2:54:13 And Ziva Cooper, who’s here at UCLA is doing some work with beta cariophiline, which is
2:54:19 probably probably the second most abundant terpene, I think from Nick Chocomas’ work.
2:54:23 I think Mersine may have been the highest prevalent terpene across all types of cannabis.
2:54:31 Beta cariophiline is probably the second, and limonene I think is probably the third.
2:54:35 And so they’re looking at, I think Ziva’s work is in the context of pain.
2:54:38 So they’re trying to look at if a fixed dose of THC, if you add in varying levels of beta
2:54:40 cariophiline, does this influence this?
2:54:43 So because again, you do see this in patient communities where they say, well, this strain
2:54:45 helps my pain better than that strain.
2:54:48 And so it’s like, okay, is there actual legitimacy to this?
2:54:50 Or again, is this just an expectancy bias?
2:54:54 Is someone who sold this to you told you that this strain is better for pain?
2:54:57 And the problem is, these are all subjective endpoints.
2:54:59 I mean, this is pain, sleep, anxiety.
2:55:02 These are all, and it’s how someone personally experiences it.
2:55:06 And we know from all the clinical trials that study pain, sleep, and anxiety, there’s massive
2:55:10 placebo effects that happen in all these conditions.
2:55:15 And so it’s very difficult to actually make any kind of sound statements about this in
2:55:19 the absence of there being kind of clinical trials that have clearly started to do this.
2:55:23 But it’s like, as you can imagine when you start doing the math, given the amount of
2:55:26 terpenes and the amount of combinations at different levels, how overwhelming this could
2:55:27 become.
2:55:30 Because maybe you know there’s a few that you need in there that interact with THC, not
2:55:31 just one.
2:55:35 There is like a lot of work that’s happened in the last few years that has really started
2:55:39 to try and look at if these terpenes or minor cannabinoids act at the cannabinoid receptor,
2:55:41 which none of them seem to.
2:55:46 So this isn’t like you’ve got things that modulate how THC is binding to CB1.
2:55:49 If they’re doing something else, it’s probably through an interaction with another
2:55:53 particular chemical system that’s influencing what THC is doing.
2:56:00 So I’m not against the idea that different chemovars or what people call strains of cannabis
2:56:03 could do different things subjectively.
2:56:08 I just am remiss to believe this until I see some blinded data because I think outside
2:56:10 of that we know how powerful an expectancy bias is.
2:56:15 So it makes it very, very challenging to make any kind of firm statements.
2:56:22 And so kind of in the context of how you introduced this, that was again, I think one of the issues
2:56:28 that I took with the other podcast was because as you’ve said, I understand the thought process
2:56:29 you went through.
2:56:32 Like you had this paper where people were reporting subjective effects.
2:56:35 There’s some neuroimaging data that’s been done with cannabis.
2:56:39 You kind of said, “Okay, this is what that was, and that was what Sativa did versus this
2:56:41 is what Indica did.”
2:56:44 So I think it’s important that you explain that because I do think that like-
2:56:48 Well, that’s what the data pointed to, but now what I’m realizing is that anytime we’re
2:56:55 talking about cannabis, because of the 70 plus cannabinoids present that could modify
2:57:02 or join, so work in parallel with the effects of THC, we’re really talking about polypharmacology.
2:57:03 It’s not a pure subject.
2:57:08 It’s not like giving anandamide or it’s not like adjusting levels of endogenous anandamide.
2:57:13 This raises I think an equally important issue for us to resolve which is CBD, which we didn’t
2:57:14 talk about earlier.
2:57:19 When Nolan Williams, who’s a psychiatrist, he’s one of these phenoms, triple board certified
2:57:24 psychiatry neurology, a colleague of mine from Stanford School of Medicine who mainly
2:57:29 works in Ibogaine and transcranial magnetic stimulation, but we talked about cannabis
2:57:35 a bit when he was on the podcast and he mentioned a strain of cannabis that is available in
2:57:44 Colorado, which is pure CBD. I think it’s called Charlotte’s Web and the parents of children
2:57:51 who have epilepsy will move there or go there just to get this strain because it seems to
2:57:53 help their epileptic seizures.
2:57:58 Yeah. I would say that’s definitely not true nowadays. That pre-legalization anywhere outside
2:58:01 of Colorado, that was true. People were gravitating there towards it.
2:58:06 Yeah. The questions are, could you tell us a little bit about the biology of the CBD
2:58:13 receptor, mainly as it relates to CB1 or not? Does it bind CB1 as well? If not, how is it
2:58:16 working? You mentioned that people will not report any subjective effect of taking a pure
2:58:22 CBD compound, so lacking THC, but it sounds like it may have some usefulness for treatment
2:58:31 of epilepsy. What are some other established, meaning clinical trials and/or lab data to
2:58:39 support the use of CBD for any type of either psychiatric condition, pain, et cetera?
2:58:41 The first thing that’s interesting that I think a lot of people don’t understand about
2:58:49 CBD is CBD doesn’t really exist in any form of street cannabis and it hasn’t for a very
2:58:50 long time.
2:58:51 There’s no CBD in there?
2:58:57 There’s some. There’s very, very low levels of CBD. The reason that is, is because THC
2:59:02 and CBD are both made from the same precursor molecule. Which direction it goes in is based
2:59:08 purely on which synthetic enzyme converts it to either THC or CBD. As people have clearly
2:59:13 chased THC and wanted cannabis that’s rich in THC, and so cannabis has been bred to become
2:59:19 higher content in THC, by default, CBD has been bred out of the plant. It has largely
2:59:26 been bred out of the plant for quite some time. I always find it interesting that this
2:59:30 community that’s like, “Oh, well, THC is the recreational cannabis and CBD is the medical
2:59:37 cannabis.” I’m always like, “That’s bizarre.” Historically, THC has been what people have
2:59:43 bred cannabis for. Any medical benefits that people have reported from cannabis, per say,
2:59:49 usually are THC and CB1-driven. CBD is this other molecule that we can go to the pharmacology
2:59:55 in a second, but again, it’s just, I mean, I think in the analysis at Nixiecoma State
3:00:00 of all these strains and types of cannabis that exist in the United States when they
3:00:03 went through their thing of thousands and thousands of kinds of cannabis, it was like
3:00:11 3% of them maybe had more than 1% CBD. It’s very low. There’s almost none. In Canada,
3:00:17 to get a CBD-rich strain, you have to basically explicitly buy it because it has to be bred
3:00:21 to make CBD. This is the kind of chemovar distinction I think you did allude to this
3:00:26 last time, which is the type 1, type 2, type 3. Type 1 is high THC. Type 2 is like somewhat
3:00:32 balanced in type 3, is high CBD. Now, I think like 90 to 90, something low percent of all
3:00:36 cannabises that are out there are type 1. They’re all high THC because that’s what’s
3:00:41 been bred. There’s a few that have been mixed, so are kind of equal proportions, but you’re
3:00:47 never going to get high equal proportions. A high THC cannabis is like 20% to 30%. If
3:00:52 you go for type 2, which is mixed, they’re both going to fall around 12%, maybe a little
3:00:56 more, but in that range. Then same if you get a type 3, it’s high CBD, it’s going to
3:01:03 be 20-ish percent CBD and very low THC. No one has ever grown CBD-rich cannabis outside
3:01:08 of this recent boom in the last decade that’s happened about people wanting CBD because of
3:01:14 the Charlotte’s Web, which was popularized by I think Sanjay Gupta on CNN in like 2012
3:01:18 or something. It was a while ago, but that was what got a huge movement going around
3:01:24 this idea of CBD. The Charlotte’s Web was, I believe that was what they had named that
3:01:28 kind of cannabis that they’d extracted it from. It was a tincture that they were using
3:01:33 that was very high CBD content that they were finding was controlling pediatric seizures
3:01:39 in kids. Now, this has actually been studied pretty effectively. Most of it’s come out
3:01:46 of Boston. Elizabeth Thiel has been one of the main leads on this, and she’s a neurologist
3:01:50 there that has done a lot of the work on this. They have, I think, very clearly, and the
3:01:56 data is incredibly compelling. Their research is one of the reasons why CBD has been descheduled
3:02:00 or changed in its scheduling down to, what is it, five? What is it, class?
3:02:09 CBD. CBD, I mean, given the availability of CBD everywhere, in gummies and drinks, you
3:02:12 can get it in a convenience store.
3:02:17 It’s been kind of a lot of it’s been shifted in its classification status because it actually
3:02:24 has been shown very clearly to have medical benefit. It was a very specific form of pediatric
3:02:29 epilepsy called Dravet syndrome. Now, there’s other forms of pediatric epilepsy. I know
3:02:35 Elizabeth has studied an addition that has found comparable levels of efficacy, but essentially
3:02:44 what they have shown is that very high doses of CBD are relatively effective at calming
3:02:48 down the seizures. In some kids, it’s profound. In some kids, you’re talking about kids that
3:02:52 we’re having dozens of seizures a day to essentially none.
3:02:53 It’s interesting.
3:02:54 That’s super impressive.
3:02:58 I mean, from a grassroots perspective, I can understand if you were a parent who had a
3:03:03 child with a disease like this that was largely intractable and not that well controlled from
3:03:07 the medications they were on, and then something came around that showed this level of efficacy,
3:03:11 you would gravitate towards it. That makes sense to me.
3:03:15 I think the work that Elizabeth and her colleagues have done has been really important to establish
3:03:23 the efficacy of CBD in these disease states. I don’t think at this point there’s a lot
3:03:25 of controversy around that.
3:03:31 The question that comes out though is, “So, how is it working?” We don’t have a mechanism.
3:03:35 As you had said, CBD receptor, there is no receptor that CBD binds to.
3:03:39 I was under the impression that CBD also bound to the CB1 receptor.
3:03:42 No. I mean, certainly not.
3:03:49 Or that under some conditions, it can modulate the shape of the receptor to adjust THC binding,
3:03:53 but now you’re telling me that these two things rarely coexist together. I guess the question
3:03:59 is, you can dose them. You can have products that are made that are oil-based products at
3:04:02 least that have a certain amount of CBD and a certain amount of THC, and people do go
3:04:07 for those. One of the arguments people make is they say, “Oh, introducing CBD reduces
3:04:11 the adverse effects of THC,” and I’m like, “Well, if you’re using it in a strain, that’s
3:04:13 simply because the strain of cannabis has less THC now.”
3:04:14 Right. It’s impossible to say.
3:04:18 You’ve bred it out, but a lot of this was based on some work that came out a long time
3:04:24 ago from Brazil where they showed that giving CBD with a relatively high dose of THC could
3:04:28 curb some anxiety that came out from high-dose THC.
3:04:35 I thought the explanation for that was that CBD can modify the CB1 receptor in some way
3:04:38 that makes THC less able to engage with the THC.
3:04:42 There is some evidence to support that, like we would call these allosteric modulators.
3:04:48 There’s some evidence to suggest that CBD may interact with a allosteric site on the
3:04:51 cannabinoid receptor that makes THC bind less.
3:04:53 It doesn’t sound like you’re particularly convinced by that evidence.
3:04:54 I mean, like the paper.
3:04:58 I’m looking at the look on your face with those and listening. I’m looking at Matt.
3:05:02 I think he’s being generous here. Let me ask it a little differently.
3:05:03 It’s definitely more complex than that.
3:05:05 Does anyone know what CBD binds to?
3:05:09 The most convincing thing that I’ve seen that CBD binds to is the work that C.C.
3:05:15 Hillard has done, looking at its ability to essentially block adenosine uptake. It can
3:05:17 inhibit the adenosine transporter, so it causes-
3:05:18 So that should make people feel more alert?
3:05:22 No, because you’re getting more adenosine. So you get an accumulation. It blocks the
3:05:24 adenosine transport mechanism.
3:05:25 I see.
3:05:29 So you get an accumulation of adenosine, which is more sedative.
3:05:36 And that, I mean, in the PNAS paper that C.C.’s lab had from 2006, they showed that that also
3:05:40 mediated. It was the adenosine, I think, 2A receptor that drove the anti-inflammatory
3:05:43 effects of CBD. So it was the secondary effect by-
3:05:45 Sort of the opposite of caffeine.
3:05:46 Of caffeine.
3:05:47 Yeah, I know. I remember doing-
3:05:50 Yeah, and the way you’re describing this, it sounds like the anti-caffeine.
3:05:53 That’s kind of how I described it. People, if they ever ask me for what the pharmacology
3:05:58 of CBD is, I’m like, that’s not the only mechanism. But the thing that was important in C.C. studies
3:06:02 that I think is relevant is that it was not super high concentrations of CBD that caused
3:06:09 that. So you could get this adenosine accumulation at, you know, you’re not talking like micromolar
3:06:14 levels of CBD, which is what a lot of studies have done. And so even when we’re talking about
3:06:18 the allosteric modulatory site, yes, there’s evidence for it. And it is convincing evidence.
3:06:23 It’s just the dose range in there. You’re kind of like, who’s getting hit with CBD at
3:06:27 that level where you’re getting these effects? And more so, when they’ve done the blinded
3:06:31 work, like when Ryan Vandery at Hopkins again, who is one of the main people who’s done a
3:06:37 lot of this work, has actually blindly given people CBD dosing with THC finds the opposite,
3:06:42 that it actually amplifies some of the effects of THC. And this was something we learned from
3:06:46 the pediatric epilepsy world was that when you start giving CBD at relatively high doses,
3:06:51 one of the things it does is saturate a lot of liver enzymes. And so some of the efficacy
3:06:57 in the pediatric epilepsy space may be a secondary effect due to an accumulation of some of the
3:07:02 anti-epileptics as well, because they’re not being metabolized the same way. And this has
3:07:07 now been very well replicated. We know that once you start taking CBD, when they hit doses
3:07:11 that are at the clinical level, you’re going to start having hepatic effects. So it’s going
3:07:15 to affect the liver and it’s going to affect the ability of the liver to chew up other drugs.
3:07:22 And there’s very specific SIP enzymes, like the cluster of enzymes that metabolize things,
3:07:26 there’s very specific ones that CBD hits. And so as a consequence, one of them is what
3:07:32 choose THC. So you can get a potentiation of THC by inhibiting its metabolism if you
3:07:33 have high enough CBD on board.
3:07:37 Given the effects on the dentistry that you described before that it’s sort of what we’re
3:07:42 calling just for sake of discussion, the anti-caffeine. How do we explain the preponderance
3:07:46 of CBD added to energy drinks that also contain caffeine? There’s like no logic there.
3:07:51 There you go. Everything can’t be expectancy bias. I have a feeling it’s going to be interesting
3:07:56 to see in the comments section on YouTube. I mean, presumably there’s some regular pot
3:08:02 smokers listening to this. And the expectancy bias is so strong, as I alluded to in the placebo
3:08:08 episode and we’ve been talking about here. And yet it’s so strong that I think people
3:08:12 will also be convinced that there are real differences between different strains because
3:08:20 they’ve maybe done the non-formal blind, someone gave them their weed and someone else and
3:08:23 then they got a completely different effect. They’re not expecting something different
3:08:27 necessarily in a particular direction, but they get a very different effect.
3:08:33 But that to me just speaks to the idea that, again, cannabis sounds like polypharmacology,
3:08:40 70 different cannabinoids, THC being among the more powerful components, but it’s yoked
3:08:45 in the sense that, as you said, people self-regulate their intake provided they’re smoking, not
3:08:49 ingesting it by edible. And so it’s almost like THC is being held constant and then there’s
3:08:53 this constellation of other things around it that are modified and people eventually
3:08:57 veered towards what they like, what they can afford, what works with their lifestyle. And
3:09:01 then they come up with a bunch of theories based on packaging, what they’re told, but
3:09:06 presumably also some real effects of these terpenes, the CBD component, etc. It can’t
3:09:07 all be just psychological interpretation.
3:09:11 Yeah. I mean, so what you’re saying is like what we said is the entourage effect. And I
3:09:15 think that is a theory that is held by a lot of people that this exists. I mean, the reality
3:09:20 is these terpenes and minor cannabinoids exist at such low levels that like there’s a couple
3:09:25 of kinds of cannabis that might have like a high enough level where you’re seeing something.
3:09:32 But yeah, I mean, I agree to the extent that it would be a little wild if everyone’s subjective
3:09:36 experience across different kinds of cannabis was entirely driven by some kind of expectancy,
3:09:41 which I can’t imagine is accounting for all of it. But I think when we talk about sativa
3:09:47 versus indica, I think there’s a huge bias that’s going into there. But one of the things
3:09:54 with CBD that’s interesting, unlike THC is you can actually do pretty clean blinded studies
3:09:58 because it’s really hard to give someone THC and them not know they’re on THC.
3:10:02 This was the big problem with the MDMA trial that happened recently is that people who
3:10:06 got the placebo knew they got placebo, people who got the drug knew they got the drug. It’s
3:10:09 very hard. You could do a dose response, but it’s very difficult.
3:10:13 It’s very challenging to give someone a psychoactive drug and a placebo and them not know which
3:10:17 one they have. Whereas because CBD doesn’t produce an intoxicating state and it’s not
3:10:23 really perceptible from the person who’s taken it, that it’s doing anything, that actually
3:10:27 does make it far more amenable to do blinded trials with.
3:10:31 The interesting thing with CBD, and this is where I get a lot of people that get angry
3:10:37 at me as well, is that I would argue that the overwhelming majority of the effects of
3:10:43 CBD that people report are all placebo effects. I say that because people leverage the epilepsy
3:10:46 stuff and some of the clinical work and say, “But we know it does things.” My response
3:10:50 to them is, “Do you know what dose those people are getting?” Because this is something
3:10:54 that for some reason has not made the transition from science into pop culture.
3:11:01 This is a similar phenomenon with GLP-1. I and other people have pointed to the fact
3:11:07 that certain food products or certain drinks or certain activities can increase GLP-1.
3:11:13 Google gone like peptide, which is now becoming more commonplace knowledge because of ozempic
3:11:18 manjaro, et cetera, as very powerful weight loss tools, although there’s questions about
3:11:25 muscle loss, et cetera. Then we had Dr. Zachary Knight on who explained that even a four-fold
3:11:29 increase in GLP-1 brought about through a prescription drug or ingestion of a particular
3:11:36 food or drink does not lead to any appreciable weight loss. However, when one achieves 1,000
3:11:40 fold increases in GLP-1 through the use of things like ozempic manjaro, you see profound
3:11:46 weight loss, meaning that you need enormous effects in order to see that the clinically
3:11:52 relevant changes in that case weight loss. It sounds like a similar thing with CBD. If
3:11:57 somebody takes a CBD gummy and they feel that they sleep better, you would argue that that’s
3:12:01 entirely expectation bias. I think that’s a placebo effect, and I say that because
3:12:04 the majority of gummies are about like 2 megs, 5 megs, 20 megs maybe?
3:12:09 I’ve never taken a CBD product. I know a few years ago they were all the rage. I was never
3:12:14 tempted to do it. I’m aware and we’ll talk about this a little bit more that there is
3:12:18 evidence, according to Matt Walker who did a six-episode series with us on sleep, that
3:12:24 THC does help certain people fall asleep, but it can dramatically alter the architecture
3:12:28 of sleep in ways that are probably not great.
3:12:33 Yeah. Yeah. I mean, THC and sleep is definitely a whole other thing. But sure, a lot of people
3:12:38 report this with CBD. But again, so most CBD edibles or things that people take that are
3:12:44 sold through commercial markets are in the range of 2 to 25 megs of CBD. So then I say
3:12:49 to them, so you’re aware that in the pediatric epilepsy studies, the dose ranges are like
3:12:56 1,500 to 2,000 megs, and then you’re talking about a child who weighs on the order of what,
3:13:03 20 kilos maybe, like 40, 60 pounds somewhere in that range versus … So if you start dosing
3:13:06 by weight, which is how most of these things are done, well, they’ll say 20 megs per keg
3:13:14 or whatnot. So someone my size, so I weigh a bit over 200 pounds, for me to take that
3:13:22 dose of CBD, and let’s say 20 megs per keg at like 90 odd kilos, I mean, you’re talking
3:13:24 about me taking … A liver-damaging dose.
3:13:30 An insane … Well, maybe I wouldn’t say damaging. It’s definitely influencing how the liver
3:13:33 metabolizes other things because it’s going to saturate those enzymes, but you’re taking
3:13:38 a very high dose. So if, for instance, you were to take a high dose of CBD and then maybe
3:13:42 have a couple alcohol-containing drinks, that could be problematic, right? Because you’re
3:13:46 talking about the two-hit model. Yeah, I can’t speak to that because I actually
3:13:49 do not know the metabolism of alcohol well enough. I don’t believe so because that’s
3:13:54 alcohol dehydrogenase. So that would probably be a separate enzyme pathway than the SIPs.
3:13:58 This is more like … Separate enzyme pathway, but you’re challenging the liver.
3:14:02 Yeah, but I don’t know if it would have an effect in that capacity. I mean, they’ve
3:14:06 definitely seen this … They know the list of medications that this is a problem for.
3:14:11 So it’s things like warfarin and blood thinners and the anti-upleptics funnel into the same
3:14:15 metabolic pathway as this THC. So there’s certain things that this would influence.
3:14:20 I don’t know if I would say this would be in the context of alcohol, but I think more
3:14:24 so … I mean, what I try and point out to people repeatedly is I have yet to see a blinded
3:14:30 clinical study that has found any effect of CBD that’s efficacious, that’s under 300
3:14:37 to 500 milligrams. And yet in the wild, and people who are using it on their own, we’re
3:14:41 using doses of 10 to 20 milligrams and reporting these effects. And the thing is that I think
3:14:47 a lot of people don’t also realize is CBD has absolutely horrific bioavailability.
3:14:51 So if you take it orally in an oil or in a gummy or whatever you consume it in, now this
3:14:54 might be different with some of these beverages that are out there. I don’t know if anyone’s
3:14:58 actually ever done the pharmacokinetics on them, at least I’ve never seen it. But standard
3:15:05 roots, we’re talking 4%, very, very little, actually leaves your gut into your bloodstream.
3:15:10 Now we do know from the studies from GW who created the pharmaceutical version of CBD that
3:15:15 was used for a lot of the pediatric epilepsy studies that they did, I don’t know if it
3:15:20 was random or intentional, find that opposite to something like alcohol, if you had just
3:15:25 eaten a fatty meal, that actually enhanced the bioavailability of CBD dramatically. So
3:15:29 then it went up to like maybe 20% and got into the blood. But that’s probably because
3:15:33 again, CBD is a fatty molecule, it likes fatty environments, and for some reason having fat
3:15:37 in the stomach and then the gut seems to promote its ability to get into the bloodstream.
3:15:45 You can see now it’s the steak in CBD or the CBD with omelet protocol. I’m just kidding
3:15:51 folks, I’m not suggesting that protocol. But yeah, and so because of this, it’s like you’re
3:15:56 taking very low doses of CBD that have very poor bioavailability and then people really
3:16:00 stand by the effects of these. And so I’m like, what I would always say is if it works
3:16:06 for you, there’s no reason to stop it because you’re having benefit from it. But would I
3:16:11 ever recommend someone do this? No, I wouldn’t because I can’t say that I think that this
3:16:16 has any biological activity. Because even when we start looking at these potential targets
3:16:19 of what CBD could interact with, and there’s a couple receptors, people have said, you
3:16:24 know what might interact with serotonin receptor? There’s some of these like random orphan receptors
3:16:27 that we don’t know a lot of what they do that CBD might interact with. But like the concentrations
3:16:33 you need to hit those are reasonable and you’re not getting that in the blood and certainly
3:16:39 not in the brain of people from consuming incredibly low doses of CBD. So the whole market
3:16:44 that exists for CBD to me is a little bizarre. And I think for a lot of us in the cannabis
3:16:48 field, this has been one of the most bizarre social experiments we’ve ever watched because
3:16:52 like, you know, if you asked me in 2010 to walk into a room and ask how many people knew
3:16:58 what CBD is, like maybe one out of a hundred, like no one knew what CBD was. And now it’s
3:17:03 like 80 to 90% would know what it is because everyone, you can’t walk down a street in any
3:17:08 city in North America and not see CBD products, whether it’s some kind of cream or like a shake
3:17:13 or some random like concoction that people have added CBD because now it’s gonna, you’re
3:17:17 saying the energy drinks, like it’s just, it’s bizarre to me how much this has taken
3:17:21 off because it seems to have somehow migrated into being a health product in some capacity.
3:17:26 So yeah, I’ve never tried any of these CBD containing products. I think a lot of what
3:17:33 you’re describing speaks to the fact that, you know, people are eager for things that
3:17:39 can help them adjust their anxiety and sleep better, which is a large reason why a lot
3:17:46 of this podcast has focused on respiration-based tools and other based tools that can help
3:17:52 people with anxiety. I think that many people suffer from just too much activation in their
3:17:58 autonomic nervous system. And I would argue there are much better things that are not
3:18:02 of a ingestible type, you know, things that one can do that are science supported, right?
3:18:08 There are clinical studies, meditation, breathwork, not so much breathwork I would argue, but certain
3:18:12 patterns of breathing, meditation, cognitive behavioral therapy, there are a whole bunch
3:18:17 of different things as you know. So I don’t know what explains the CBD craze, but you
3:18:22 certainly have shed light on what is and mainly what is not known about CBD. And I think it’s
3:18:27 really important for people to hear. Yeah. I mean, again, it’s, I think from my point
3:18:30 of view, it’s an ethical thing as well, because like this isn’t covered by insurance, people
3:18:34 are spending their own money on this. And so I find it really challenging to recommend
3:18:37 someone to be spending what can, I mean, if you’re especially talking about an actual
3:18:41 clinical dose, I mean, for someone to take CBD at the level where it could actually be
3:18:46 shown to have some benefit in some condition, of which currently it really is just pediatric
3:18:52 epilepsy, like this idea with sleep, pain, anxiety, there’s not a lot of super conclusive
3:18:57 data. And I’d say most of the trials that have been done have not found really good
3:19:02 evidence of benefit in any capacity. So it makes it very challenging to recommend this
3:19:06 in any capacity, especially, I mean, if someone, if finances aren’t an issue, sure, go for
3:19:11 it. But you know, I understand people are like you say, looking for solutions. So it
3:19:15 doesn’t sound like CBD is the solution. I would, I am not convinced by the data that
3:19:20 exists that it’s really doing what a lot of people claim it’s doing, except supporting
3:19:24 the placebo effect perhaps, perhaps. It’s a great study of the placebo effect.
3:19:30 I want to make sure before we close that we touch on some of the potential harms or asserted
3:19:36 harms of THC, because I think there’s a lot of misunderstanding about this. We talked
3:19:42 about psychosis and the lack of evidence for a direct causal effect. You give a beautiful
3:19:46 description as to how we should think about all of that based on the current literature.
3:19:53 But cannabis and driving is a potential hazard, right? And some people will laugh. They’ll
3:19:57 be like, oh, driving too slow as opposed to, you know, driving drunk or driving too fast.
3:20:03 Okay, we can talk about that. We talked about the potential for addiction and the evidence
3:20:11 potentially for and against that, right? There’s also the big black or gray box of, you know,
3:20:16 all the things we don’t know about what regular cannabis use could do. And yet, I know a lot
3:20:21 of people who have used cannabis for years mainly as a replacement for alcohol, at least
3:20:26 that’s how they describe it. Well, it’s not as bad as alcohol, but you hear that a lot.
3:20:32 But what are some actual, if any, what are some actual harms of cannabis use that people
3:20:37 need to take into account and just weigh against the fact that every compound, caffeine, even
3:20:41 water can kill you if you drink too much of it? And then let’s make sure that we touch
3:20:46 on this issue of cannabis and driving or operating machinery. But I think the machine, most people
3:20:55 are thinking about these days is driving. Yeah. So health harms, I mean, someone smoking,
3:20:59 obviously there’s risks for lung damage. I would say the evidence for things like lung
3:21:03 cancer certainly don’t hold the way they do with cigarette smoke because people are smoking
3:21:08 less of it or there’s just fewer carcinogens in there. I don’t think you could make the
3:21:13 argument about fewer carcinogens per se. I think probably it relates more to the frequency.
3:21:17 I mean, Donald Tashkin, who’s in California here, I think he was at UCLA. I’m not 100%
3:21:21 sure, but I know he was in California. He did like very long-term studies tracking cannabis
3:21:26 smokers and basically did not find associations of lung cancer the way that you do with cigarette
3:21:29 smoking. Why that’s the case? I don’t think anyone has it. Like people have theories.
3:21:33 Some suggest because a lot of this in vitro animal work with really high dosing suggests
3:21:37 it could have anti-proliferative effects for tumors, whether that’s real or not. I don’t
3:21:42 know, but I think more likely it’s because most people who smoke cigarettes at least
3:21:47 that were the relationship with lung cancer were people who were smoking regularly throughout
3:21:52 the day. It’s very rare someone smokes cannabis at that frequency. Maybe if they isolated
3:21:55 that population, they would see relationships with lung cancer. I just don’t think it’s
3:22:00 been borne out by the data the same way. Certainly lung damage, emphysema, things like that are
3:22:03 on par. If you have any combustion product, you’re going to have damage there. There’s
3:22:09 no question about that. Again, harm reduction perspective would be oral roots of administration
3:22:13 bypass lung damage. They come with their own issues with dosing and whatnot, but if you’re
3:22:17 talking about physical harms, that’s one thing to avoid that you could bypass that aspect
3:22:26 of it with. I don’t think we are at a point where we can say the state of it. There is
3:22:34 something with cardiovascular function and cannabis that relates to higher frequency
3:22:40 of strokes, perhaps, or cardiac events in some capacity. The data is not entirely clear
3:22:46 in this sense yet. We don’t see, again, it’s not super clean relationships. We’re there
3:22:51 when we established cigarette smoking and lung cancer. I think that effect was so profound.
3:22:58 The population of smokers used to be so high. Can this potential, I want to highlight potential,
3:23:06 relationship between cannabis use and cardiovascular issues be bypassed, no pun intended, by using
3:23:11 edibles, not inhalants, or is it related to THC itself?
3:23:18 I would probably guess, and this is a guess, that anything, again, combustion smoke-wise,
3:23:23 and maybe not vaping plant matter, but at least the combustion from smoking probably exacerbates
3:23:27 this just because any kind of combustion product is going to have some vascular effects to
3:23:32 some degree in the system. I imagine it may get worse, but THC itself has a very complex
3:23:40 effect on cardiovascular function because it tends to cause, typically, vasodilation.
3:23:44 You get widening of the blood vessels, which is why it relates to a lot of people who will
3:23:49 experience postural hypotension. Sometimes what that is, if you stand up and your blood
3:23:54 pressure doesn’t catch up with you, you get really lightheaded and people will collapse.
3:24:00 This is not uncommon to happen to people and with edibles as well. It’s not just from smoking,
3:24:02 but when they’ve consumed cannabis in some capacity, there are some people that seem
3:24:06 to be very sensitive to the vasodilating effects. When they stand up, their blood pressure can’t
3:24:10 match the shifting gravity that happens. Not enough blood perfuses the brain and they
3:24:16 go down, and that can be transient. They’ll come to a minute or two later, but it happens.
3:24:22 As a consequence of the vasodilation is it triggers tachycardia, which is an accelerated
3:24:31 heart rate. That’s a very reliable physiological response for a lot of people who use cannabis.
3:24:37 It’s a bit of a tricky thing because, obviously, if there is some underlying heart or cardiac
3:24:45 sensitivity or issue, the tachycardia itself can be a problem. If someone has an underlying
3:24:52 heart condition where at rest it may not present itself, but the shifts into that beating faster
3:24:57 to compensate for the fact that you’ve got to drop on blood pressure can put strain on
3:25:03 the heart in a way that could unmask a vulnerability or an event. Again, this is me theorizing what
3:25:07 I think it could be based on what we understand to some degree about how it affects cardiovascular
3:25:14 function. There are occasionally people who have reported having elevated blood pressure.
3:25:19 Some of that also could be from an anxiety state or whatnot coming around, but the typical
3:25:24 response, and this is usually driven by cannabinoid receptors that are in the vascular beds themselves,
3:25:29 that it causes a vasodilatory response. That is usually the first step. The second is the
3:25:35 uptick in the heart rate. You get these effects over time. There’s some work looking at like
3:25:42 vascular stiffness that can evolve over time, and cannabis users, there’s some evidence
3:25:47 to suggest that you might get more of that emerging. Again, that could relate to a vulnerability
3:25:55 to have strokes or other cardiovascular events in that sense. I think the issue in terms
3:25:59 of why it is more difficult for us to say anything definitively at this point is just
3:26:05 obviously the timeline of this. Cigarette smoking was an easier thing to establish in
3:26:09 that context because once antibiotics and medicine advanced in the 40s and the 30s and
3:26:13 stuff and people started living longer, you started seeing a lot of these effects of cigarette
3:26:14 smoking emerge.
3:26:19 You had to take a while for the medical community to adopt the idea that cigarette smoking was
3:26:20 bad.
3:26:25 Oh, I know. Physicians would smoke in clinic. There are ashtrays in the doctor’s office.
3:26:29 My grandparents grew up in Belfast. They had smoked for years and they had even said like
3:26:32 when they were younger doctors would say, “Oh, have a cigarette after a meal. It promotes
3:26:35 digestion.” It’s kind of wild to hear that stuff when you think of how cigarettes are
3:26:43 viewed nowadays. I don’t think we’ve been able to track this long enough to be able
3:26:49 to say with certainty what we’re seeing. If people ask me about risks and harms of cannabis,
3:26:54 the first thing I always say is schizophrenia and bipolar. Those are the main concern areas
3:26:59 I think where you want to avoid cannabis. I would also say if anyone has cardiovascular
3:27:03 issues, they should avoid cannabis just because that’s more of I would say a being safe because
3:27:07 I don’t know how to actually explicitly say what I would say the harms associated with
3:27:11 it are, but I think there is something there. I’ve seen enough evidence that’s starting
3:27:18 to coalesce into a story that’s like there’s something here. That’s where I would say that
3:27:19 I think there’s risk.
3:27:24 There’s also things like this bizarre cyclic vomiting syndrome, which is this really strange
3:27:29 thing that has become really apparent. We’ve seen this in Canada a bit more now with legalization
3:27:34 again because people are going into ERs more where it’s this somewhat strange phenomenon
3:27:41 where it’s usually people who are pretty excess cannabis users. They just start like puking
3:27:48 and they can’t stop it. It’s like this intractable vomiting that they get into and then bizarrely
3:27:53 one of the things that seems to cure it is a hot shower. I can’t even begin to understand
3:27:54 this.
3:27:59 I’m chuckling at the example because you are so very clearly rooted in science, but that
3:28:03 just came out of nowhere like, “Okay, cool. Hot shower. Deliberate heat exposure, folks.
3:28:04 There it is.”
3:28:07 I have been trying to understand how this works.
3:28:10 I’m not enjoying it because it’s deliberate heat exposure, but it just speaks to the fact
3:28:18 that we’re talking about smoking being a regular part of the medical community’s behaviors
3:28:26 up until a few decades ago, and then a hot shower being the treatment for this chronic
3:28:31 vomiting. It speaks to the fact that with science and medicine, we do know a ton. It’s amazing
3:28:36 how much we’ve progressed especially in the last 100 years, the last 25 years even, but
3:28:44 it’s also astounding how the seemingly surprising antidotes to uncomfortable conditions can hold
3:28:48 up over time in the absence of any randomized control trials or mechanistic data.
3:28:52 I mean, I’ve really struggled to understand because certainly I don’t think it was doctors
3:28:56 that figured this out. This was people, I think, who were experiencing this, and then
3:29:02 they started telling doctors this. I could only imagine I’m like, “Maybe they’re going
3:29:06 in the shower because they’re vomiting on themselves,” and then inadvertently realized
3:29:10 that being in a hot shower somehow seemed to calm this down. I have seen a study where
3:29:13 they actually applied capsaicin cream, and that also seemed to provide benefit.
3:29:18 Something about activation of the heat thermal regulation, because the other thing that seems
3:29:22 to have shown some benefit is propanolol, which, again, would suggest some kind of sympathetic.
3:29:23 Which is a beta blocker.
3:29:28 It’s a beta blocker. It’s your effect. There’s something with autonomic. It must be messing
3:29:32 up some kind of autonomic balance or something with thermal regulation. Why that results
3:29:37 in this bizarre vomiting syndrome? I have no idea, but I remember when I first started
3:29:41 hearing the stories of this years ago, and I was just like, “How?” Because, I mean, it
3:29:47 is, again, surprisingly counterintuitive because one of the medical uses that people have used
3:29:51 cannabis for is as an anti-nausiant, especially in the context of chemotherapy. Something
3:29:56 that typically has anti-nausiant qualities suddenly triggering a vomiting syndrome is
3:29:59 kind of a paradoxical …
3:30:04 And yet, we started off today’s conversation with you explaining beautifully how activation
3:30:11 of these CB1 receptors are homeostatic in some sense, the thermostat analogy. And maybe
3:30:17 after chronic use, the seesaw gets flipped to one side and gets stuck there.
3:30:20 Yeah. I think that’s how most people have tried to kind of conceptualize what’s going
3:30:25 on is maybe like … And it seems to involve the insular cortex, at least the anti-nausiant
3:30:29 effects of cannabinoids are involved through the insular cortex. And so, maybe you have
3:30:34 burned out those receptors from chronic use. And so, that endogenous mechanism isn’t working
3:30:38 or it’s somehow flipped in the other direction now, and that circuit becomes sensitized.
3:30:46 But it is a very bizarre but very real thing that seems to happen. Again, this isn’t common.
3:30:51 I’ve heard a couple of people I’ve met describe it, but it’s not like it’s happening to every
3:30:55 10th or 20th person or something. It’s a little more infrequent, but it’s certainly happening
3:31:00 enough that we’ve now captured it at a federal data level that this is a thing that people
3:31:02 are showing up in the R4. Interesting.
3:31:05 So, a hot shower. Yeah. So, apparently, if it happens, hot
3:31:10 showers are what people claim. So, yeah. So, for me, I would say the main harms that people
3:31:16 need to be aware of are the schizophrenia bipolar, possible cardiovascular effects. And then,
3:31:19 this is one of these syndromes that can come out of it as well as possible lung damage
3:31:24 from smoking. Those are the main, I think, genuine bona fide health issues associated
3:31:28 with cannabis that people should be aware of. I mean, I know we’re not going to probably
3:31:31 go into depth with it. On the other side, with the medical stuff, it’s a little bit
3:31:36 more challenging. I mean, a lot of this is just because we really don’t have good studies
3:31:41 that have been done in any capacity that have really definitively told us if cannabis has
3:31:44 really bona fide medical benefits. Yeah. I was going to ask you about that. It’s always
3:31:49 nice to end on a positive side, and we don’t want to demonize cannabis, nor do we want
3:31:56 to glorify it. But the examples that I’ve heard of medical uses for cannabis include
3:32:02 appetite stimulation. We talked about that. For glaucoma, lowering eye pressure and glaucoma,
3:32:09 the age and age-related increase in eye pressure are two of the major risk factors for glaucoma,
3:32:15 which is the most common blinding disease, second to cataract, more than 70 million people
3:32:19 suffer from it. Everybody, regardless of age, get your eye pressures checked. There are
3:32:26 drops for this, but okay, cannabis can reduce eye pressure, glaucoma, nausea, you mentioned,
3:32:33 and then anxiety. It sounds like if people get the dose right, and it’s right for them,
3:32:36 that in some cases, it can help them with their anxiety. The reason I raise that one
3:32:42 is because it seems that most people who decide to use cannabis regularly are using
3:32:47 it as perhaps for its euphoric effects, but as a kind of a mild sedative, a way to relax
3:32:51 in the same way that they would use a glass or two of wine. What are your thoughts on that?
3:32:53 Because I think this is the most common use case.
3:32:57 Yeah. I mean, you look at, I mean, the other one that wasn’t on there, but you’ve mentioned
3:33:01 this before, and I have as well as pain. So chronic pain is, I would say the number one.
3:33:06 So pain is certainly the one that there’s the most amount of evidence for, and I would
3:33:10 say when you talked about this in the previous podcast, you were mostly correct about this
3:33:15 component of it in the sense that it’s not that cannabis is a profound analgesic, it’s
3:33:21 that cannabis, it has some analgesic properties, but it’s not like super sledgehammer in that
3:33:24 sense. But what it does seem to do is, it seems to strip away the affective component
3:33:29 of pain to some degree. And so what I have consistently heard from chronic pain patients
3:33:33 when they use cannabis is they say, “Yeah, my pain’s still there, but now the pain’s
3:33:37 background noise. So I can sleep at night.” And just being able to sleep, I think is
3:33:42 actually providing a huge amount of the benefit to that community. But it’s the day-to-day,
3:33:46 like they’re able to function with the pain because it doesn’t, they don’t become focused
3:33:49 on it the same way because they’re able to kind of push it to the background. That seems
3:33:54 to be the main ability of cannabis. I mean, yes, there’s some mild analgesic properties
3:33:57 to it to some degree, but it really seems to be much more of that component of it. And
3:34:01 I think you’d alluded to something like that in the previous podcast you’d said, something
3:34:04 about how it’s changing the emotional state of pain.
3:34:10 And we know from the biopsychosocial model of pain that emotions and interpretation of
3:34:15 the sensation of pain is a huge component of what people refer to as chronic and acute
3:34:16 pain.
3:34:19 Yeah. So the pain thing, I think, is a central one. And that’s one of the only ones that
3:34:22 there’s a little bit of actual research on. Most of it’s either with isolated THD. I think
3:34:26 there’s one or two studies that have actually looked at small cannabis and found small signals
3:34:31 of benefit. But so anxiety is an interesting one. And so I mean, obviously this is more
3:34:36 near and dear to my heart because I study stress and anxiety as my primary area and
3:34:43 cannabinoids and endocannabinoids in that space. And yeah, you look at questionnaire-based
3:34:47 studies about why people smoke cannabis and like 85% of them, we’ll say, because it reduces
3:34:51 stress and it makes me feel less anxious. I mean, that was like a big impetus as to why
3:34:55 we started studying endocannabinoid regulation of it because similar to feeding and pain
3:34:59 where we know endocannabinoids are involved in regulated feeding circuits, and endocannabinoids
3:35:05 are also integrated into pain circuitry and can provide some endogenous analgesic signals.
3:35:08 We figured the same was going to be true for stress and anxiety, which to some degree it
3:35:13 is. But it’s very complicated because it can be, like I said before, biphasic, where
3:35:18 some lower doses are anxiolytic, higher doses can promote anxiety. But for the majority of
3:35:23 people who use cannabis regularly, it’s because it helps reduce anxiety. Now, whether that
3:35:29 would hold weight in a clinical trial is a different story. There is some old evidence
3:35:34 from like, I’d say the ’70s or early ’80s where they were using synthetic forms of THC,
3:35:37 like nabalone, which is some of you can get in Canada or Marinol or Drannabinol, which
3:35:41 I think is what’s accessible in the States, where they did find some evidence to suggest
3:35:45 it was on par with like a benzodiazepine, like diazepam or something. I can’t remember
3:35:50 exactly what the comparator they’d used there, but there was some evidence for there being
3:35:57 some anti-anxiety properties of THC. And that tracks generally well with the self-reported
3:36:04 literature that’s out there. Now, whether that’s the same as an ability to have benefit
3:36:07 in something like PTSD is a different question. It gets a little bit more complicated because
3:36:13 obviously PTSD has an anxiety component to it, but there’s a lot more to it as well.
3:36:17 And again, there’s very little research in this space. There was one really, really small
3:36:22 study done by the Canadian military. First, they did one version of it that was an open
3:36:26 label, open label trials for people who don’t know. It’s just basically everyone knows what
3:36:30 they’re getting. It’s not blinded in any way, but because of the self-reported data from
3:36:35 the veteran population about cannabis helping, especially with sleep. And the big thing that
3:36:40 they reported was that it suppressed their nightmares. And so post-traumatic stress disorder
3:36:45 is a very complex disease for many reasons. And one component of it is the re-experiencing
3:36:50 events that happen during sleep, where there’s a lot of nightmares and individuals will kind
3:36:56 of re-experience the trauma that led to the development of the PTSD. And there does seem
3:37:00 to be some suggestion that because they’re remembering it and maybe changing the details
3:37:04 because they’re in a dream scape space that they re-consolidate it a little bit more.
3:37:08 And there’s often a high degree of sympathetic activation and arousal that goes on with these
3:37:13 nightmares. And some of the belief is that this is part of the sensitization process
3:37:18 that can happen in PTSD where the disease can worsen over time because the re-experiencing
3:37:22 and the re-consolidation and the sensitization of the disease that happens over time in this
3:37:28 kind of sleep state can make it worse. And so the majority of veterans who have used cannabis
3:37:32 and report benefit, if you actually talk to them about it, as I’ve done in a few different
3:37:37 situations and also just look at the anecdotal data, almost all of it talks explicitly about
3:37:41 sleep. And they say, “Oh, we use cannabis or THC before bed. We find we don’t have
3:37:46 the nightmares.” And just the simple trickle-down effect of that is hugely beneficial for them.
3:37:49 And so the Canadian military did an open-label trial on this. Again, not blinded. It was
3:37:54 small numbers, but they basically found, as soon as they put people on nab alone, this
3:37:59 synthetic version of THC, it very, in a large proportion, I think like 85% of them, almost
3:38:03 stopped having these nightmares. And this was a treatment-resistant population that
3:38:08 was pretty severe. So this was a big benefit. So they then took the open label and did what
3:38:12 you should and moved forward to do a double-blind placebo-controlled. Now, it was a very small
3:38:16 sample studies. And that is obviously always a problem with human work, is if this was
3:38:21 like 15 or 17 people. So not powered enough to really make any kind of firm conclusions,
3:38:24 but interesting in the sense that at least it was done in a proper crossover design,
3:38:28 where they got placebo at one point, they got nab alone at one point, it was switched.
3:38:33 They didn’t know which one they were on. Because they’re taking it right before bed,
3:38:37 maybe that will remove some of the subjective bias. Again, you can’t totally remove it,
3:38:40 but like if someone’s taking it within an hour or so of going to sleep, they may not
3:38:44 feel behind the same way. But even under the double-blinded conditions, they found a very
3:38:49 effective suppression of the nightmares and the re-experiencing. And then they also, at
3:38:53 the same time, found this increase in kind of quality of life measures, which tracked
3:38:57 with the fact that they were probably sleeping better. I don’t think they actually reported
3:39:02 any change or even looked at maybe the overall PTSD score. They only reported or really focused
3:39:06 on the nightmare component of it, because that was the primary outcome of the study.
3:39:09 But so I thought that was interesting because if you look at the anecdotal data in PTSD,
3:39:14 that’s where a lot of it is focused on is using it as kind of, I wouldn’t maybe call
3:39:18 it a sleep aid, because it’s really more of a modulator of the dream state.
3:39:21 Presumably because it’s reducing the amount of rapid eye movement sleep you’re getting,
3:39:27 which most people will probably hear and interpret as bad. But REM deprivation is actually one
3:39:33 treatment for depression. So there are certain case conditions where dreaming and REM is
3:39:36 not advantageous and you’re describing one.
3:39:40 I mean, and depression and PTSD are both two disorders that are characterized by changes
3:39:43 in REM. Like they have earlier onset to REM, so they go into REM faster. They tend to have
3:39:48 some altered architecture of the REM component of their sleep. So in those states, maybe
3:39:53 suppressing REM isn’t actually a bad thing. At least certainly for PTSD, I would imagine
3:39:57 in terms of the context of the nightmares, that’s providing some benefit. Whether or
3:40:02 not it globally is changing the disease severity or improving the disease, I don’t think we
3:40:05 really have any evidence to say.
3:40:11 But again, I can understand the desire for people to kind of self-medicate, let’s say,
3:40:15 by using this as an approach to try and reduce that component of their sleep so that they
3:40:20 sleep better, they feel better, maybe down the road, it would help the prognosis of the
3:40:25 disease long-term if it’s not sensitizing the same way. But I don’t think we have any
3:40:29 strong data that we can leverage in that capacity to be able to say it. But to me, it’s one of
3:40:35 the more interesting areas. I think anxiety disorders in general, there’s definitely some
3:40:36 potential.
3:40:42 So as I had mentioned earlier, the font inhibitor that elevates anandamide levels, so Johnson
3:40:46 and Johnson did do a trial on social anxiety disorder. It was published, I think, from
3:40:50 a few years ago, at 21 or something, I can pull up the reference for that, where they
3:40:54 did find some benefit. It wasn’t huge. And some of this had to do with the design of
3:40:59 the study because they kind of underdosed the patients a bit. And so not everyone actually
3:41:02 showed the elevation of anandamide when they went back and looked, but when they actually
3:41:06 isolated the group of people that had higher anandamide, in that proportion of the patients,
3:41:11 they did see some symptom improvement. So it did support it. And this is, I mean, very
3:41:15 similar, like for us, this is a big thing because all of the work that we focused on
3:41:20 is looking at how stress and stress hormones regulate largely anandamide signaling. And
3:41:24 one of the main things that we’ve demonstrated that’s been replicated relatively well over
3:41:28 the years is that stress exposure can actually cause a rapid loss of anandamide signaling
3:41:33 and it’s that loss of anandamide signaling that seems to facilitate some synaptic strengthening
3:41:38 in the amygdala and promote activity in areas that are involved in these anxiety circuits.
3:41:44 And so the thought has always been, well, if anandamide, you know, it’s that job as its
3:41:47 kind of tonic housekeeper at keeping things in that homeostatic range, let’s say we’re
3:41:52 talking about explicitly an anxiety circuit, you know, there’s individual variation that
3:41:56 exists in humans across everything. So one of our predictions has been maybe people who
3:42:00 are on the high end of the anxiety spectrum might be on the low end of their tonic anandamide
3:42:04 signaling spectrum. And we’ve gotten a little bit of support from that from animal work where
3:42:08 we’ve screened animals based on anxiety and looked at endocannabinoid levels in the amygdala
3:42:10 and found lower anandamide.
3:42:16 That’s extremely interesting because it squares with my, again, non-laboratory observation
3:42:22 that a lot of people use cannabis to deal with their anxiety. Right? So what you’re saying
3:42:27 is that, you know, there’s a range of kind of, let’s just say baseline circuit activation
3:42:31 within the amygdala and related structures in mice and humans, presumably in other animals
3:42:40 also. If people take a compound that adjust the sort of homeostatic level of what’s considered
3:42:45 low moderate and high activation of those circuits that include the amygdala, then perhaps they’re
3:42:50 bringing their anxiety into range in a way that perhaps is different than with alcohol,
3:42:53 which is more acute. You know, people have a couple drinks, they’ll feel relaxed, but
3:42:58 then there’s this phenomenon of anxiety, you know, the next day, feeling a little anxious
3:43:03 when they’re not drinking. Whereas it’s interesting that many people who use cannabis for this
3:43:08 purpose are not using it all day long. They are perfectly able to wait until the night
3:43:12 time or evening. And of course, people can wait for a happy hour for a drink as well.
3:43:15 But it’s far and away different than the way we envision something like alcohol use disorder
3:43:20 where somebody discovers that alcohol really helps with their anxiety and then they’re drinking,
3:43:24 you know, maybe one at lunch, maybe a couple at dinner, and then in the evening to fall
3:43:28 asleep at night. I’m describing extremes here, but I find your hypothesis to square
3:43:32 really well with the real world observations. And it’s an interesting one.
3:43:36 There is some evidence to actually support. So my buddy Sachin Patel, who’s at Northwestern
3:43:41 now, but he was at Vanderbilt when he did this study, they basically played with these
3:43:45 drugs that you can use to prevent endocannabinoid synthesis. So you can create a state of like
3:43:51 impaired endocannabinoid function. In humans. And they did this in rodents. So this was
3:43:57 done in mice. And they basically, but one of the questions was is, so A, does like reductions
3:44:01 in endocannabinoid function produce states of anxiety? And they did demonstrate that.
3:44:05 So you could deplete endocannabinoid levels and you got the emergence of an anxiety state.
3:44:10 So then you could give drugs that would boost the endocannabinoids to normalize this. So
3:44:13 again, it kind of fit with the idea. But then they did one key study where then they gave
3:44:19 THC and saw, could THC fill in the gap? And they found that like boosting endocannabinoids,
3:44:25 giving THC on a background of low endocannabinoids was able to reverse that anxiety phenotype
3:44:30 and bring it back into more of the normal range. So again, maybe for some people this
3:44:33 is if this is again, this is theoretical. So I don’t know how much of a spectrum there
3:44:37 is if there are people that are at this low end, but certainly I think from the animal
3:44:40 literature, there’s some foundation for making a theory that’s similar to what you’re saying,
3:44:45 which is maybe some people are trying to fill in a gap of something that’s deficient in
3:44:50 them and therefore that can help them feel less anxious. And that again, may be very different
3:44:55 than someone who is like, you know, very anxious for different reasons or has normal endocannabinoid
3:44:58 function or something else might be a play there. So very interesting.
3:45:01 Yeah. I think I could explain some of the heterogeneity that exists out there for sure.
3:45:07 So perhaps genetic differences in sort of baseline levels of anxiety, perhaps map to
3:45:11 endogenous levels of anandamide and might predict propensity for THC use.
3:45:16 Yeah. I mean, we have definitely found in human populations through work I’ve done with
3:45:20 a lot of clinical collaborators and others like, you know, we look at endocannabinoids
3:45:24 in the blood and it’s not in the brain, but they are lipids that can move pretty easily
3:45:29 back and forth. And we have found relationships between peripheral endocannabinoid levels and
3:45:35 mood states, both anxiety and kind of depressive measures, which does, you know, somewhat relate
3:45:42 to the possibility that this could be real. We don’t know. It’s been hard obviously for
3:45:46 various reasons to really track this, but we’ve never looked at an anxiety disorder
3:45:50 population. We’ve done some work with post-traumatic stress disorder populations. There’s been
3:45:53 working depression populations that have found some relationships that are pretty similar.
3:45:58 So it’s certainly a possibility. But again, this is all like our theory at this point.
3:46:02 So we’ll see as things kind of move forward if they pan out, but yeah.
3:46:06 Fantastic. And I really appreciate that you’re able to share some of what your laboratory
3:46:13 is working directly on now and looking into the future. And I want to thank you for what
3:46:19 has been an incredibly clear, precise, and in many cases actionable, whether or not it
3:46:26 leads to a yes or a no actionable information here because cannabis and CBD, as you pointed
3:46:33 out, are kind of everywhere around us. And people are making decisions about cannabis
3:46:39 and CBD. And I also want to thank you because what initially started off as a bit of a
3:46:45 confrontation online, which I alluded to in the introduction that I gave, has now evolved
3:46:51 into a collaboration that I’m certain based on the exquisitely clear and generous information
3:46:58 that you’ve provided has led to better education, more clarity, and therefore better informed
3:47:03 choices for all the people listening and watching. So I really, truly appreciate you coming out
3:47:08 here, sitting down with me discussing these issues, clarifying points that were unclear
3:47:16 before, and also point into the fact that this is a complex system, a complex biology.
3:47:21 There are a lot of things about psychosis, about negative effects, about potential positive
3:47:28 uses of cannabis that just are not yet clear. And thanks to excellent researchers like you
3:47:34 are likely going to be clarified in the years to come. So thank you ever so much for your
3:47:39 time, for your research, and for your attention to the public health education effort around
3:47:40 cannabis.
3:47:44 Thanks. And I think it’s also important. I think it’s good as you had said that for
3:47:49 people to see that scientists can have disagreements, I think it’s important. I think it’s good
3:47:56 that you kind of provided me an opportunity to correct the record and did so in a very
3:48:01 appropriate manner. I think this was a great discussion for people to understand, different
3:48:08 perspectives, also good to highlight where it was that I had had issue with your previous
3:48:13 podcast. And I think the discussions that came out of that were for the better. So that’s
3:48:18 all the best. And hopefully, if there’s other contentious issues that happen down the road,
3:48:21 similar things, move forward and you chat with people in the area as well.
3:48:26 Yeah, if somebody who is expert in a particular area takes issue with something specific and
3:48:32 can substantiate it with something that can foster better understanding, without fail,
3:48:37 I’ll reach out to them. Now, how quickly we’re able to get them here, et cetera, is always
3:48:43 an issue. Sometimes we can put an addendum to a podcast. Nowadays, that’s easier using
3:48:47 what’s called dynamic insertion, where we can go back and actually make a correction.
3:48:52 But listen, the best situation is always when this podcast can mimic the real world of research
3:48:57 science, as you and I both know it to exist, where if we had been in a meeting and you
3:49:01 presented data, I presented data and we disagreed, what we would probably do would be to head,
3:49:05 well, traditionally would be to the bar, but we’d grab a cup of coffee or go for a walk
3:49:11 and we would talk about it, hash it out and then potentially bring it up again at the
3:49:16 next meeting. So in some sense, what we’ve done here over the last month or so, and certainly
3:49:19 during today’s podcast is to do something to that effect.
3:49:24 And I think it’s really good for people in the public to know this is how science progresses.
3:49:28 This is someone says something, someone disagrees with it. You get an opportunity to clarify
3:49:33 things and I think that that’s really good just to move things forward. So I think that
3:49:36 was a good process that we’ve gone through.
3:49:39 Yeah. Likewise. And it’s certainly within the spirit of the podcast. In no way, shape,
3:49:44 or form, do I purport to get everything right and where I’ve made mistakes. I really strive
3:49:49 to correct them. And listen, it’s been a real honor and privilege to have you out here.
3:49:53 Thanks for coming all the way from Canada. And I do hope to have you back again as the
3:49:58 research evolves. And we can learn more about these topics and more. So thank you so much,
3:49:59 Matt. Appreciate you.
3:50:05 Thank you for joining me for today’s discussion about cannabis with Dr. Matthew Hill. I hope
3:50:09 you found the discussion to be as informative as I did. If you’re learning from and or
3:50:14 enjoying this podcast, please subscribe to our YouTube channel. Please also subscribe
3:50:18 to the podcast on both Spotify and Apple. That’s a terrific zero cost way to support
3:50:22 us. And on both Spotify and Apple, you can leave us up to a five star review. Please also
3:50:26 check out the sponsors that I mentioned at the beginning and throughout today’s episode.
3:50:30 It’s the best way to support this podcast. If you have questions for me or comments about
3:50:35 the podcast or topics or guests you’d like me to consider for the Huberman Lab podcast,
3:50:40 please put those in the comments section on YouTube. I do read all the comments for those
3:50:44 of you that haven’t heard. I have a new book coming out. It’s my very first book. It’s
3:50:48 entitled protocols and operating manual for the human body. This is a book that I’ve
3:50:52 been working on for more than five years and that’s based on more than 30 years of research
3:50:58 and experience and it covers protocols for everything from sleep to exercise to stress
3:51:04 control protocols related to focus and motivation. And of course, I provide the scientific substantiation
3:51:11 for the protocols that are included. The book is now available by presale@protocallsbook.com.
3:51:15 There you can find links to various vendors. You can pick the one that you like best. Again,
3:51:19 the book is called protocols and operating manual for the human body. If you’re not
3:51:24 already following me on social media, I am Huberman Lab on all social media channels.
3:51:29 So that’s Instagram, ex formerly known as Twitter, Threads, LinkedIn and Facebook. And
3:51:34 on all those platforms, I discuss science and science related tools, some of which overlap
3:51:38 with the contents of the Huberman Lab podcast, but much of which is distinct from the contents
3:51:43 of the Huberman Lab podcast. Again, that’s Huberman Lab on all social media channels.
3:51:47 If you haven’t already subscribed to our neural network newsletter, our neural network newsletter
3:51:52 is a zero cost monthly newsletter that includes podcast summaries, as well as protocols in
3:51:57 the form of brief PDFs of one to three pages, where I spell out the specific dues and in
3:52:02 some cases do nots, but mostly dues related to things like how to optimize your sleep,
3:52:07 how to regulate your dopamine levels. There’s a protocol for neuroplasticity and learning,
3:52:11 as well as protocols for fitness, which we call the foundational fitness protocol includes
3:52:15 everything sets reps, cardiovascular training, again, all available completely zero cost.
3:52:20 You simply go to HubermanLab.com, go to the menu tab, scroll down to newsletter and provide
3:52:25 us your email. But I should point out, we do not share your email with anybody. Thank
3:52:29 you once again for joining me for today’s discussion with Dr. Matthew Hill. And last,
3:52:32 but certainly not least, thank you for your interest in science.
3:52:35 (upbeat music)
3:52:38 (upbeat music)