Your Brain on Drugs Ep 3 – Let’s Get Weird

Lollie: Alright, I also want to talk to you about a drug that’s very hot in the political climate right now, and that’s marijuana. So, cannabinoids. We have THC, CBD… They can also be laboratory-made, so those are sort of based off of the plant. The lab-produced, so synthetic, cannabinoids like Spice and K2. And while most of these-the synthetic ones kind of work through these loopholes, but most of these cannabinoids are illegal under federal law, and yet some states have legalized medical or recreational marijuana. What do these drugs do, are they dangerous? There’s just a lot of debate around this right now.

Ben: Cannabinoids are another one of those drugs that were discovered before we discovered the actual system on which they have an action. Cannabinoids act through cannabinoid receptors, and the cannabinoids our body uses are called <1>endocannabinoids (like for endorphin).

Lollie: So, we have morphine and endorphins, and cannabinoids and endocannabinoids.

Ben: Exactly, exactly. It’s really funny. Cannabinoids actually have a very specific mechanism of action, they’re called retrograde neurotransmitters. So, they are released from the post-synaptic neurons to send a message to the pre-synaptic neurons to either increase their activity or decrease their activity, depending on what the post-synaptic neuron needs or wants.

Lollie: Okay, so to sort of bring back language that we used in the first podcast: we have the releasing neuron, and the receiving neuron. Most drugs affect the releasing neuron in some way, unless they’re mimicking the effects of a neurotransmitter in which case they act upon the receptors of the receiving neuron. The really weird thing about cannabinoids, and the reason they’re kind of in their own class of drugs, and why they’re so bizarre and really interesting to study, is that they actually work by affecting the receiving neuron- what would normally be the receiving neuron- to go backwards in this process to affect the releasing one.

Ben: Yeah. Usually how it works is that the releasing neuron sends a message to the receiving neuron. In this case, cannabinoids are a message from the receiving neurons to the releasing neurons.

Lollie: Wow, that’s so interesting! So, what does that mean?

Ben: They do not have any incredibly specific function, like dopamine, for example. Cannabinoid receptors can be found all over the brain. They’re involved, for example, in pathways controlling hunger and energy metabolism, this is why we get the munchies, right? They’re involved in sensory perception, they’re involved in memory formation- they’re distributed in many, many areas of the brain.

Lollie: Yeah, the hippocampus which is one of the main formations of the brain relating to learning and memory, has a lot of cannabinoid receptors.

Ben: Exactly, yeah.

Lollie: And these are just things that we’re born with. We’re born with these receptors for endocannabinoids. What is the point? Why do we have endocannabinoids?

Ben: Endocannabinoids* are signaling molecules that help the brain respond in an appropriate way to different stimuli. So, they kind of modulate the activity of the releasing neurons (I think you called the pre-synaptic neurons the releasing neurons). They help the releasing neuron modulate its activity, so modulate the release of other neurotransmitters such as GABA, such a dopamine, such as, like, any other neurotransmitter. They control, they modulate, the release of other neurotransmitters.

*Natural endocannabinoids are really essential for forming clear memories and maintaining a normal appetite- which is why cannabis is often used medically to help stimulate appetite in people with various issues with that. It’s also used to help pain management and motor coordination.

Lollie: So, when we take an exogenous, or a cannabinoid that comes from outside our bodies- so when you smoke weed, when you take a dab, when you have an edible, or when you use Spice or K2 (to a certain extent, these are much less researched)- basically when you take an external cannabinoid and put it in your body for these effects, whether they’re medical or recreational, we end up with the extreme versions of the effects of endocannabinoids.

Ben: Exactly, because like any other neurotransmitter, like any other endo molecule (if we want to call them that), endocannabinoids are released at specific times, in very small quantities, in precise areas of the brain where they are needed to function. When we take external cannabinoids, like THC, like marijuana, the effect is widespread on every single cannabinoid receptor in the brain for a very long time, and usually these cannabinoids are in a higher concentration compared to the endo version.

Lollie: Okay, so what would be the dangers of taking too much?

Ben: There’s not really a critical danger that I can think of for THC. It can induce severe motor incoordination so you’re not able to walk or talk properly. It can induce drowsiness, but really not much more than that.

Lollie: It can make you eat a lot.

Ben: Ha ha, yeah exactly.

Lollie: Yeah, there’s never been a recorded lethal overdose on marijuana.

Ben: No, probably because it’s- I’m speculating, but because THC does not have a direct, as we said before like cocaine has a direct effect on dopamine, cannabinoids are more, like, a controlling regulatory mechanism.

Lollie: And yet there are long-term effects seen in chronic users. These are mainly in areas of the brain related to learning and memory, which is, in a way, sort of ironic that this chemical that we have, that we produce naturally to enhance our ability to form clear memories, when taken in larger amounts from an external source actually decreases our ability to form very clear memories.

Ben: Yeah, because the brain, as for other drugs, gets used to this unnatural level, or patterns, of stimulation and when this equilibrium is shifted after a long period of taking large amounts of THC or marijuana, the brain equilibrium is shifted, is changed, so the normal status of your brain is the status where there’s a constant flow of marijuana, there’s a constant flow of THC, which is not a natural status.

Lollie: Tolerance, right?

Ben: Exactly, tolerance. So, this is why your brain cannot function anymore, because it adapted over a long period of time to this new status.

Lollie: And recovery is seen in people who stop smoking, so there’s hope.

Ben: Yeah, the brain is very plastic.

Lollie: Meaning very adaptable.

Ben: Adaptable, sorry.

Lollie: Going into your neuroscience talk.

Ben: So yeah, it has the ability to bounce back.

Lollie: So, Dr. Ben, I think one of the most fascinating classes of drugs is the one we decided to talk about last.

Ben: Oh, fun.

Lollie: Because they’re just sort of a mystery, as far as I understand, in terms of the science behind them, what actually happens in the brain and this is psychedelics.

Ben: Totally, yeah.

Lollie: The class of psychedelics includes psilocybin (mushrooms), LSD (acid), MDMA (Molly, Ecstasy- well, part of ecstasy), and ketamine, PCP… a lot of drugs fall under this category. So, what exactly are psychedelics- how does a drug get into that category, and what do they do?

Ben: Psychedelic drugs have one thing in common, which is that they act on another neurotransmitter (another brain molecule) called serotonin. Serotonin is another molecule involved in reward and pleasure. It’s involved specifically in mood regulation, so this is also why, for example, antidepressants are often serotonin reuptake inhibitors. They should better your mood. You talked about a bunch of different psychedelics, and they are grouped in different classes. The first class, which is the classical psychedelic, [includes] LSD (acid) or mushrooms. Then we have a class of psychedelics that includes all the MDA, MDMA, so Molly–it’s called empathogens. And then there’s a third class which is called dissociative psychedelics which includes ketamine, for example.

Lollie: And PCP and stuff?

Ben: Mmhmm.

Lollie: And cannabinoids are actually considered a psychedelic. Is that correct?

Ben: Yeah, it is correct.

Lollie: Okay, so do they all work in the same way, or do they work in different ways?

Ben: No, they have fairly different mechanisms. So, classic psychedelic drugs like LSD all act as agonists of the serotonin receptor. So, they mimic the function of serotonin. The brain mistakes LSD, or psilocybin (which is the principle of mushrooms) for serotonin.

Lollie: So, if all of these psychedelics affect serotonin, why are they so different? Why is taking acid going to be so different than taking ketamine, for example?

Ben: As I was saying before, the mechanisms are fairly different. So, the classic psychedelic acts as serotonin. They are serotonin receptor agonists.

Lollie: The classics being mushrooms, LSD, etc.

Ben: Yeah, and mescaline. Whereas the empathogens, like MDMA, induce the release of both serotonin and dopamine. So there’s a difference, right? LSD mimics serotonin, whereas MDMA induces the release of serotonin. And ketamine has a very complex mechanism. Ketamine acts on a whole bunch of different receptors. It acts on glutamate receptors, it acts on opioid receptors, it acts of serotonin receptors–it has a really wide range of interaction in the brain.

Lollie: Wow, I didn’t know that! So, ketamine mimics all these different things? How could it possibly mimic everything, or we don’t really know?

Ben: I mean, I for sure don’t really know. I’m not a real expert on ketamine. But yeah, the main effect of ketamine is given by its action on the glutamate receptor.

Lollie: What makes this class of drugs, psychedelics, mysterious, in terms of research and our current understanding?

Ben: It’s really interesting because the most characteristic, the most important, effect of psychedelics is hallucinations, right? It’s fun, we see things, we see colors, we experience synesthesia sometimes.

Lollie: Synesthesia is when the senses are basically crossed.

Ben: When you can, for example, see a sound or taste a color. This is synesthesia. So, research on drugs is done on animal models, especially rodents or mice. We have ways to tell when a mouse is sad, we have ways to tell when a mouse is happy, when a mouse is curious, when a mouse is active–everything. All these basic states we can actually study. But, we cannot study hallucinations. We cannot ask a mouse, “what are you seeing right now?” So, that’s what makes these drugs difficult to research, because the only research you can do is on humans so they can tell you their experience. And their experience is very subjective, and also it’s really hard to explain. So, that’s what makes this kind of research very, very hard.

Lollie: I would imagine it’s difficult to get somebody who’s tripping balls to sit still in an MRI, or an fMRI.

Ben: Yeah, or like do a questionnaire or whatever.

Lollie: “Fill this out,” and they’re like, “but the words are floating away!”

Ben: Haha, exactly.

Lollie: It’s also very difficult to even get certification to study these, right? Because they’re technically considered Schedule I, which is alongside heroin. It’s considered to have no medical use, considered to be some of the most dangerous drugs, which is very interesting.

Ben: It’s very interesting. Actually, in the last few years, ketamine is coming out as a kind of preventative drug against depression, and it seems to be very, very powerful. But there’s still a lot of research to be done on that.

Lollie: Yeah, we don’t really… there wasn’t the freedom to fully explore the potential long-term consequences of using these drugs in general. That said, there’s a lot of fake research, I guess you could call them research chemicals, research psychedelics, that are coming out. Off the top of my head, 2CB, 25-I– all these ones with these number names that are hallucinogens, they’re psychedelics, but we don’t really understand how they work, we don’t know why they work, we don’t really understand any long-term consequences, whereas with things like LSD or psilocybin we have a better idea of what the potential consequences of these are.

Ben: Yeah, they’ve been around for a long time.

Lollie: And there’s also this danger of MDMA, Molly, being sold as Molly but it’s actually synthetic cathinones, or as many people know them, bath salts. They technically work in a similar way to MDMA, but we just, again, don’t understand the consequences of their use as opposed to MDMA where we have a better idea. So, it’s kind of an interesting, dangerous landscape right now. A lot of things being sold as LSD are these research chemicals, a lot of things being sold as MDMA are bath salts. The danger is often in the lack of awareness about these lying dealers.

Ben: If you want to try a drug, make sure what you’re taking, at least.

Lollie: And make sure you are fully aware of what could happen.

Ben: Exactly.

Lollie: Another thing we hear about is this kind of depression following extended, high use of certain kinds of psychedelics, because you can build a tolerance to these very quickly. For some reason there’s this rumor that was floating around for a while that you couldn’t build a tolerance to LSD or mushrooms or MDMA (Molly), but you do. You actually build it pretty quickly.

Ben: Yeah, you can definitely build a tolerance to all sorts of drugs.

Lollie: Taking them in high doses, in close-together time, you’ll basically not feel effects by a couple days into it because you’re dried up.

Ben: Yeah, the effect on mood is actually kind of easy to explain. As I said, serotonin is the molecule that regulates mood, so high levels of serotonin usually means a better mood. So, this is why we’re happy when we take acid or when we try MDMA, because there’s a lot of serotonin running everywhere in our brain. If we take MDMA, for example, it induces the release of serotonin from the presynaptic neuron, or the releasing neuron. Neurotransmitters, brain molecules, like serotonin or dopamine, are stored in teeny tiny bubbles, called vesicles, at the end of a neuronal terminal–at the end of…

Lollie: Of the arm of a releasing cell.

Ben: Exactly.

Lollie: So, they have these little bubbles packaged up in their little end.

Ben: There’s a little storage, a little stock, of these neurotransmitters. The neuron keeps producing them, but it cannot produce them as fast as the drug releases them, so the whole storage of serotonin, if you take MDMA many, many times in a really short period of time, consumes the whole stock of serotonin. So, your brain does not have serotonin anymore to release, even in a normal situation, so your mood is shifted towards a bad mood, towards a depressed mood.

Lollie: Depression, sadness–that’s pretty common for a lot of people following heavy MDMA use. Which is also why you would see chronic users, who take MDMA more than 2-3 times a year, experience long-standing depression because it takes a long time for your brain to recover from just dumping all this serotonin. Very interesting, good stuff.

Ben: Really… Definitely, sorry.

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Next Time on Let’s Talk Drugs…

Episode 4 Coming Monday, July 24th

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