understanding the neural effects of cannabis

Jean Mary Zarate: 00:04

Hello and welcome to Tales From The Synapse, a podcast brought to you by Nature’s careers section, in partnership with Nature Neuroscience. I am Jean Mary Zarate, the senior editor at the journal Nature Neuroscience, and in this series, we speak to brain scientists from all over the world about their life, their research, their collaborations, and the impact of their work.

In episode one, we start with exploratory work being carried out on the neural effects of cannabis and other illicit drugs, and why it’s important.

Natasha Mason: 00:40

My name is Natasha Mason. I am an assistant professor in the department of psychopharmacology at Maastricht University. So this is a yeah, a small pretty town in the south of the Netherlands.

And yeah, and I have been living here for for eight years doing research and studying the effects of cannabis, and also psychedelic drugs on brain and behaviour.

So psychopharmacology is the study of the effects of drugs on behaviour, cognition, and affect, or mood.

And there is also a subdiscipline of this, which I would also connect with, which is neuro-psychopharmacology.

So this is similar, but perhaps has more of a focus on the neural mechanisms of drug effects and how they alter behaviour, via understanding how they are working in the brain.

So this, this field, I think, is quite interdisciplinary. That’s because I think the outcomes can be used across different fields. So drugs can be used as tools to understand brain function and, behaviour.

If you know the mechanism of a drug, if you know the system the drug is working on, you can use it to perturb the system and see what happens.

So what changes behaviourally or biologically, and then you can say something about the role of that system in that outcome.

As well as that, it is more of a fundamental level. There is also a high need, of course, for effective pharmacological treatments for mental health disorders.

So a lot of work has has always been going into this, I don’t know if it is growing, but to understand how certain substances interact with the brain and behaviour to give rise to therapeutic effects, or using drugs, again, as tools to understand the underlying mechanisms of these disorders.

Yeah, so my, my study area. I am interested in which way drugs change brain function, and subsequent behaviour.

So this is both acutely, when individuals are under the influence of the drug, and also in the long term.

And here, I am interested in both sides of the story. So both the therapeutic effects, and the potential negative effects. And when it comes to negative effects, it is how we can mitigate them.

And here, when I say drugs, I am actually talking about recreationally used drugs, or historically recreationally used drugs.

So cannabis, the most widely used illicit drug in the world. And also psychedelic drugs, which are, yeah, they have a long history, but their use and interest in them is is also growing. And within these two different drugs, I have different interests. I think in regards to cannabis, I am interested in the behavioural effects of these substances.

Also the the underlying brain mechanisms which give rise to these behavioural effects. Here I have been focusing on tolerance.

So we know that when you continue to use cannabis, individuals start displaying tolerance to the effects of the drug.

And I find this really interesting because I think that this can have both positive and negative outcomes. So recreational users tend to use cannabis for the relaxing or the euphoric effects.

So here tolerance can be seen as kind of a maladaptive thing, and that you have to use more of the drug to get the high that you want. And this can go down to, you know, this is where addiction dependence can come in.

But I also think tolerance can be a good thing in regards to the clinical use of this drug. So this drug is now being prescribed or used for more clinical reasons. So pain, for example. And individuals who are using cannabis for pain, do not want the high. They do not, because this also comes with the impairment as well.

So the impairment in motor ability or concentration attention. They just want to be able to go and live day to day, right, without this pain.

So here this would be seen as a positive effect. So I am very interested in understanding the brain mechanisms underlying this occurrence of tolerance.

So with the more widespread usage of cannabis, both recreationally and chronically, important kind of legal implications arise.

So for example, if you are prescribed cannabis daily, you have to consistently use a drug for your indication, but you also have to perform day to day operations, right, like driving to work or the store.

Currently, let’s say you’re an individual who is clinically using cannabis every day. They drive to the store, they get into an accident.

And currently, what happens is legal individuals may take a blood sample and say, “Okay, you have cannabis in your blood, you were driving under the influence.”

But we know it is not so easy, because people develop tolerance, behavioural tolerance to the drug.

So although you have a certain level of drug in your body, that doesn’t mean that you are behaviourally impaired.

So this is really a challenge now from a legal standpoint, to find a way to actually assess cognitive impairment, or motor impairment, in users who have developed tolerance.

So finding a way to measure behavioural tolerance. So you know, okay, who was actually impaired by the drug at that point and who was not. Because currently, blood or what we use with alcohol, like a breathalyzer, is not enough because it doesn’t consider these other factors.

So in my line of work, we’re trying to assess two lines of research. These are the acute effects of cannabis on the brain, and also the long term effects of cannabis on brain and behaviour.

So to do this, what we do is we recruit different cannabis-using groups. So, individuals who use cannabis once a month, one time a week, or people who use cannabis daily, and we bring them into the lab, and we put them in an MRI scanner.

So the MRI scanner allows us to look at at brain function. And while they’re laying in the scanner, what we do is actually we vaporize either cannabis or placebo, into a balloon, with kind of a long straw on it, basically.

And we give the patient the balloon in the straw, and we have them inhale the cannabis or placebo vapor in the scanner.

And then yeah, we start recording. We start looking to see how, how the brain is functioning and compare this to the placebo condition.

So with this acutely, we’re able to see how certain changes in the brain relate to feelings of subjective high. And also, behavioural impairment. So particularly attention, impairments and attention.

So with this design, we’re able to see the underlying brain changes that relate to how high people feel, and how impaired their attention is.

And what we found is that certain pathways in the reward system are actually implicated in this.

And very interestingly, what we do is we also take blood samples to see how much of the concentration of the drug is in blood.

And we found that in order for people to feel high, or for people to show an impairment and behaviour, or/and also to show this brain response, these concentrations in blood half to surpass a certain threshold.

And this is, this is super interesting, this can be quite important. And so this combination of brain behaviour and peripheral blood information can be used to inform clinicians on how to prescribe cannabis as a drug to maximize efficacy of the drug and decrease risk.

So if you can prescribe the dose of cannabis to people that induces a therapeutic effect, but doesn’t surpass this threshold to induce the high or the behavioural effect, you know, then they can go about day-to-day after operations without having these kinds of side effects in that regards.

So additionally we also ran a similar study in individuals who smoke cannabis daily. Here, we administered cannabis the same way.

And what we see is that individuals had developed tolerance. So they were not experiencing the subjective high of the drug, they were not experiencing the behavioural impairment of the drug.

And also, we did not see these brain changes. So really making us believe that we found a biomarker of cannabis tolerance.

And this can also be very useful. So finding a measurable biomarker of tolerance, it can be an objective tool to quantify a subjective state.

So future research could study at what dose of cannabis and use frequency is necessary to produce this biomarker, to produce tolerance. And this can be used to, again find a correct dosing regimen for people who do not want to experience the high or the impairment.

So a more clinical use, it can also be useful for recreational users actually, because when they start developing tolerance, it can get a bit risky. They start using more of the drug.

So if you have a biomarker of tolerance, you can inform people, you know, how much of the drug can you use before you develop this. So maybe this is the time that you take a tolerance break.

Right, you stop smoking cannabis for a few days so this does not develop and you can have a more informed way to use the drug safely.

So I grew up in the United States, and I originally went to school to study pharmacy.

So I’ve always been interested in how drugs affect the brain and behaviour. And in America, when you say that, they said, “Okay, you should be a pharmacist.” So I thought, “Okay, I will be a pharmacist.”

So I went and started studying pharmacy, and also working in various pharmacies to gain experience. And here, yeah, (as well as arguably getting a little bit bored with the job) I was also confronted with the fact that the patients coming in, a lot of the conversations were revolving around complaints about their drugs actually not working.

So here, there were particularly two drugs that stuck out. Drugs for depression and anxiety. People were reporting a lot of side effects that they just shouldn’t have to live with.

And then another kind of class of drugs that stuck out were opiates. Not complaining that the drug wasn’t working, but you could kind of see a deterioration in some people that, you know, becoming more dependent on the drug.

And I became very unenthused with this career choice, I didn’t want to go to school to study. All of these drugs that actually were not effective, were not good options for people.

And so during my studies, I started looking into alternative treatment options. And here is where I came across the kind of preliminary research into psychedelic drugs. So my journey started there.

And reading that, you know, one administration of a psychedelic drug could induce long term reduction in symptoms. To me, that was fascinating. I had never heard about that in my pharmacy classes. And it was also, I felt getting to trying to like this was a substance, a potential substance that could start to fix the problem, versus the substances we had right now were just kind of like a band aid, just reducing the symptoms, but not actually addressing the underlying problem.

So I dropped pharmacy completely, I started doing more experimental psychology, and also working in neuro-psychopharmacology labs.

And after graduation, I just knew I wanted to pursue research into you know, alternative drugs, psychedelic drugs for in order to try to understand more their therapeutic potential, and how the mechanisms of this therapeutic potential.

And here I came across a lab in Maastricht University, the lab I’m at now, and contacted them and just asked, “Can I work with you?”

This is quite common in the US, I think, unpaid interns or research assistants or something. I was really desperate. I would have done that, not allowed in the Netherlands for good reasons.

So they said “Yeah, come do a Master’s here and you can do an internship with us.”

And so I did the Master’s so I can do the internship. did my internship actually on cannabis. So that was an ongoing project at the time, which turned into a PhD and some psychedelic work as well.

And that turned into a postdoc, and now an assistant professor position. So I’m hanging around as long as possible. It’s a very lovely group to work with. And yeah, we’re able to do some really interesting experimental studies.

So when you ingest cannabis, its main psychoactive component called THC ends up in the brain.

And what happens is THC acts like keys throughout the brain, unlocking locks that are called receptors.

In the case of THC, these are called cannabinoid receptors, which are receptors that are part of the endocannabinoid system in the body. And the endocannabinoid system is always there, right? So without consuming cannabis, it works via modulation of endocannabinoids. These are naturally occurring neurotransmitters that our body makes.

So there are examples like anandamide and 2-AG. These are endogenous, naturally occurring, and it just so happens that THC is very structurally similar to these naturally-occurring endocannabinoids and thus can activate all of these receptors.

So what happens then, so the endocannabinoid system is involved in a lot of physiological processes. So appetite, pain, moods, memory, age, general activity of the nervous system, and THC acts on cannabinoid receptors located throughout the brain.

So high densities of these receptors are found in areas that are implicated in motor movements, and memory, and attention, in kind of reward. This is where you get the high from.

So yeah, people notice when you smoke cannabis, you really experience a wide range of effects. And these are because these receptors are implicated in a lot of processes and are located throughout the body.

So the therapeutic potential for the cannabinoid system, I will say that it’s, I think it’s largely undiscovered.

So the system is involved in, in many processes. So appetite, pain, mood, memory, you know, activity of the nervous system, maybe some inflammatory processes, but from my understanding, yet, we’re just beginning to to understand how the system is working and interacting.

So because of its involvement in a wide range of processes, the therapeutic potential, you know, to activate this system and, and correct these processes when there’s a paraments. I think it’s there. But I’m not sure how explored it currently is actually.

So what has neuroimaging taught us about the effects of cannabinoids on the brain? And here I would actually say that that neuro-imaging still has so much more to teach us.

So due to the legal status of this drug, a lot of research has been has been held back. I would say that we’re still very preliminary in our work. A lot of the work has been comparing brain function of, of chronic cannabis users to that of non-using non-cannabis using controls, assuming that changes in brain function of these chronic users are due actually to repeated use of cannabis.

But there are so many other factors here that may be involved. So the differences in brain function we see may not be due to cannabis at all, but maybe due to you know, underlying lifestyle things.

So a lot of work needs to be done here assessing the acute effects of cannabis on brain function, and this would allow us to start to understand if there are long term adverse effects from using the drug repeatedly over time.

Adverse effects such as persisting or lasting harm to brain function, and inductions of psychosis, potential addictive properties and also drug drug interactions.

For example, commonly used drugs like alcohol, and in what populations and in what age?

So we know that developmental age when you start using cannabis, depending on the age you start using cannabis, one can assume that this would have alter the impact of that.

And then of course, we could go even further. There’s a lot of interest in the therapeutic, therapeutic potential of this drug.

So administering cannabis to people with different indications such as epilepsy, multiple sclerosis, pain and PTSD, or anxiety related disorders, and seeing what’s changing in the brain. And if this relates to symptom outcome would teach us a lot about how this drug can be used clinically.

So it’s a call to people to start researching this and performing these types of studies so we can answer a lot of important and open questions.

So far I’ve been trying to understand both the acute and the persisting effects of cannabis consumption on the brain and behaviour.

And now we’re actually expanding that work. And we’re going to be comparing it to the acute and persisting effects of synthetic cannabinoids.

So we want to see the differences in brain activity and behaviour between the kind of normal cannabis and its synthetic counterparts.

So we’re trying to kind of map and fingerprint different drugs in the brain.

So over the next few years, I want to continue my line of work, assessing the effects the acute and persisting effects of cannabis on brain function.

So as I said that this drug is one of the most widely used illicit drugs in the world. So I think it’s really important to understand the neuro-behavioral consequences of this use.

And if there are, you know, potentially negative consequences of this, how we can mitigate these consequences since people are going to continue to use cannabis? We can’t stop that. And I’m not saying we should. But we should be putting work and research into understanding how to use the drug responsibly, and how to help people do that.

Jean Mary Zarate: 22:30

Now that’s it for this episode of Tales From the Synapse. I’m Jean Mary Zarate, a senior editor at Nature Neuroscience. The producer was Don Byrne.

Thanks again to Natasha Mason, and thank you for listening.

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