Drugs, Addiction & Neuroplasticity: Psychedelics, MDMA, Opioids, Cocaine, Amphetamine (Adderall), Nicotine, Marijuana & Alcohol | Robert Malenka | #162

About the guest: Robert Malenka, MD, PhD is psychiatrist & neuroscientist. He has spent most of his career at Stanford University, where his lab studies synaptic plasticity, mechanisms of drug action in the brain, and the neural basis of behavior.

Episode summary: Nick and Dr. Malenka discuss: mechanisms of synaptic plasticity in the brain, such as LTP & LTD; addiction & the dopamine reward circuitry of the brain; psychoactive drugs ranging from stimulants (cocaine, nicotine, amphetamines) to opioids (fentanyl), psychedelics, MDMA, THC, and alcohol; and more.Related episodes:

* How Does Ketamine Work & Is It Addictive? | Christian Lüscher | #90

* Neuroscience of Social Behavior, Pain, Empathy, Emotion, Brain Mechanisms of MDMA | Monique Smith | #159

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Robert Malenka 2:32

Well, I'm a neuroscientist and a psychiatrist who has spent my career at institutions in the Bay Area at Stanford than a place called UCSF and back to Stanford, and my lab. Initially, I've had a lab for a long time for 35 years. My lab initially focused on a topic that we call synaptic plasticity, which is a catch all term that encompasses how synapses, the connections between nerve cells, how they change in response to experience. And that experience can be a form of learning and memory, that experience can be administration of a drug or the experience of a drug, a stressful event. And Most neuroscientists believe that part of the way we encode new Acts experiment we encode experiences and remember them and their impact on our brains, and therefore how our brains adapt to experiences and change our subsequent thoughts, feelings and behavior. Most of us believe that changes in the properties of synapses play a very critical, important role. So really, probably for the first 2025 years of my career, a lot of my work focused on how to these changes in synapses, in response to changes in the patterns of activity in the brain. How does that actually happen? Which proteins at the synapse, which receptors, and I apologize, I'm not sure, who's listening to this, I don't know if I need to define the terms such as receptors, but the proteins in the membranes of nerve cells that respond to chemical messengers that we call neurotransmitters, anyhow, how these changes in synapses actually happened at a pretty at a fairly molecular level. And then that led me to start doing work in the behavioral relevance of the of these various forms of synaptic plasticity. That is, I'm studying synapses and how they change in very reduced systems and I became very interested in Okay, If this is really important, I should be able to correlate these changes with behavioral changes in my favorite experimental species, which is a mouse, or mice. And then gradually, over the decades, while I continued to study the molecular mechanisms of synaptic plasticity, that led me into all sorts of different research topics, including how a neuromodulator, we call dopamine, how it works, what it does in the brain, studying changes in what we call the reward circuitry in the brain, which my guess is we're going to end up talking about in the next hour, hour and a half. That led me to studying another neuromodulator that goes by the name of serotonin, and some of its important functions in the same reward circuitry. And then finally, that led me to studying certain psychedelic drugs. But there was actually a natural progression of how I, my research led me from studying pretty molecular mechanisms to the behavioral effects of psychedelics, there's actually a thread throughout my scientific career.

Nick Jikomes 6:22

Interesting. Yeah. And hopefully we sort of trace that thread to some extent. And, and I think we will, when, when you were just getting started back in the early days of synaptic plasticity, and some of the early discoveries of the initial mechanisms that we discovered, when we think about things like NMDA receptors and long term potentiation. And we can we can briefly define those things, but but I've talked about them on the podcast before a lot of people listening will have some familiarity with those terms, when those things are being discovered the mechanism through NMDA receptors by which you know, this coincidence detection, synaptic strengthening happens. What was the thinking, like leading up to that, that people have a notion for how that would work? Or was it completely surprising what what was that initial sort of set of

Robert Malenka 7:06

discoveries like, it's a fun scientific story. So, you know, it sounds like here, listeners, and you certainly know that the major form of plasticity that I have studied and others in the field of study is called long term potentiation, or LTP, which is shorthand for long term potentiation of synaptic transmission. It's been studied primarily in a region of the brain called the hippocampus, which made a lot of sense, because we know the hippocampus is critical for the storage of memories, the storage of new information, it was also studied in the hippocampus, in terms of trying to understand the underlying mechanisms of LTP. We use the hippocampus because we could cut slices of it, and put them in a dish. And it offered a lot of experimental advantages. And so the big breakthroughs in LTP, were sort of a natural progression, that some of the basic properties were elucidated initially, in some classic papers by some European neuroscientist, and then a critical critical of observation was, as you alluded to the finding that NMDA receptors this subtype of receptor for the excitatory neurotransmitter glutamate, was critically required for the initiation or triggering of the biochemical events that lead to LTP. And what was really interesting about that discovery, and was a very simple experiment, just bath applying an NMDA receptor antagonist to a hippocampal slice. And the key finding there was that this antagonist to NMDA receptors blocked LTP, but it did not seem to affect what we call basal synaptic transmission or basal synaptic strength. And that was at the time, pretty bewildering. So how could a drug have this, you know, a blocker of NMDA receptors have this very clear effect and LTP but have no detectable effect on basal synaptic transmission. And that remained a mystery. It's been so long, I can't remember how many years it took. And then two different groups started studying NMDA receptors at a biophysical level. And they made the very important discovery and I hope this isn't too much scientific detail, that the NMDA receptor was a very unusual ligand gated ion channel that responds to the neurotransmitter glutamate because it was voltage dependent, that when glutamate bound to the NMDA receptor, when the cell was was just hanging out at what we call its resting membrane potential. The NMDA receptor didn't pass current and past very many ions. And it turns out that's due to the fact and again, this may be too much detail that a DI valence can ion called magnesium sits in the, the poor of the NMDA receptor. And it actually isn't quite true that no current or ions can flow in and out of the NMDA receptor channel, but it's pretty much blocked. But when the cell gets depolarized, gets activated by other synaptic inputs or for whatever reason, the magnesium is expelled out of the ion channel. And now when glutamate binds to the NMDA receptor, ions can flow currents are generated and the cell can respond, and most important, so there was a voltage dependence to the response of the NMDA receptor. And then the other key finding from two different groups was that unlike many other glutamate receptor channels, the NMDA receptor was permeable to calcium. So when the cell was depolarized, calcium and activated by glutamate, calcium could enter the cell. And so that, that those biophysical findings, let me just remember my history here were made in the 80s. And two different groups, the group I was involved in when I was a postdoc with Roger Nico, and a guy named Gary Lynch sort of looked at these papers, and realized, well, if what makes the NMDA receptor so special, is that calcium can enter through its ion channel, maybe Calcium is a critical trigger for LTP, but the calcium entering through the NMDA receptor. So then Gary Lynch's lab did an experiment, that very simple into, you know, in today's world, but back then it was a very clever experiment, I hope I'm remembering this correctly, where he recorded from individual hippocampal cells, and loaded the cells with a compound that sucks up the calcium, it's called a calcium key later and prevents the calcium from binding to other proteins and doing its magic. And if I'm remembering correctly, that blocks to LTP. And so that was, although the finding actually didn't get as much attention as maybe it should have. And then work I did with another postdoc, and Roger Nichols lab, Julie cowher, and Roger Nichols lab and this was worked on at UCSF, we showed not only that, we replicated that observation, that if we calculated the calcium by loading or the postsynaptic cell, from which we were recording synaptic responses, which are called IX, e PSPs, excitatory postsynaptic potentials, we could block the generation of LTP. And then very importantly, we showed if we use some very cool molecules that we could load into the cell, and they held on to the calcium but when we flashed a light, calcium was released in the cell, we showed that could cause an LTP, like if effect, so we had both necessity, meaning if we blocked the key later, the calcium prevented it from doing its thing, we blocked the generation of LTP back shows necessity, then we showed sufficiency by showing if we just released the calcium independent of activating NMDA receptors, when we could cause an LTP like effect, we could strengthen synaptic transmission. So that then, really, I think, opened up the field because now there was a very clear explanation for the initial triggering events of the LTP and why it required depolarization of the cell. And in the real brain, we think that happens by the coordinated activity of different inputs onto that sandwich starts act depolarize in the cell making it more excitable, so then when another synapse is activated, in a temporally coincident manner, the cells already depolarized the glutamate that is released from that synapse activates the NMDA receptor, because the cell is depolarize. Calcium can enter that specific cell naps trigger a cascade of biochemical events that lead to LTP. And so everything came together in a very beautiful scientific. I mean, it's how science should work. I mean, when it took, I mean, the truth is, I mean, LTP was first described, I hope I'm remembering this right? In 1973. And it really took 15 years till the late 80s. to elucidate what is really a relatively simple mechanism. It's a combination of the initial description of LTP, the discovery of NMDA receptors and their role in LTP, the description of their biophysical properties. And then labs, like the work I did in Roger Nichols lab with Julie Carr, and Gary, putting it all together and saying, testing the hypothesis, that LTP was triggered by depolarization activation of NMDA receptors and the entry of calcium. And then that led, if we're, you know, to all sorts of additional experiments before then you needed to know.

Nick Jikomes 16:09

I mean, it's, it's a, it's a fascinating story. And, you know, for those who don't know, like, the mechanism is sort of beautifully simple. It's probably one of the most beloved mechanisms in the brain that

Robert Malenka 16:21

books, it's now just standard textbook knowledge. But

Nick Jikomes 16:24

if we, so if I sort of reiterate some of what you said, we've got this sort of special receptor, this protein complex, the NMDA receptor, and it doesn't really pass much current through under normal baseline conditions. But if a cell becomes excited enough, because say, multiple neurons are simultaneously activating it, it can suddenly pass more current. And there's a couple of interesting ions involved here. On the one hand, you've got this magnesium, so like, when we when we eat magnesium in our food, some of this magnesium is being used to block this channel, so that nothing is really going through it. But then when the neuron becomes sufficiently excited, now calcium can go through it and get inside the cell. And calcium. You know, most people probably know calcium, when they think about, like, you know, their bones and their teeth. But it's important in neurons, it sounds like you're actually getting into the cell to trigger the things inside the cell that are necessary for strengthening the synapses. That's

Robert Malenka 17:16

exactly correct. Very well put, as we may get to, calcium can also decrease synaptic strength, and cause the opposite of LTP. So like everything, once you start delving into the details, the biological processes involved get more complicated and more flexible.

Nick Jikomes 17:40

And so long term potentiation. That's what we just described, that's at least one way that synapses can get stronger. Are there other? Is that the primary mechanism? Or are there like a whole bunch of ways you can shrink the synapse that work and strengthen

Robert Malenka 17:55

there? You know, it's a very good question, I have to go through the Rolodex in my head, it turns out that added some cells, including the hippocampal cells, that are the main source of of the scientific information we have about how synapses change, you can actually if you act depolarize, the cell repetitively with action potentials, you can probably load the cells with calcium via what are known as voltage dependent calcium channels, which is just another source of calcium, that when they are these calcium channels are repetitively activated to a sufficient degree, that can lead to the strengthening of synapses. Now, whether that actually ever happens in the awake behaving brain remains unclear. Let me just think, are there other example? Yeah, it turns out at certain synapses, there's a very different way of strengthening synaptic transmission. So what we just talked, and then I hope, we're going to talk about the weakening of synapses, which is, could be as important depending on the circuit in which those synapses are embedded, but at certain sets of synapses in the brain, which are embedded in certain circuits. In specific brain regions. There's a form of LTP that rather than being triggered by post synaptic activation of NMDA receptors is triggered presynaptically due to certain repetitive activation of the presynaptic terminals that release the glutamate. And, you know, historically that was first described that a set of synapses in the hippocampus called mossy fiber synapses. And so it's a very different form of synaptic strengthening, called mossy fiber LTP interestingly at all So involves the key triggering mechanism is the entry of very high amounts of calcium in the presynaptic terminal through these voltage dependent calcium channels. But I think most of us in the field believe it's NMDA receptor dependent LTP, which we were talking about previously, which is what I would call the prototypic form of LTP. And synaptic plasticity, it occurs at many different excitatory glutamatergic synapses throughout the mammalian brain.

Nick Jikomes 20:40

different brain regions, exactly.

Robert Malenka 20:42

This this other form I was describing, which is this presynaptic form of LTP, we call mossy fiber LTP. I mean, it's only so far, it's only been found at a few, a very small number of kind of specialized synaptic inputs in the hippocampus at the mossy fiber synapse, and at a certain synapse in a region of the brain called the cerebellum, which is important for motor movement for controlling motor movement. And maybe one or two others that I'm not just remembering at the moment. And then that beyond NMDA receptor dependent LTP, mossy fiber, I'm, I'm sure, when we're off this, I'll think of one or two others, but there's not a lot.

Nick Jikomes 21:32

So the sort of classic NMDA receptor LTP is a major, major way that's an emphasis or strengthened across.

Robert Malenka 21:40

Most neuroscientists would agree with that. Absolutely. You know, and that's why, at least historically, it's not a very popular topic, currently, now that we're in 2024. But in the 70s 80s, and 90s, it was a very popular topic to study that received a lot of attention.

Nick Jikomes 22:04

And so sort of the flip side of this is, as you've alluded to earlier, you know, you not only want to strengthen synapses in the brain, you want to weaken, and sometimes get rid of synapses in the brain. How does that happen? Okay,

Robert Malenka 22:16

so that that phenomenon is called, you know, I guess we're not neuroscientists are not that imaginative. It's called long term depression of synaptic transmission, or Ltd. And, you know, it's an interesting history, once LTP was described in the early 70s, you know, all neuroscientists started thinking, Well, you know, it might be advantageous for several different reasons to have the opposite phenomena. That is long term depression, some people argued, you don't want to have a permanent strengthening of synapses, you want to have a way of weakening them, perhaps that's a mechanism of forgetting, which I actually am not sure it is, I think it's more complicated than that. Other people just posited that circuits and circuits within the brain would have a lot more flexibility and power, if they could utilize the bi directional control of synaptic strength, that is, if synapses mediating information processing and this or that circuit, could both strengthen the synapse and weaken synapses. If you do simple minded computational modeling, the flexibility of how that circuit functions is enhanced enormously by having both LTP and LTD. So and the let me get my memory, right. You know, in the 70s, and 80s, there were, you know, there were papers published, reporting phenomenologically, various forms of Ltd, primarily in the hippocampus, but they never really gained traction, I think primarily because experimentally, they were a little bit ephemeral, they were hard to induce different labs couldn't maybe couldn't get the same reliable generation of Ltd. Whereas LTP once you know what you're doing, most people, even very novices in the field could generate LTP, relatively easy, let's say in a hippocampal slice. So then in the early 90s, a colleague of mine who's now at MIT Mark bear, developed a very simple protocol based on some theoretical work he had been involved in for inducing Ltd in the hippocampus at the same set of synapses, at which LTP had been studied for decades. And then Mark continued to study this form of Ltd and then I I noticed it, because he was a friend. And he told me about and I said, Hey, do you mind if I work on this? And so we started studying Ltd app in the hippocampus, as I said, at the same set of synapses. And very, because we knew how to study synaptic plasticity mechanistically, from all the years we had been studying LTP, we were it was very easy to very quickly elucidate some of the basic triggering mechanisms of this other form of plasticity synaptic plasticity. And interestingly, what we found is that Ltd and was NMDA receptor dependent just like LTP. But it required a different pattern of activity at the synapse. And the simple model we followed, which was actually first proposed by a neuroscientist named John lisman, at who was at Brandeis, Unfortunately, he passed away several years ago. And what John lisman had proposed in a theoretical paper is that LTP involves an NMDA receptor dependent increase in calcium in the postsynaptic cell, but it had to be a very large increase in calcium beyond some critical threshold, let's say the threshold was 10 micromolar, it had to be above that. And that perhaps, Ltd could be triggered if a much lower level of calcium was achieved via the NMDA receptor may be in the range, I'm making this up of one to two micromolar. So we actually test it that kind of thinking and hypothesis. And all of our results were consistent with it. And to be honest, I think it's now kind of dogma in the field, I believe it's in textbooks that there is a there is an NMDA receptor dependent Ltd, due to the increase in calcium in this narrow window, and then I don't know if we're going to talk about the biochemical cascades activated by calcium, but a certain set of enzyme calcium dependent enzymes are activated by a low level of calcium, that trigger Ltd. and then LTP NMDA receptor dependent LTP requires when I said a much higher level of threshold, and then that led to people looking for different forms of Ltd all over the brain. And there, there are probably many more forms of synaptic depression or Ltd, than there are forms of LT P. And why that is and how the nervous system and circuits in the brain utilize these different forms of synaptic plasticity is still an active area of research.

Nick Jikomes 28:05

So it sounds like there's a lot of ways to make synapses weaker. Yeah,

Robert Malenka 28:09

I know that I said that I have to now be I can I have to start going through the Rolodex in my head. And I think there are several Yes.

Nick Jikomes 28:18

So why do you think that might be? Why is it so important to weaken synapses? What have we done experiments where we prevent the brain from from doing Ltd? And does that impact learning?

Robert Malenka 28:31

A very good question. And I you know, I haven't worked on these phenomenon Oh, my God in a long time. Yeah, I mean, actually, I think the home one hallmark example, is in is in the cerebellum. There is a form of Ltd. That requires a god and I have to, it's been so long since I read these papers that involves two different inputs onto the major a major cell type in the cerebellum called the Purkinje cell. And if the timing of these two synaptic inputs is appropriate, there's a weakening of the synapse between a set of axon inputs called the parallel fibers. And then there has been quite a bit of work, proposing theoretically and then experimentally demonstrating that this form of Ltd seems to be required and involved in certain forms of cerebellar dependent behavioral plasticity. And so that's one example. I'm trying to think of other examples it's going to take me a while to but basically,

Nick Jikomes 29:47

there's multiple mechanisms of synaptic plasticity. Synapses can get stronger, they can get weaker. There's a number of ways each of those can happen. Calcium is critical for all of this calcium getting into neurons is super important. Pretty

Robert Malenka 29:59

much except there's another form of Ltd, which has gotten a lot of attention. And again, calcium is sort of always directly or indirectly involved. But this is a very interesting form that involves got, it gets a little complicated the release of these endogenous brain modulators called endocannabinoids. I don't know if we want to get into that. But this is the brain's natural marijuana or their its natural THC. And it turns out that at certain, in certain cells, and at certain synapses, strong repetitive postsynaptic act depolarization of cells are spiking of cells can in a calcium dependent way, so calcium is still involved, cause the release of these substances called endocannabinoids, that then leave the postsynaptic cell, and then attach to receptors on what we call the presynaptic terminals, and reduce the amount of glutamate or neurotransmitter that is released. That's called endocannabinoid mediated Ltd. And that scene, you know, that scene in the hippocampus, that scene in a part of the brain known as the basal ganglia, or the striatum. And there's, there's some evidence that it's important for certain types of behavioral phenomena are real plastic, really,

Nick Jikomes 31:37

I guess, I guess what the basic idea here be that you know, if a neuron is getting too much input, it's it sort of sends an endocannabinoid backwards to the cells talking to it and says, quiet down a little bit,

Robert Malenka 31:49

I think I think that's a nice way of putting it a very nice way. And again, you know, I think describing these synaptic plasticity phenomena has been very important. And people have studied them in many different brain regions in the hippocampus, initially in the cerebellum, in various cortical areas. A larger experimental challenge, you know, which people have been taking on and working on for decades, is how are these synaptic plasticity phenomena actually used in the intact, awake behaving brain to mediate all the wonderful plasticity that happens in you know, as we experience the world, or as our mice experience, the world and there you know, there's hundreds, if not 1000s of papers on this topic,

Nick Jikomes 32:48

is when we think about neuroplasticity, and the brain's ability to change itself in response to experience. Is that is it all about synaptic plasticity? Or are there other forms of plasticity that exist outside of the synapses changing? Um,

Robert Malenka 33:05

it's a very good question. And I think there are certainly other forms of plasticity. I think, most neuroscientist would agree that synaptic plasticity is a major contributor to neuroplasticity. I mean, the term neuroplasticity especially among laypeople, and especially among certain cadre of neuroscientists is used very loosely, because it basically means any change in the brain is a neuroplasticity phenomenon, anything so, but to answer your question, so, synaptic plasticity is certainly really important, but it is very likely that there are forms of plasticity that involve longer lasting changes in what we call the intrinsic excitability of cells. You know, cells have voltage dependent channels that generate action potentials are spiking in the cells. And there are there is evidence that again, in response to certain patterns of input activity, the cell can chant, you know, or in response to certain neuromodulators. The cell can change, its spiking behavior that is, for a given amount of input into the cell, it may spike more, it may spike less, and that could be a very powerful form of neuroplasticity. And then there's forms of plasticity neuroplasticity, which are probably connected to synaptic plasticity, where new synapses new connections can be formed. So that's structural plasticity and synapses. can be taken away, they can disappear. And then most of us in the field believe that these forms of structural plasticity, the formation of new synapses, the disappearance of existing synapses are probably to, to a large extent, triggered by LTP. And Ltd. So and there's actually experimental evidence pretty strongly to support that proposition. And let me just think, and then it sort of depends on how you define neuroplasticity, because there are long lasting changes in gene expression. And that's a form of neuroplasticity, what I have always pointed out, and I don't want to say argue just pointed out that when there are long lasting changes in transcriptional, regulation and epigenetic changes and transcriptional changes, they still have to in order to affect neural circuit function, neural activity, they still have to eventually influence something about the physiology of the circuits, they have to eventually change the spiking behavior of the cell, or, or how synaptic inputs are influencing that cell. Otherwise, they're not really having a myth. They're not influencing the functions of the brain. That is our thoughts, our feelings and behavior. So I hope I'm answering your question. So there are many different forms of neuroplasticity. And

Nick Jikomes 36:44

there's also this concept of meta plasticity that others have discussed, we might loop back to this when we talk about things like drug addiction and psychedelics, but what's meta plasticity as opposed to just plasticity?

Robert Malenka 36:56

You know, it's been so long meta plasticity is the plasticity of plasticity mechanisms.

Nick Jikomes 37:05

So, how easily a cell can use employ those mechanisms? Yeah,

Robert Malenka 37:10

I mean, so I have to remember. So it can be for example, you know, we talked about the triggering mechanisms for NMDA receptor dependent LTP. And Ltd. Meta plasticity would be in response to some experience, that the actual patterns of activity that trigger LTP and LTD had had have changed. So the mechanism LTP and LTD may still be the same, but the patterns of activity, because of changes in the circuit have changed. It also can be that the biochemical mechanisms triggering NMDA receptor dependent LTP and LTD have been modified over the course of days or weeks. So it's really the plasticity of plasticity. And it even can be that additional mechanisms, that before this behavioral experience, that triggered LTP, that the mechanisms have been modified somewhat, so you need an additional, you need additional activation of a different subtype of receptor or something like that. Um, so it's it's a term that is sort of generally used, as I said, to default to say it's the plasticity of plasticity mechanisms. And

Nick Jikomes 38:39

so, an area where you've done a lot of work on synaptic plasticity is in the so called reward circuitry of the brain, the music limbic dopamine reward system, which is very important for learning and memory and responding to natural rewards. And it's also important for drug addiction and the response to various drugs of abuse. I want to talk about that stuff a little bit, very briefly and concisely. Can you just give your sort of definition or perspective on what actually counts as a drug addiction or an addiction behaviorally?

Robert Malenka 39:10

Well, I mean, you know, clinically, the definition is the continued pursuit and ingestion of a substance. And this is the key phrase, despite severe adverse consequences. So people often ask me, you know, can I be addicted to coffee? Well, not by that definition, you never hear about people robbing, you know, you know, their family members committing a crime. You know, a marriage breaking up because they need that coffee in I mean, so you can have a strong of an end so people use it loosely, but the medicals and diagnostic definition is what I said. pursuit and ingestion despite severe adverse consequences.

Nick Jikomes 40:04

So it sounds like there's there's a difference. And it might be a matter of degree, but there is a difference between really wanting something and compulsively seeking it out.

Robert Malenka 40:12

That's exactly right. And again, you know, like many diagnoses, especially in the psychiatry realm and mental illness, there's a continuum. But it's Yeah, exactly. It's this compulsive seeking despite adverse consequences. But you know, I'm very grumpy in the morning if I don't get my coffee, but I would not, you know, I run the bank to get an addict by that definition. Yeah.

Nick Jikomes 40:39

Yeah, I talked to Christian Lucia. And he made the distinction between the pendency, which is, you know, you're waking up with a headache and being grumpy in the absence of the caffeine. And the compulsion side of it, he basically said, you have to have both to qualify as addiction in the clinical setting.

Robert Malenka 40:55

You can be Yes, basically, dependency goes along. But yes, I mean, I think Christians point is very well made and well taken. I'm dependent. Yeah. A little bit. And, and you can have withdrawal symptoms without being addicted. You know, when people talk about, if they don't get there, they can get headaches if they don't get their caffeine, because they're so used to it. But that doesn't mean they're they don't meet the definition, the medical definition of addiction.

Nick Jikomes 41:28

And so there are many addictive substances out there. I'm sure we'll maybe use some as examples. Nicotine, opioids, you know, amphetamines list goes on and on. Is there. To what extent are they all acting through unique mechanisms? And to what extent is there sort of a common core element in the brain and what's going on in terms of plasticity that they all share in common?

Robert Malenka 41:51

Yeah, I mean, so, you know, a big breakthrough in our understanding of the neurobiology of addiction was the realization and and I'm forgetting. Let me just think, I think in the 80s, that it seemed that all these different drugs with high the term I like to use is addictive liability. So drugs have different addictive liability. So you know, a very a drug with very high addictive liability is fentanyl or opioids, psychostimulants like cocaine, methamphetamine. Other drugs may have slightly less addictive liability, but they all seem to cause the release of this neuromodulator dopamine in a key component of the classic reward circuitry in the brain called this horrible name of the nucleus accumbens. And I'm sure if you talk to Christian Lucia, he, he described this, and what's really so that was one major breakthrough. And then the other was that these different substances, opioids versus psychostimulants, like cocaine, methamphetamine versus nicotine, could all cause the release of dopamine in the nucleus accumbens, but at a receptor level, and at a circuit level, they do it via different mechanisms. But this realization of the key triggering phenomenon mechanism that leads to addiction being this unphysical illogical release of dopamine really opened up the field to a more mechanistic neurobiological description of how addiction develops, and has maintained it.

Nick Jikomes 43:41

So nicotine, cocaine, all of these different drugs of abuse, they might act in through different mechanisms touch different receptor systems and things in the brain. But ultimately, they're converging on elevating dopamine and certain key brain regions, beyond sort of what a natural reward would do.

Robert Malenka 43:58

And that's, that's the whole key is it's beyond a, quote, natural reward. So I have I really like donuts. And I guarantee you, when I'm hungry, and I eat a doughnut, I get a spike of dopamine in my nucleus accumbens, but it's not even remotely to the same degree. As the spike of dopamine, I would get in a target region like the accumbens, if I, you know, smoked or injected fentanyl is a different beasts. And that's, you know, the whole one of the major reasons we have somewhat of an addiction epidemic in our country is our brains evolved to respond to natural rewards, because it was really important to have a mechanism in our brain to tell us, this is really good. I need to remember where this food source was or where this sexual partner was. So our brains evolved for natural rewards. But then, you know, really for the for the modern drugs, which are things like morphine, fentanyl, psychostimulants, those who didn't even exist till the 20th century. And our our brains weren't ready for them. So and the connection to synaptic plasticity, to bring it full circle was, and you know, I will take a little credit for this is that I was studying LTP and LTD, and the hippocampus and figuring out the mechanisms. But I was interested about connecting up these forms of synaptic plasticity to some form of behavioral plasticity to put because even in the 80s, it was really hard to directly demonstrate that the phenomenon of LTP in the hippocampus was, in fact required for hippocampal dependent memory. So I started thinking about other brain areas to study synaptic plasticity. And I started, you know, reading literature and all sorts of different fields. And this is probably in the late 80s, so that we didn't really do the key experiments till the 90s. And people who had been studying the actions of drugs of abuse, and were working on the neurobiology of addiction. They had started proposing the idea that may be synaptic plasticity mechanisms like NMDA receptor dependent LTP. But in a different key region, in particular, in an area of the brain called the ventral tegmental area, another horrible name to remember. But it's the home of the dopamine neurons, of the neurons that send projections, or axons, to other key components of the classic reward circuitry. So my colleagues in the field, were proposing that maybe drugs of abuse triggered an LTP, like event onset synapses on dopamine neurons. But nobody had ever done experiments to directly test that hypothesis. So then, in the god, I have to in the late 90s, and early 2000s, with an ex postdoc of my lab, in my lab, a guy named Antonio bunchy, we actually tested that hypothesis. So we administered drugs of abuse, we started with cocaine, and then we expanded to other drugs of abuse. And this became important, and then using some what are now standard methodologies, but at the time, you are a bit clever, I would say. And it's because I had a background in understanding how to study synaptic plasticity, and how to measure synaptic strength in brain slices. So the experiment we did is we administered a drug to a mouse and that first cut first drug was cocaine. And we studied glutamatergic excitatory synapses on VTA dopamine neurons, and we made a measurement that correlated with synaptic strength. And we showed that cocaine cost and LTP like change. And then we showed in a subsequent paper done primarily in my lab, that other and this was key, because the question was, Is this LTP like effect on dopamine neurons as an only occur in response to envy, in vivo, meaning in the real mouse, administration of cocaine or to other drugs of abuse caused the same change. And then we showed that nicotine alcohol, I'm trying to remember, I think morphine all caused a similar LTP in these midbrain dopamine neurons, that then open the door for all sorts of different synaptic and circuit work on looking at how synapses and circuits that are part of the reward circuitry, how they change in response to drugs of abuse, and which changes lasts long enough that maybe they contribute to Addictive Behaviors, probably more than you needed to.

Nick Jikomes 49:35

So so so no matter what drug of abuse we're talking about, they can act through very different mechanisms, but they sort of all converge by causing an unnaturally high level of dopamine release in certain key regions of the brain. And that's tied into the strengthening of synapses through LTP. And that's ultimately going to be required for for addiction to set in.

Robert Malenka 49:59

Yeah, and In the hypothesis that at least one of the initial triggers is LTP, at synapses on the dopamine neurons, there are other mechanisms. It's that's not the only mechanism just to be clear.

Nick Jikomes 50:13

So there's, there's more than one way that the dopamine release can initiate the strengthening. Yeah,

Robert Malenka 50:19

it's a combination of a number of different biochemical and synaptic changes in response to a drug of abuse, then lead to the cascade of events that we define as addiction.

Nick Jikomes 50:35

And I like what you said earlier about addiction liability. So instead of thinking of drugs as being addictive, or non addictive, we should think of them as existing on a spectrum of addiction liabilities, ranging from very low to very high and everything in between. Absolutely. When we think about something that's usually considered to be pretty addictive, like a psycho stimulant, like cocaine, say, and we say that it has, you know, a certain addiction liability. What does that mean, in terms of, you know, does everyone have the same percent chance of becoming addicted upon repeated exposure? Or are some people likely to become addicted? And some people sort of immune from becoming addicted? How do we think about that the population, I

Robert Malenka 51:13

think, you know, like, like, everything in medicine, and everything in our human behavior, and how we react to our environment, it's complicated. And, you know, what I, you know, I teach this topic, you know, at Stanford University, the undergraduates, and, you know, what I always say is, you know, you can, you cannot become addicted to a substance, if you never ingest the substance, right, by definition. So if you're thinking of trying fentanyl, or trying methamphetamine, just be aware of that, you if you don't take it, you can't become addicted to it. But then the truth is, you know, there are people have different responses to these substances. And that's probably has to do with their underlying genetic, you know, genetic makeup. And so, let me just give you another example from my own experience, alcohol. You know, when I drink a few drinks, I, you know, I like to drink, I find it is a social lubricant for me. I have actually been in need reIated over my life. But a lot most of the time, I get sleepy, and I don't, it's not unbelievably rewarding to me. I mean, it's fun. But it's not like, but then you talk to certain people who really developed, you know, what we would call out what we used to call, they became alcoholics, we now say they had an alcohol use disorder, they will tell you the first time they had a martini or drink, it was like the best feeling in the world best feeling they had ever had in the world. And there's something genetically different, because my actual physiological response was different. And you can talk to people with the same kind of difference and continuum of responses to the use of cocaine, some people actually don't like it, they find it a little bit adversive. And other people just say, Oh, my God, first time I use Coke or meth, it was just like the best feeling I had in the world. So there is this continuum and spectrum of individual responses, which probably has a genetic contribution to it. And then in addition, as we all know, I mean, I shouldn't say we all know but I think if you think about it, your relative position in society, and what other forms of rewarding experiences you have, influence your addictive the chances of you developing a substance use disorder or an addiction. So I mean, just you know, I don't mean to lecture your audience. While it is absolutely true, that you can be affluent and come from a loving family of high socioeconomic status with high educational attainment and become addicted. And we know famous Hollywood stars who have substance use problems, or have died from their addictions. But it is also true that the prevalence of substance use disorders and addiction is much higher in individuals from lower socio economic strata. And the simple way we think about it is, you know, first Certain people, the substances because of their ability to release dopamine and the reward circuitry can be highly reinforcing. That is rewarding. And if you're living in a situation in an environment where there are no other sources of reward, you know, there's no parks to play in to get reward from playing sports, you're at the edge, the schools you go to are lousy your teachers allows the, you're coming from a home environment where there's no you're not getting, you know, emotionally support it, you're not getting that kind of reward. If there's drugs in your environment, that's a major source of reinforcement. And you don't have that much other choice. So I hope this is. So it's this combination of your individual response to the drug, the environment in which you live in. And your access to the drug. I mean, this has nothing to do this. These are, you know, social issues, they're not neurobiological issues. It's, I mean, so the type of addictions that just substances that are most prominent in different countries and different societies vary enormously. So in Islamic society where alcohol is not allowed, there is not an alcohol problem. There is an opiate problem. But there's not an alcohol problem. Whereas, you know, in Western societies where alcohol is extremely available, and is not socially prohibited, we you know, alcohol use disorder is a major problems. So probably more than you needed to know.

Nick Jikomes 56:51

No, this is great, this is great. There's also drugs, some of some of which you've studied that have little to no addiction liability. This includes the psychedelics, some of them have little to no addiction liability, some of them are even being studied right now as a way to potentially treat addiction to other substances. Before I want to preface this question with with another little question or comment, which is, right now there's there's kind of a battle going on in the literature over the term psychedelics, and what that means. And so I'll let you define the term and the way that you use it. But what is it about psychedelics things like the serotonergic psychedelics like psilocybin and LSD that make them different from classical drugs of abuse in terms of their addiction liability. So first,

Robert Malenka 57:37

you know, especially in the lay press, but even among my academic colleagues, I think, you know, the term psychedelic is used very loosely. And most of us in the field would prefer to use more precise terms because the the group of drugs or substances that underlie the use of the term psychedelics actually have different mechanisms of action and different behavioral and psychological effects in human beings. So I think mostly people loosely when they say psychedelics, they're mostly, but not entirely, referring to what I would define as classic hallucinogens, which are drugs like LSD, psilocybin, maybe mescaline, that have the common action that they activate certain subtypes of serotonin receptors. And as you know, serotonin is a major neuromodulator. Most of us in the field, believe there's pretty good evidence that at least part of the hallucinogenic property is due to activation of serotonin to a receptors. So when you really want to get really, you know, more refined in your definition, you can actually talk about serotonin to a hallucinogenics. So that's what I use the term psychedelics a bit this, you know, I grew up in the 60s and 70s. So I'm usually thinking of the classic hallucinogens LSD, psilocybin, mescaline, people now include drugs like MDMA, which has gotten a lot of attention because of the application from Lycos to use it as a treatment for PTSD. I prefer to use the term for MDMA of an intact origin. Because while there's a little bit of overlap with the effect it has in human beings, it's pretty I think, most people would say it's qualitatively different. And even though it's influencing serotonin mediated events in the brain, it makes kinetically works in a pretty different way than classic hallucinogens. Then people sometimes include ketamine as a psychedelic, I personally do not ketamine, those of us in the medical field define it as a dissociative anesthetic. So, I think scientifically, you have to use more defined terms, but even in the lay press, and as these agents become tested for their therapeutic efficacy, I do think it's useful to have use the term in a more precise way. Let's leave it at that. So then to answer your question, so I think the major reason classic hallucinogens like LSD, psilocybin, maybe mescaline are not addictive in the classic sense is that they don't cause this massive release of dopamine. They're serotonergic agents. And in fact, I have not done this experiment myself. But I have to actually check the literature. But I would predict and bet a lot of money that if you gave a mouse LSD or psilocybin, and you measured increases in dopamine, you wouldn't detect much increase maybe a little bit, but nothing like what you get with morphine or fentanyl or methamphetamine or cocaine.

Nick Jikomes 1:01:28

Yeah, I'm pretty sure those experiments have been done. And the answer is, is what what you just said it's little to no extra relief.

Robert Malenka 1:01:33

I mean, so you know, that's the excitement of studying these drugs. neurobiologically is we can actually start understanding how they really work. And it actually makes some sense.

Nick Jikomes 1:01:47

More recently, you've been studying MDMA, a