#673: Dr. Nora Volkow — Director of the National Institute on Drug Abuse (NIDA)

29:01But her work was ignored initially, especially her seminal paper documenting strokes in the brains of cocaine abusers. And then this is a quote of you. I started to present these data at meetings and people didn't believe it because there was no evidence that cocaine was toxic, she says. That's fine, I said, because this is what the data show. She applied for a grant from NIDA. of course everything comes full circle but she applied for a grant from nida to pursue her research and was turned down it took three years before the british journal of psychiatry finally published her paper and then the closing quote from you in this section is this is what happens when you come up with things before their time and my question for you is what was the experience like and what was your inner talk like going through this sequence of events and having people dismiss, having people reject over that period of time.

29:52What was that like for you? And how did you keep going? Well, I'm a very perseverant person and I never give up. So my perspective is on this issue has always been like that. And that finding, actually, I'm still working on that to try to understand how cocaine affects and producing these strokes and how we can prevent them and how we can help people. But at that time, I was very young and I, You know, you have this sense of you trust the system and you believe, well, maybe I'm not good enough. And having consolidated the belief in yourself because you are basically recently trained, you are using, no one had used that technology.

30:32So at that point, there was this belief that cocaine was safe. So here comes this person showing this data on images that others had never seen. And with the background that cocaine was at that time failed to be safe. And I submitted it to the New England Journal of Medicine, which is the most important medical journal, clinical medical journal. They review it and they came back again saying, well, there's really no evidence that cocaine can be damaging to the blood vessels. They were completely wrong. And now it's clear, I mean, all of that is history. No one will question that cocaine, as well as other stimulant drugs, produces vascular damage and pathology.

31:15But it is the way that science goes. And you sort of say science should be guided by data, but science has a religious nature to it also. And once a model is created, it becomes very difficult to change it. So, and it takes a long, long time for concepts that have been consolidated as accepted as the truth to be questioned. And I see it. I mean, it happened to me there, but I see it constantly. And that statement that I stated there is very, very valid. If you come up with something that is ahead of its time, you're going to have trouble getting it accepted. And you may not actually necessarily be recognized for it when it becomes everyday life.

32:03then we have to say, well, what's the big deal? That's in the nature of the scientific progress. But as someone that is directing and allocating resources for science, I am very sensitive to ensure that if there are situations where there may be something that is very innovative that others are not seeing, that we don't curtail it. So I tend to, in many instances, say, okay, let's give it the benefit of the doubt. Because if it is correct, it's going to be much more transformative than if we just continue doing science that follows the rules of the game very, very precisely, where basically what you are expecting, you've already seen.

32:47So I do think that we need to push the limits with open access to scientific databases. This is happening more and more, which is very exciting.

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34:25now as you mentioned you have perseverance as a superpower it is just a statement of reality that you don't stop and some people may not have that constitutionally when you are mentoring or having conversations with say younger scientists who are facing their first pushback they're getting rejected they're having to try again and again maybe they're feeling demoralized what do you say to them? I say, you know, this happened to me. I mean, my first grant was basically just red line, totally and absolutely. And I was very depressed. And at that time, actually, people in the Institute at NIDA said, Nora, try again.

35:10And I was in that respect. And again, I do not take no for an answer. Because sort of like, and this is a message that I say to young people, You should dare to do things. And no one has the right to say you cannot bring a new perspective into things. And so I always say, be daring and persevere. With all of my postdoc students, they get rejected on a paper. They get rejected on a grant. I mean, the answer is just stand up and jump back on the horse. I mean, it's just like as simple as that. And for those who aren't watching any video, you are very tough, you're very physically fit, you're very mentally fit, and you walk the walk.

35:54So I want to just give people further evidence that you very much walk that walk. And I'm going to segue now to perhaps a discussion of the difference between studying compounds and experiencing compounds. And I was hoping you could tell the story of how you became acquainted with Demerol. It's interesting, you know, because I love Demerol. I probably shouldn't be saying these things. But what happened to me, I was in a horrible car accident. I was the passenger, and there was one of those hits that the car, it was I see the car, does a 90-degree flip, and the car in the opposite direction comes in and strikes me in the passenger seat.

36:38Seeing the car coming to me, I did not want my brain to be hit by a car. And so I said, okay, I put my foot into the car to protect my head and to get my head as far away as I could from the door because I saw it coming. And so I did not get hit in the head, fortunately, but the door came crashing and I was trapped. My leg was trapped. It was broken. I was under a lot of pain and I wanted to lose consciousness because the pain was so intense. And so they finally, they had to come up with this joss of life to open up the door because they couldn't get me. They get me into the ambulance, take me to the hospital.

37:15And there the doctor says, Nora, we have to try to move the fracture so that we can accelerate the healing. So otherwise we're going to have to go for surgery. So we're going to give you Demerol. And they injected me with Demerol. It was extraordinary. I mean, it was not just the intensity of the suffering was disappearing. everything was fascinating. And opioids make you sleepy. And I was forcing myself not to sleep because everything was so extraordinary. And so it gave me an insight of how powerful that drug was, that despite everything that was there, I wanted to be aware of every sensation.

37:54And they admitted me to the hospital and I had to spend there two nights and three days. and I recall I was in the terrible pain and they would give me the Demerol and it was this sense of well-being, extraordinary sense of well-being from the opioid. And that is the only time I really that I've had a real ability to have a consciousness of how an opioid makes you feel. And so when they discharged me, they discharged me on Monday, the accident was on Friday. I was waiting on the car and I felt all chemical. Everything felt very unreal. And the doctor had sent me home with two weeks of medication for the pain and I stopped cold turkey.

38:38Lo and behold, I did have withdrawal over the night and it was so bad. I didn't understand at first what was happening. I was restless. It was worse than pain. And sometimes you need to experience these things to understand that you say, what can be worse than pain? It was just I could not be comfortable no matter what. So I took one of the pills that he had given me, and that was the last I took. And then the physical dependence that was responsible for that withdrawal disappeared. And that's it. That's my story with opioids, which made me very aware that I do not want to be exposed to opioids unless I have horrible pain, because I can see their allure.

39:17I can see how someone would easily fall into that nirvana, that chemical nirvana that they create. And that's the story of that Demerol. And that's why I say I did. I have to be honest. It was an extraordinary experience for me to have been able to feel what it was. But it was also a very scary one. Super scary. I had nothing nearly that severe, but I had a terrible shoulder injury that ended up requiring reconstruction. but in the emergency room when I ended up in the hospital, they were overbooked, understaffed. They had gunshot victims and so on who took precedence, of course. So I was sitting there with my arm dislocated, sort of sticking out of my chest for hours, and they gave me morphine.

40:04And I remember thinking two things. The first was, this is incredible. The number two was, I should never, ever touch anything like this again. And so after my surgery, when they sent me home and they gave me Vicodin and this, that, and the other thing, they gave me a whole collection of different painkillers. And fortunately, some of them I took for just a few days and they made me nauseous. And I was very happy that they made me nauseous because it made me less likely to use them. But I do have a, I suppose, a firsthand acquired fear and then a developed fear just from the experience of people in my family and my friends.

40:41What is the current state? How should people think about the current state of addiction and overdose crises in the U.S.? It's unfortunate. I wish it were different, but it is really a state of very severe overdose deaths that are very difficult to control and regulate. And what we are observing is that we are seeing more and more people die with very diverse demographics from overdoses, which, again, makes it so very hard to control. Because at the beginning, the crisis started because we started to overprescribe opioid medications and people diverted them and people also who should have not been given them because they didn't have severe pain syndromes became addicted.

41:30And that opened up the door for heroin. And then we started to see a rise in 2011, more or less, of heroin injection and people dying. And then in 2016, there was a transformative, very malignant change, which was the introduction of fentanyl. And fentanyl, we've all been hearing about it in the news, is a synthetic opioid that was developed in order to have a more potent analgesic. is widely utilized in medicine for breakthrough pain for cancer patients. For example, when the medications that they have no longer controls the pain, you can use fentanyl. But it's also widely used by anesthesiologists because when you combine fentanyl with an anesthetic, you actually can control and regulate much better the level of consciousness of your patients.

42:20So it's a very useful drug. But by its potency, it is highly, highly addictive. It's also highly dangerous because of its potency. It can make you stop breathing very, very rapidly. And it's a drug that is very cheap to manufacture. You don't need to cultivate any plant. You synthesize it, and the synthesis is very simple. And because it's so potent, you need a 50 times less volume of drugs, so you can bring it through the borders much more easily than with heroin or any other drug that we know of. And so it has both pharmacological effects that make it dangerous, but also the production makes it actually very enticing for the drug dealers.

43:06So they are incentivized to distribute it. And that's what we've seen accelerated during the COVID pandemic. Basically, fentanyl permeated all of the country everywhere. And so they started to also mix it with other drugs like cocaine or methamphetamine. And now more recently with counterfeit pills that are sold like Adderall, which is an amphetamine, or like Ativan, which is a benzodiazepine that you use for anxiety or sleep. Or even these guys as Vicodin, which is an opioid medication for pain. They go and buy it on the web and they are less expensive than the real thing. So it's not just that people that are addicted to opioids can overdose.

43:49Now those that are taking cocaine can overdose. Those that can take methamphetamine can overdose. And students that may buy a pill in order to study for an exam may overdose and die because the pill they got had fentanyl. Or a person cannot get their physicians to prescribe them a sleep medicine. They go and buy it on the web and they overdose. So this is the nature of the major challenges that we have. And we're seeing more and more new substances emerging, which is like, again, running in a treadmill because we develop antidotes for the overdoses from fentanyl. But now they are mixing fentanyl with an aesthetic that is using veterinary medicine, xylacine.

44:33and that actually, silacin does not respond to Narkin, which is the antidote that we use for fentanyl. So this shifting nature of the drugs that people are exposed to, the fact that they are increasingly more potent and the fact that they are basically disguised in many ways is expanding the number of people that are now overdosing. And in some instances we don't have good strategies that we can use to help them to revert those overdoses. It's such a complex, evolving ecosystem of compounds. And as you mentioned, there are so many incidental or accidental ways to ingest, for example, fentanyl.

45:20And I know of many direct stories where people have gone to a bachelor party, they try a little bit of some drug that ends up being cut with fentanyl. I know of two people specifically, one just dropped dead on the floor. one fell into a coma from what would have been considered low doses of illicit drugs but they happen to be cut with fentanyl which is horrifying and in fact my friend who died was not himself an addict he was collateral damage one of my other friends i grew up with there are a lot of drug issues where i grew up was a heroin addict he developed just an incredible tolerance to fentanyl and he gave it to my other friend to help with his hangover.

46:00And my other friend had never used any opiates and he fell asleep and just never woke up. So the sheer ease with which the fentanyl, as you mentioned, sort of permeates different corners and neighborhoods of society, which does not discriminate, or I shouldn't say it doesn't discriminate, but it has infiltrated every socioeconomic class. It's really pervasive and really terrifying. What is your perspective on the war on drugs and perhaps any other approaches that you think may be more effective? I'll answer it, but I guess actually the story that you just told of your friend, that how he by taking fentanyl, unbeknowing what it was, it just killed him.

46:49And this is what we are observing a lot. And I think it's important to educate people that this is a seriously dangerous drug. And unfortunately, I think that we have cried wolf so many, many times that we've lost credibility. But if there was a way that we could convey that in very objective, we don't need to exaggerate in any way. I mean, fentanyl, it's two milligrams, will kill you. And the counterfeit pills contain five milligrams, some of them, two doses to kill you. So it is very, very tragic. But coming back to your question in terms of the war on drugs, I think that what it did was it created a mechanism that could perpetuate structural racism.

47:39It is very tragic to see how its enforcement led to the incarceration of young Black Americans. And again, that punitive system where someone could be stopped, and this will happen if you are Black, on the notion that you had drugs with you and thrown in jail or prison because you had drugs on you, is such an unfair system. And it didn't work in any way because it did not reduce the amount of drugs that people were taking or the negative consequences to our society. So it did not work. And I think one of the aspects that it did show is if you do throw a person that's taking drugs in jail, if you criminalize that person that's using drugs, like, for example, we did horribly with crack cocaine.

48:30So if you were smoking crack cocaine, it was like, I don't recall exactly, but it was at least 10 times greater penalty than if you were just snorting cocaine. Snorting cocaine or injecting cocaine hydrochloride was much more favored by white people, whereas crack was favored by black people. So cocaine hydrochloride white, crack cocaine black. Why do you see such a difference? It is the same cocaine. Basically, it's cocaine is cocaine. And yet one connoted a much higher penalty than the other. That's an example of the consequences. But what science has shown is that when you do throw people into jail or prisons that have a problem with substance use disorders, Then when they leave, they are at much greater risk of, first of all, relapsing immediately into drug taking and escalating their drug taking.

49:26So you are exacerbating the nature of the problem by putting them in jail and prison. So it doesn't work no matter what you do. And that's why the whole notion of criminalizing the person that takes drugs is basically very negative vis-a-vis the outcomes of the person and also in no way it benefits society. It is actually very costly by itself. When an issue becomes politicized, then it becomes much harder to change and shift. I think that we've seen over the past, I would say, certainly five or eight years, an openness to recognizing that the war on drugs did not work and that criminalizing drug users is basically a negative and it's promoting structural racism.

50:19So I'd like to cover quite a few things, and I would like to get to harm reduction, but I'd like to do that a little bit later and to hear your perspectives on that. first I wanted to go from the problems that you've described to looking at pushing the limits daring to do things some of the perhaps novel or developing potential approaches to treating addiction and there are several things I'd like to talk about certainly you have recently I want to say written about TMS and deep brain stimulation I would like to talk about those first I thought we might speak about psychedelics and psychedelic-assisted therapy.

51:02And I wanted to congratulate and thank you for being one of the first, if not the first, institute director to fund psychedelic research with humans after the scientific winter following the Nixon administration, which interestingly enough, at least I've read that some of the Controlled Substance Act and And Nixon's decisions around that were motivated by controlling certain demographics or having the pretense of being able to search and seize and so on. That was from, I think it was Ehrlichman in his, might not have been cabinet, but sort of inner circle. But coming back to the treatment side of things, could you speak to perhaps what we know already about psychedelics as treatments?

51:48What is interesting and what milestones, I think this is a question on a lot of minds, and you're very qualified to speak to this, what milestones still need to be reached to instill confidence in these drugs as therapeutics? I think it's a very interesting, potentially promising area of therapeutics. The way that I see it is the evidence that exists is very limited, but is sufficiently intriguing that you cannot ignore it and behooves you in terms of why we are identifying this as a priority area of research in the whole issue of psychotherapeutics, of the use of psychedelic drugs. The data is strongest for the use of psilocybin for depression.

52:33Studies have shown, and I think that even though the sample sizes are not very large, they have consistently shown improved the outcomes on patients with terminal illnesses. Most of them, I think, if I recall correctly, were with cancer in whom the psilocybin allowed them to accept better emotionally the fact that this was a terminal illness and improved their depression scores. And that was quite significant. There's also data showing potential for PTSD, the use of psychedelic drugs. So these may be the two disease conditions for which there's more data. The clinical trials are limited in sample sizes and in numbers, but the effect sizes are significant despite the small sample sizes.

53:22There are some studies that have been done in substance use disorder. Nicotine is one of them. Alcohol use disorders, alcoholism, is another one. And again, both of them are on psilocybin. And for both of them, there is also this positive effect. And what's intriguing, and speaking about it in terms of the nicotine, is that the effects actually appear to be larger than the ones that you see with medications that we use for the treatment of nicotine dependence, just like Chantix or nicotine replacement therapies. So the number of people that stop smoking is actually significantly greater than that.

54:04That is the percentage that stop smoking with medications that have been approved by the FDA. But it's study number one, only one study, and the sample sizes are small. So that's why we're funding the researchers. This is a group at Johns Hopkins University to actually replicate that study. So the data is quite interesting, but it is very preliminary. And I do want to emphasize this because sort of people like to make conclusions before the evidence is out there. And my concern is that, and you already see it, you go into the web and there's a lot of sites advertising treatments with psychedelic drugs, not just for mental illnesses, but for also for well-being when the data is not there.

54:50And so we don't know, first of all, we need to replicate. But assume that you replicate and it does work. What are the doses? How to give it? What are potential negative side effects? I mean, what clinical trials have reported is in a small number of people, there is a risk of suicidal behaviors and suicidality. So who is at risk to show that? How do you actually, if you start to see it, how can you prevent it? How should you administer that psychedelic drug? It is believed that the psychedelic drug is adjunctive therapy, that it is the interaction with the therapist while you're under the influence of the psychedelic drug, that it is therapeutic.

55:31That's one of the hypotheses. So how you should be administering? How do psychotherapists get involved? And all of these are scientific questions that we need to basically explore with research because we don't have the data there that is needed to build up. And if we don't build up and people start to use it and they start to have negative effects like suicides, then that can lead to actually jeopardizing the future use of these medications. The FDA may say this is too dangerous or the DEA may say this is too dangerous. We are not going to agree to its utilization. And that is where the danger comes around of pushing something to preliminary.

56:15I agree that certainly the positioning of psychedelics as panacea, which we see a lot, is really putting the cart before the horse in a lot of ways. And there are risks, which is why there are exclusionary criteria at places like Johns Hopkins for certain conditions, whether it's schizophrenia or bipolar disorder or others. And I'd love to chat a little bit about study design and what researchers might do or consider to make their studies and grant applications more appealing to institutes like NIDA. And the reason that I'd love to explore that a bit is many smart scientists are now paying attention to this, including younger scientists who are considering this as a career focus.

57:04And as it stands right now, there's a very small pool of serious independent philanthropists or foundations who are providing funding. It's very small. I would say it may be in the 15 to 20 person range, really, when we're looking at anyone donating above$100 ,000 a year. It's very small. and then on the other hand you have and i think there's a role certainly an important role for market-based for-profit solutions and providers but you have sponsored research on the other end of the spectrum and nida has been very forward-looking in the sense that you've provided funding to dr matt johnson and so on at hopkins looking at nicotine addiction i would love to know And I'll just provide a little bit more thought.

57:54I know this is going to be a very long question. And then to get your thoughts on what people might do to make their applications or studies more appealing. One of the challenges is certainly that is brought up oftentimes is blinding. And these studies or these compounds and the experiences associated are really highly discriminable in the sense that most people know they are either in the control group or not. And you have potential active placebos and people have experimented with niacin. Some people have considered higher doses of, say, cannabinoids. But it's difficult, it seems, to find lookalike drugs that do not also bring similar actions or effects.

58:38Do you think there's a place for, say, comparative efficacy studies where you might have, by analogy, psychotherapy versus X, right? The people who are getting psychotherapy are going to be aware they're getting psychotherapy, but you could compare it with another therapy or you could compare psilocybin for, say, nicotine addiction to nicotine replacement therapy. Those are just a couple of, I suppose, a bit of connective tissue for people who may not have more context. But what would you like scientists to pay attention to? What would you implore them to try to do with their studies and designs if they want to try to get more federal funding?

59:15There's no simple solutions, I mean, of how difficult it is to control for a placebo. But it is an important one. So one of the recommendations is to use a very low dose of the psychedelic drug. So you are giving them the psychedelic drug, but a dose that is considered to be sub-therapeutic. And that's what some of the researchers are doing right now. And to follow all of the guidelines and practices, if you're going to be doing a randomized clinical trial, which are the ones that you basically divide participants, some gain the active intervention, others do not, and you randomize it and you follow them.

59:52And that's the way that you actually collect data that then allows you to determine if there is a difference or not. But I think that the grantees that are coming up with proposals are no these. I mean, how to propose one of the randomized clinical trials. One of the things that we work with grantees, too, which is important, is that we help them in terms of the interactions with the FDA. because the FDA at the end of the day is the one that's going to be able to say what data do they need in order to be able to consider that a clinical trial is done in a way that they make it feel comfortable to approve an indication for a psychedelic drug or not.

1:00:35So it is crucial that they work with it from the beginning as they are planning to do their clinical trial that they engage with the FDA and we absolutely help them. I mean, we try to provide them support in if the FDA, for example, wants them to do toxicology X or toxicology Y or look at the biodistribution. There are certain things that we can, through our contracts, help them obtain. And we are specifically requesting this, and I'm speaking right now of clinical trials, if grantees, there may be other scientific questions that are very valid, that are not just a randomized clinical trial that we also would be very interested in funding.

1:01:16For example, with brain imaging, you can now look at how, and there was a paper, there's one paper that actually looked at the effects of psilocybin. I think it was psilocybin, either LSD or psilocybin, I don't recall. And you're looking at, we have these brain networks that interact with one another. And what they showed was that that architecture of network was significantly disrupted during the hallucinations take when the drug was on board. And so if you can do research that can identify biomarkers of the effects of the psychedelic drug, that's one area that were interesting. But also through those studies, can you understand the mechanisms that are responsible for the therapeutic benefits?

1:02:01So by looking at how the brain changes its operations, and then you can determine if that is associated with therapeutic benefit, you can start to understand mechanisms of actions of psychedelic drugs. We're also funding researchers to develop, we know what the psychedelic drugs that we currently have, but with chemistry, you can create other psychedelic drugs, for example, that may have the same pharmacological target, but they don't produce hallucinatory experiences, which would make it much easier to actually implement. So we are interested on a whole gamut of research that could help advance our understanding of the potential of psychedelic drugs for therapeutics.

1:02:49The entire category of non-hallucinatory psychedelic compounds is very interesting. I think there appear to be some very interesting indications that might be really favorable targets for these, what are sometimes called the psychoplastogens, like cluster headaches in the case of LSD or LSD analogs. What would you make, and the answer could be that they're mistaken, of researchers who report based on all the documentation from subjects in these various studies, whether at UCSF? And I think the imaging that you were mentioning may be Robin Carhart-Harris and his team, because they do a lot of functional MRI and imaging, looking at the perhaps increased entropy or connectivity or both communication-wise in the brain on these experiences.

1:03:40And in that case, it would be psilocybin or psilocybin. And what would you make potentially of the importance of meaning-making? And that is to say, beyond the activity signature that you can track or the receptor affinity, the reports from subjects that it's the meaning-making in these sessions, which seem to be in part hand-in-hand with the hallucinations, the psychedelic experience, relating to how they see themselves and the world that lead to the behavioral change and the durability of some of these effects. rather than dendritic spine growth or any number of changes that you can observe.

1:04:22But given that the duration of some of these sessions is four to six hours, let's just say, and the half-life is pretty short, but some of the effects seem to be quite durable with, say, the existential distress in terminal cancer patients and also for nicotine. Is there a way to include those factors as an area of inquiry? in addition to the sort of mechanistic studies and the basic science and the imaging? Of course. And there's been actually papers that have done that, that actually have looked at the association between the intensity of the subjective experience and their therapeutic benefits, and then have shown that those that have the more intense mystical experience had the better therapeutic response.

1:05:09But that element of meaning and understanding is basically not in any way exclusionary with that of neuroplasticity. Because it may be that, in fact, that that experience that you have there, while you are living it under the effect of the hallucinogenic drug, may generate a longer-lasting memory because of those neuroplastic effects. And again, highlighting why that combination of that drug itself with a psychotherapeutic intervention becomes crucial. So you cannot certainly separate them. To me, if it can be corroborating that there is this neuroplasticity and we learn to use it properly, then imagine how extraordinary it is to be able to generate a window in time whereby exposing you to a stimuli under the effect of the psychedelic drug.

1:06:05If it in fact turns to be the case, you could strengthen a particular memory. And that would allow you to actually cover a memory that may be very painful. So you are competing one memory against the other. So I think that this is, to me, one of the most fascinating areas about why I think that these psychedelic drugs deserve attention for research. Because to have a means to monitor, to accelerate learning and memory process, this neuroplasticity, long-term potentiation phenomena that we've been studying in neuroscience, would be a very powerful tool. Yeah, it's been very exciting to be involved with some of the early stage science and to see it develop over time and to also have a lot of misgivings about the public discussion when it veers into the land of panacea, because these things are absolutely not panacea and they're very, I believe, powerful compounds based on the data that we have so far.

1:07:04One more question, maybe two more questions about this, and then I would love to move to TMS, which I am increasingly fascinated by. I was a subject in a study involving TMS a long time ago, but the technology was pretty primitive then. My question is about substance use disorders in the very preliminary hypothesis that psychedelics, and specifically psilocybin, so the same molecule, appears to have effects across drugs of abuse, meaning, or potential abuse. So if you have, let's say, the work of Michael Bogenschutz and others at NYU looking at alcohol use disorder, psilocybin, then you have Matt Johnson, Dr.

1:07:47Matt Johnson, and nicotine. You also have people like Peter Hendricks looking at cocaine. If it turns out that those can be replicated, we can hopefully, and I'm very optimistic that there'll be more federal funding for these things, because there is a bit of a chicken and the egg problem in terms of sample size and funding availability, which is challenging. But what could it mean if it turns out that something like psilocybin is effective across multiple compounds? Is that common? I simply don't know in other sort of frontline treatments. Or would that be something novel that would raise very interesting questions in your mind about the nature of addiction?

1:08:31I've been studying as a researcher multiple addictions. I mean, cocaine, alcohol, methamphetamine, nicotine, and more recently opioids and heroin also. And I've been intrigued about what do all of these addictions have in common. In fact, I've been intrigued about what something like morbid obesity has in common with addiction, if you look at the brain, because they all share as a common phenomenological presentation the compulsiveness of the behavior and the loss of self-regulation. So you cannot stop it and you just basically escalate on that behavior. So I've been intrigued about recognizing the common elements in the brain and then, of course, studying also their uniqueness.

1:09:15But the neurocircuitry is basically very similar. What is different is the way that you engage it. So to me, in and of itself, it's not surprising that you have a therapeutic that is going to be valuable for multiple addictions. And we're funding other type of research with other molecules with the aim of basically targeting just a medication for addiction in general so that we could also start to address the problem of polysubstance addictions that we have without having to just go specific. So it doesn't per se surprise me. What I would be very intrigued in that notion is if we were to understand the mechanism.

1:09:55And the common mechanism across all of the addictions is that you create long-term potentiation in reward circuits. So you are strengthening the signaling on systems that basically are associating the drug with pleasure and reward. And you are weakening the signaling that's associating pleasure and reinforcement for other stimuli and reward. So just a strengthening processes and a weakening processing. And you generate it in such a way that you've created an artificial need for the drug, just like you have a need for food, now you have an artificial need for the drug. And I'm very much intrigued about the similarities with pain.

1:10:35When you have pain where the insult is no longer there, but the memory of that pain continues making you feel it, Just like in the addicted person, the memory of the pleasure leads you to continue wanting it. So it's not just that I think it could be beneficial for different types of drugs, but I do think there's value in actually even considering the extent to which, if they are shown to be able to modify neuroplasticity, treatments for these chronic pain conditions, which are devastating, and for which we really don't have anything. I mean, not that I know that there's much research into it, But I'm just telling you where my brain is jumping into.

1:11:16Yeah, absolutely. So a few things come to mind. If you haven't looked at the work of Gould Dolan, G-U-L-D-O-L-E-N, she's at Hopkins. Her perspective is quite different from, say, Robin Carhart-Harris. And I think she has some very interesting hypotheses around a reopening of critical windows with respect to, say, plasticity. and then on the chronic pain topic i will say this was done at a above board very well run clinic with proper medical supervision but i went through two weeks of ketamine infusion several years ago not because i was depressed but because i wanted to be able to speak firsthand to the experience because i knew i would have a lot of questions about it from friends and also audience and so on i'm not a doctor i don't play one on the internet just to be very clear but what was fascinating to me is I went in having read a lot of the research related to depression, and I've since had Dr.

1:12:11John Crystal from Yale on the show to have a very long conversation about all things ketamine. What I didn't realize though when I went in, because I was not going in with any severe depression, is, or I couldn't have anticipated what happened, and that was for me, I had chronic back pain in my mid-thoracic back from a long-standing injury, which was very severe, had daily pain, intense pain for 10 years, let's call it. And when I left my two weeks of infusions, I had no back pain for about six months. And it turns out one of the other primary indications is chronic pain. So there's a lot to recommend psilocybin over ketamine at psychedelic dosing, but it matches very well with what you were saying about the potential overlap of plasticity and not just for indications like depression, but also for something like chronic pain.

1:13:06I wasn't thinking of ketamine because I wasn't thinking, I mean, ketamine is not considered, as you know, a classical psychedelic drug, but there is a lot of work on research ongoing for the value of ketamine for the treatment of chronic pain. I look at it in terms of what has been done. Again, all of these areas are under-under investigated, but I'm going to check it out because I want to see if anyone has published anything on psilocybin for chronic pain. So I was jumping into the classical psychedelics, which have very different mechanism of actions than ketamine. And I think ketamine was the drug that let us open up the doors to say, here we have a drug that nobody, that is a dissociative type of drug, that it's also a drug that can produce addiction, a psychedelic, classical psychedelics don't.

1:13:55And yet, despite everybody's prejudices, show to be beneficial for treatment of depression. Yeah. So I think that that is an example about why we cannot just close our eyes and say no. And we need to look at these classical psychedelics. So I would like you made me now curious about it. Also the fact, as you were mentioning earlier, that there is room for potentially stripping out some of the psychedelic effects. I think we need to keep in mind that the business motivations may not always be aligned with clinical outcomes. Of course, it would be much more convenient to work with these compounds if they didn't elicit the types of hallucinations we've discussed.

1:14:32But even something that is non-classical psychedelic, let's say salvanorin A, right? So you have a kappa opioid agonist, may have some really interesting applications for minimizing damage after stroke for vascular problems. Super, super fascinating. Of course, more research is needed. So I wanted to shift to TMS and deep brain stimulation. And this is very interesting to me. We were talking about sort of different activity or maybe pathological activity in different neuroanatomical structures. I don't know if the nucleus accumbens fits into both that prior discussion and the TMS and deep brain stimulation.

1:15:13But could you speak to what TMS is, what deep brain stimulation is, and why they are of interest? Well, they are incredibly interesting. I'm going to introduce you to a new technology that has my brain even more excited than TMS. Okay. TMS goes for transcranial magnetic stimulation, and it's a technology that is not invasive. You actually administer magnetic currents in the scalp, and then these magnetic currents actually go into the cortex of the brain, and they are signal-transferred as electrical signals. And it can be used to modulate either at high frequencies to stimulate or sort of lower frequencies to inhibit the areas that you are targeting.

1:15:59And by understanding how in the cortex, because the brain is a very complicated network, and so it links with almost everything else, but they are hubs. They are areas that act as hubs. That is, they have many more connections. Some of them go deep into the brain. So as you understand better that pattern of connectivity, you can deliver TMS in such a way that you can start to reach areas that are deeper in the brain, which are very important for diseases of depression and diseases of certainly addiction. I mean, you were speaking about the nucleus accumbens, which is the main reward region of the brain and all of the drugs of abuse, all of them stimulate it.

1:16:40And when you stimulate it in animals with electrical currents or with optogenetics, you generate rewarding signals. But the transcranial magnetic stimulation cannot reach deep, but you can reach it indirectly. And that's what they use it, and it's a technology that's approved for the treatment of depression. Deep brain stimulation then basically is an invasive procedure. You put the electrodes inside the brain. It's being used, for example, for treatment of addiction research. It's being used for research, also treatment of depression and other diseases. And the nucleus accumbens is one of the main targets, both for depression as well as for addiction.

1:17:22But there are other neuromodulation technologies, so transcranial magnetic. The other one is direct electrical current stimulation, which instead of giving magnetic signals from the outside to give the electrical pulses. But the one that I am very intrigued and I want to actually introduce you to it, if you haven't heard about it, is low-intensity ultrasound. So, it uses ultrasound and if you can use it with high intensity or low intensity and you apply it on the outside of the brain. If you use high intensity, you can very specifically create an ablation. So, you can do what you could do with surgery, but very precisely without having to open the hair.

1:18:03But that's high intensity. The beauty of the low intensity is you do not produce damage to the tissue, but you can modify it for a long time. So they are doing research right now and the high intensity ultrasound was recently approved for Parkinson disease. And they are now doing... This is the high intensity. The high intensity, but the researchers are looking at low intensity for neurological diseases and for addiction and other mental illness. And the beauty is that sound goes through the tissue so you can target your nucleus accumbens directly with a much greater precision than with transcranial magnetic stimulation.

1:18:44Okay, that's super interesting. It's fascinating and you need to apply it for 10 minutes and the pilot data is showing that you see it for say, the effects are two weeks or four weeks with a single stimulation. With a single session of 10 minutes. Yes. Wow. The pilot data is very, it's pilot data. That's why I say, now that you're speaking to me and last time we spoke, I was, I'm very excited of TMS. I'm not in any way going to minimize it. But actually what I like so much, and I'm just going to say, you push the limit. And I said, let's push our own thinking. if you are able to do this long-lasting effect through these, as you learn to understand better how these frequencies for ultrasound stimulation affect the tissue, I think that one day we may be able to cure addiction.

1:19:35And no one has ever heard me speak about cure addiction. So why do I think it is possible? Because we know that when people have strokes in certain areas of the brain, particularly frequently involving the insula, there are cases where people just stop taking the drug. They forget about taking the drug. They don't care anymore about it. So there's been instances which have shown that the insult, a stroke in a particular area, cure the person of their addiction. So what about if we gain that knowledge about what are the relevant circuits and areas, And we have the tools now to manipulate them in ways that are much more effective than we had in the past.

1:20:19That opens up the possibility of in the future that we may be able to cure addiction. Well, that makes me feel much more optimistic. And I also feel like at some point, and I'm getting ahead of myself, but looking at these novel cutting-edge technologies, or in some cases very old technologies like psilocybin being applied to conditions in novel ways, that at some point there might be polytherapies that combine some of these factors. Let me ask you a question about the Parkinson's for a second, though, because I have Parkinson's on one, I think now both sides of my family, so it's of intense interest.

1:21:01If they're using high frequency, and for those who don't know the term ablation, and I want you to please correct me if I'm wrong, but that can be surgical removal of tissue or I suppose destruction of tissue might be another way to put it. I want you to correct my definition if I'm getting it wrong, but how would that strength of effect be used in Parkinson's? It is the high-intensity ultrasound, and the high-intensity ultrasounds become sublative. So you are targeting, for example, the subthalamic nuclei, just like you do with surgery. But in this case, you are not opening it up, and you can very precisely damage it.

1:21:40Yeah. So this brings psychosurgery to a completely new level. Wow. And so they applied it. And there are also, I think that one of the targets is a subtalamic nuclei, but I also think that they've targeted parts of a very small nuclei in the thalamus too. So it is fascinating also from that perspective of in instances where psychosurgery may be valuable, that you can do it as minimally invasive and as precisely and as small an area as possible. So I think it's quite remarkable. In the case of, now you got me all excited about this low-intensity ultrasound, I've been following the TMS pretty closely, and in particular the shorter-duration, higher-frequency dosing of TMS.

1:22:26So let's just say multiple sessions a day over the span of five days. There's some interesting work being done. And certainly, I know the plural of anecdote does not equal data, but anecdotally I've seen a number of outcomes with friends' children who are patients that have practically just defied belief. But on the low-intensity ultrasound side, you mentioned, and we'll put links in the show notes for people, and maybe I'll get some links from you or your team just where people can learn more about this. I know it's pilot data, so hold your horses. The jury's still out. But nonetheless, very interesting place to begin.

1:22:58In addition to the durability that you were mentioning, which I think was two to four weeks, let's just say, after a single 10-minute session, is the onset of effect immediate or near-immediate as well? It's basically almost immediate. Wow. And one of the consistent findings that they are seeing is that they see a reduction in anxiety. They see a reduction in craving. It's pilot work. I want to reiterate that. It needs to be replicated. But, you know, when I saw that pilot data, I said, oh, my God. And it was the group at West Virginia who has been doing the deep brain stimulation for the treatment of opioid addiction.

1:23:35and they insert these electrodes and then they've basically observed that in three of the four individuals that they've treated on that pilot study, they were able to, again, very dramatically reduce anxiety and they decreased the consumption of opioids. So it showed a positive effect in three or four. They basically told me these effects that we're getting with a low, low intensity ultrasound that they've tested eight people are as dramatic or more dramatic than what we're seeing with the deep brain stimulation of the nucleus accumbens. So they target also the nucleus accumbens with low intensity ultrasound.

1:24:14So it's very intriguing. You know, I'm a scientist and I love and I get excited with data, but I do want to reiterate it's very pilot. It's very, very pilot, but it has to be studied. It's like with what we were saying with a psychedelic drugs, is very interesting. It has to be studied. Everything starts small. Almost everything starts small, right? We all start with the pilots. So the jury is still out, but it's exciting that you're pushing the limits and daring to push the envelope and experiment with new things, of course. I mean, that's part of the charter, but you also have a history of doing this well.

1:24:49And I don't think you would have arrived where you are today had you not been very dogged and determined. And it goes all the way back to when you were turned down by NIDA. And here you are as the director. It's just remarkable. It's just a remarkable story. So Dr. Volkov, you've been very generous with your time. I've enjoyed the conversation. I could keep going for another two hours, no problem. But you have an incredibly busy schedule. Is there anything else that you would like to share with people out there? You know, there are two things that I would have liked to add. one of them is that addiction is very frequently comorbid with other psychiatric disorders.

1:25:29And most notable is anxiety, depression, suicidality. And I bring it up because you need to address these comorbid conditions because otherwise it's not going to be possible for the person to be able to recover. And also from the perspective that if you are depressed, if you're anxious, if you are suicidal, you are likely to take drugs as a mean to auto-medicate, to escape that mental state. And it is crucial to send this message because it's not as simple as saying that you take drugs because you want to get high and you're taking the drugs. I mean, people are taking the drugs too many times.

1:26:07Initially, yes, for curiosity, or many times to feel good. But once you become that it is really to escape a mental state that is very difficult to stay at. It's very painful. And the other point that I did want to bring to that we haven't discussed, which is in understanding how we understand the effects of drugs and addiction and how we understand also mental illness, is how important the environmental factors are and how crucial they are, particularly when you are a child or an adolescence. I think that we've all become much more sensitized to them with a COVID pandemic because we came to realize that there are certain people that were at much greater disadvantage.

1:26:50And that's those that deal with people that are in circumstances of economic inequality, of trauma during childhood, and what we call the social determinants of health that are really playing very important roles in people's encounter with drugs and how they respond to it. and how they ultimately also may be given an opportunity or not to access treatment and to how they respond to treatment. So as you were speaking, for example, with psychedelic drugs, we are very concerned that if our psychedelic therapies, if they get into mainstay clinical practice, if they are proven to be useful, that they are equitable.

1:27:30And it doesn't end up with like many of the very fancy treatments that we have now that are only accessible to a very few. So that's the only other thing that I would want to say. Yeah, 100 % agreed on both. And that's also part of the reason that I hope we will see whether it's with psychedelic therapies, psychedelic assisted therapies or other modalities, in some cases options for group treatment. And at least the testing of the hypothesis that outcomes can not only be equal to individual treatment, but potentially even better. And I think there is the possibility that that is the case, which would also have the wonderful side effect of decreasing costs quite significantly.

1:28:17And there's so many questions of insurance reimbursement and ultimately reclassification, which would be sort of a precursor to a lot of these things happening. But I agree with you absolutely completely. And it's also as upsetting and pessimistic as one can become when they look at the compounding of many of the addiction problems in the U.S. I feel like we are at a point in history also with some of these burgeoning technologies, as you mentioned, and I think it was obvious in the excitement in your voice. I mean, there are things potentially on the horizon that could really change how we not only treat addiction, but how we think about addiction as well, which is very exciting.

1:29:06And I think cause for a certain degree of cautious optimism. Oh, yes. I'm very optimistic, Tim. And I'm going to abandon you at this point. I'm going to jump off that screen. But it's been a pleasure speaking with you. Thank you so much for your time, Dr. Volkov. I have learned so much. I have so many things to look into. And for those listening, you may also have things you want to look into. We will have links to everything in the show notes, as per usual, at tim.blog slash podcast. Until next time, be just a little kinder than is necessary, not just to others, but also to yourself. And as always, thank you for tuning in.

1:30:11discovered or have started exploring over that week. It's kind of like my diary of cool things. It often includes articles I'm reading, books I'm reading, albums, perhaps, gadgets, gizmos, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcast guests. And these strange esoteric things end up in my field and then I test them and then I share them with you. So if that sounds fun, again, it's very short, a little tiny bite of goodness before you head off for the weekend, something to think about. If you'd like to try it out, just go to tim.blog slash Friday, type that into your browser, tim.blog slash Friday, drop in your email, and you'll get the very next one.

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