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Clinical Education Initiative [email protected]

STIMULANTS: FROM CRYSTAL TO AND BEYOND Petros Levounis, MD, MA Professor and Chair, Department of Psychiatry Associate Dean for Professional Development, Rutgers New Jersey Medical School Chief of Service, University Hospital

2/11/2021

Stimulants: From Crystal Methamphetamine to Bath Salts and Beyond [video transcript]

00:08 This second part training is 'From Crystal to Bath Salts and Beyond,' it is a three part training. If you did not join us last week, welcome. And if you have an opportunity, make sure you also make next week's which is the last training and it'll be more interactive, and we'll be able to see everyone with a live video. I'd like to share with you a little bit more about Dr. Petros Levounis, which will be our presenter again today. Dr. Levounis serves as a Professor and Chair of the Department of Psychiatry at Rutgers New Jersey Medical School. A Phi Beta Kappa graduate of Stanford University. He studied chemistry and biophysics before receiving his medical education at Stanford, and the Medical College of Pennsylvania. He trained in Psychiatry at Columbia University and further specialized in Psychiatry at NYU. Dr. Levounis served as Director of the Addiction Institute of New York from 2002 to 2013. And in 2017 was elected as an honorary member of the World Psychiatry Association. Dr. Levounis has published 13 books including the textbook of and Co- occurring Psychiatric Disorders, and the Pocket Guide to LGBTQ Mental Health: Understanding the Spectrum of Gender and Sexuality. His books have been translated into French, German, Hungarian, Japanese, Portuguese, and Spanish. So we are very excited to have Dr. Levounis work with us in the development of this series and join us today for part two. Without further ado, I'll turn it over to you Dr. Levounis.

01:54 Thank you so much, Angelica, and wonderful to be back and giving the second part of the series. Last week we talked about and and ecstasy. Here I have no disclosures. Some objectives. And here is the outline for the sequence. So last week, we talked about caffeine, cocaine, and ecstasy. And today we're gonna be talking mostly about crystal methamphetamine, with a few words about bath salts and beyond. Next week, which is the third part in the sequence, as advertised, is going to be a more interactive one. I have prepared some cases that I could discuss with you. But I would very much rely on you to bring up clinical vignettes, to ask questions, to have a discussion about different matters of use, and of course, co occurring psychiatric disorders when that is relevant.

03:03 So with that, let's just move on to our crystal methamphetamine discussion which of course, came into the scene in earnest in the 2000s. Of course, it was there beforehand. But the epidemic, the crystal methamphetamine epidemic, really saw its heyday in the early 2000s. Here are the crystals, they often have a pinkish hue, and that is due to which is a contaminant in the preparation of crystal methamphetamine. The ones of you who have watched the , you may very, very well remember Walter White and his phosphine compounds and using phosphorus to make very pure crystal methamphetamine. Here's the molecule. We've discussed it somewhat last week. The thing I would like you to remember more than anything else is that every time you see an aromatic ring, something that looks like this, separated from a by two , and all these angles here represent carbons. This is a phen, phen is this aromatic ring here. Ethyl, the two part here. , which is this nitrogen group here. It is a , and whenever you see a phenethylamine there is a

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very, very good chance that this molecule will have psychoactive properties of the stimulant type. People who may want to be really really into that stuff, the meth part is this methyl group right here. The A part is the alpha position of the M, which is the other methyl group right here. The phe has to do with a phenyl group, et has do the ethyl group right here, and the amine is the nitrogen at the end. So that's where the name methamphetamine came about. It pretty much describes the entire molecule.

05:11 Contrast that with adrenalin. This is epinephrine. Another one of those , the aromatic ring separated from the nitrogen by two carbons. And of course, otherwise known as epinephrine has very, very strong psychoactive properties. Well, the other thing to notice here is this is , Sudafed. This is what we get for nasal congestion and flu like symptoms and the like. It does not have very active psychoactive properties. But it is very, very similar to crystal methamphetamine. As you see here, this is pretty much the same thing with the exception of this hydroxy group right here. I'm bringing all these structures up to bring home the point that it is rather easy to make crystal methamphetamine, you just get this pseudoephedrine, dehydrate this molecule, you make a double bond right here, which is particularly stable, and then you had hydrogenate the double bond, and boom, there you have it, you have crystal meth. I'm not divulging anything. The recipes are all over the internet. So, you know, it's a very, very easy thing to do.

06:29 And of course, that gave rise to all the crystal meth labs. This particular one was in New York City, we very often do not think about New York City as having the space for a crystal meth lab. Of course, you know, the West, the Southwest, the Northwest, have much more open spaces and trailers and garages, and they can have crystal methamphetamine labs much more easily. But we do have them in New York City, as well. All that is a little bit passe, because we have moved now to the super labs that manufacture crystal methamphetamine, primarily in Mexico and India. Think about the primarily from , and the synthetic stimulant primarily from Mexico and India. This is a picture of a super lab. And of course, they can have much greater quantities of crystal methamphetamine.

07:35 Alright, let's digress here for a few minutes and talk about what these molecules do in our brains and where crystal methamphetamine stands compared to other of abuse. Right. All of us have these reward pathways in our brains, this circuitry in the more primitive part of the brain, and the job of these pleasure reward pathway of the brain is to scan the world at all times for things that are pleasurable and rewarding. In fact, they do something more than that. They scan the world for things that are salient, for things that are important. So imagine your very own level, which is the chemical that integrates this pleasure reward pathways of the brain. Think about your own dopamine level at the , the nucleus accumbens being the center of the pleasure reward pathways of the brain. And it's about 100%. Nothing too good is happening, nothing too bad is happening. It's just hovering around 100%. If you had a wonderful meal right now, that would jump to about 150% of its baseline. And if you had sex that would do twice the job of food, and would jump the dopamine level at 200% of its baseline. And

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these are the everyday pleasurable rewarding things that we all know and love. Now, out of 30 million chemicals that we have identified in all of the universe, there are only about 250 that have this particular ability to go exactly at the very same centers in the brain and activate the nucleus accumbens in a way similar to food and sex, as you see here that jumps the dopamine level to about 200-250% of its baseline, and they end up being the of abuse. Cocaine on the upper right hand corner, has the extra punch of the stimulant and jumps the dopamine level of the nucleus accumbens to over 300% of its baseline. Enter the and the methamphetamines, look at the y axis of this graph. And jumps the dopamine level at the nucleus accumbens over 1,000% of its baseline. Crystal methamphetamine is hypothesized to jump the dopamine level of the nucleus accumbens to several 1000% of the baseline, given the context within which it is used, and the dose also of methamphetamine that people use.

10:26 Now, this has clinical implications. Because before crystal methamphetamine came to town, a big part of addiction treatment was to convince people that life in sobriety will be as exciting, if not more exciting, than it was when they were drinking or drugging. That was a big part of addiction counseling. That's how I was trained back in the 20th century, in addiction psychiatry. You can't look at a crystal methamphetamine addict in the eye and say, trust me, sex in sobriety will be as exciting, if not more exciting, than it was when you were high on crystal methamphetamine. You simply cannot compete with these kind of spikes at the nucleus accumbens, and therefore we have devised other ways of talking with our patients. And we talk about trade offs. Sure, you're not going to have this kind of sex again, if you want to be sober from crystal methamphetamine. But perhaps, you may want to keep your teeth, or you may want to keep your life, or you may want to keep your children, or there may be other things that are salient, that are important for you instead of using crystal meth. And that's how we do counseling in 2021.

11:49 Alright, some things to remember. And contrast between cocaine and methamphetamine. Cocaine is a quick drug, in and out. Some people hypothesize that crystal methamphetamine did not make it as big in New York City because we want our drugs over here to be in and out. We do what do we do over the weekend, but we have to show up at nine o'clock in the morning, Monday morning, and give 150% of what we've got to our job, a lot of our identity as human beings is defined, it depends upon our work. Which may not be the case in other parts of the country, or maybe not quite as strongly as it is over here. Different theories about why methamphetamine never made it that big in New York City outside of , or of gay men, but that was one of the reasons that it was proposed. Anyway, cocaine metabolizes rapidly, methamphetamine metabolizes slowly. So you expect the effects of cocaine to last an hour or two, while you should expect the effects of methamphetamine will last up to a day. Similarly, not only the highs are higher, but the lows are lower as well. And that withdrawal lasts much longer than with methamphetamine than with cocaine. With methamphetamine you get the terrible Tuesdays, you go out partying on Saturday night, then the idea of the withdrawal hits you around Tuesday. Something of course, that does not happen with cocaine, you can party on Saturday, you can be feeling miserable on Sunday, and then Monday you're good to go again.

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13:47 Some of the other consequences of crystal methamphetamine, of course, we have a crystal methamphetamine mouth, you've seen pictures of that sort. Several reasons, one is the vasoconstrictive effects of stimulants, they clam up the vessels and therefore you end up with less salivation. Salivation is the process that keeps bacteria in check. So when you don't salivate enough, you end up with caries and a mouth like this. The other thing of course is if you're always high on crystal methamphetamine, dental hygiene is not very high on your priority list. Another picture of a woman with crystal methamphetamine within a year and a half. You often see these lesions in the face or also on the forearms, which has to do with . Formication is an effect of crystal methamphetamine, it is a , a tactile hallucination, when you think that ants are crawling below your skin and you start picking the ants in your face or on your forearms, and you end up introducing strep and staph underneath your skin with these obvious lesions that you see and sometimes full blown abscesses.

15:17 Okay, I've been hinting to crystal methamphetamine having hit a gay male subculture quite heavily. And that's very true. And I want to spend some time addressing how crystal methamphetamine made it into our communities, some gay male communities. This is the first poster that was put up in Chelsea, the neighborhood, a gay neighborhood in Manhattan, of course. Back in 2000, a private citizen, Peter Staley, just bought the space and put up this the signs alerting the community to the connection between crystal methamphetamine use and HIV transmission. 'Huge sale buy crystal, get HIV free' was the message at the time. Here's how it goes. You get high with crystal methamphetamine, and that directly results in decreased inhibitions and judgment, while at the same time the sexual sensation seeking and sexual arousal skyrocket. So you have decreased inhibitions, increased sexual arousal, and that results in unsafe sex and HIV transmission. There are other things that come into play as well. One of the most unique effects of crystal methamphetamine is the fact that makes everything about yourself better. I've had quite a few crystal methamphetamine patients who would report the exact same thing. They stand in front of a mirror, they look at themselves, and they are more handsome or their muscles are bigger, their penis is longer, taller, whatever they want to think of themselves, everything just becomes better. And of course, that results in increased socializing and it is a very pleasurable effect of crystal methamphetamine, but also in increased sexual arousal and sexual connections. It's not that these patients do not know about safer sex guidelines. They just in the context of crystal methamphetamine intoxication, those guidelines go out the window. We do not know what exactly is going to be the situation with PrEP and PEP, primarily of course with PrEP, and how that will affect the balance of inhibition and judgment, as well as sexual arousal. My hunch is that, of course, being on PrEP is a great idea if you're being sexually active, but I wouldn't be surprised if the crystal methamphetamine use may have a negative effect on how adherent people are with PrEP regimen. Alright, we don't have the evidence in that. So something that is helpful with crystal methamphetamine when it comes to HIV transmission is the fact that crystal methamphetamine gives you , what is often called the crystal dick problem, which is a euphemism, it's anything but. So it's a built in protective mechanism of crystal methamphetamine, you get high, you want to have sex, but you cannot really perform all the different positions you may want to do. I don't

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know if people remember back in the early 2000s, the whole thing of who is top and who is bottom became huge in the gay male community. Not that it still is not today, but back then it really was a very big issue, primarily because people who were high on crystal methamphetamine could not assume the the top position because of the crystal dick problem. Enter . Sildenafil is commercial name of Viagra and the other erectile dysfunction agents, being a big one with the commercial name of Cialis, and the problem of erectile dysfunction went out the window. So people could get as high as they would want and not have any problem having sex, therefore eliminating the protective mechanism inherent in crystal methamphetamine. And of course that is something that people have associated with a sharp increase in HIV transmission that we saw in the early 2000s. This is the work of Perry Halkitis, who's now with us at Rutgers. It's a complicated slide, but I really wanted to include it because Tina, by the way, is the nickname for crystal methamphetamine, one of the nicknames of crystal methamphetamine, Crystal, Christina, Tina. So when you are on crystal methamphetamine, then a lot of safer sex guidelines go out the window. And people who know that they're HIV negative, engage in sex with HIV positive partners or who have an unknown HIV status, and they engage in much higher rates of condomless sex, that was data from 2005. Again, it would be wonderful to see what would be like in the context of PrEP.

21:06 So that was back in the early 2000s. And I love this this title here from a CNN report, 'While America wages war on opioids, meth makes its comeback.' We do have crystal methamphetamine comeback situation over the past two or three years, which keeps on going up and up and up in terms of individuals using crystal methamphetamine. And this is the most recent data that was released only five months ago from SAMHSA, showing that the older population, 26 and older, keep on using more and more and more crystal methamphetamine and not so much of a difference in the younger populations, but 26 and up we are seeing a sharp increase. I don't know how much I believe this slide here. It's an oversimplification of the issue, but I couldn't resist putting it up because it does focus on the major concern. The major concern in the East is . The major concern in the West is methamphetamine. However, the majority of methamphetamine is very often cut with fentanyl, and fentanyl very often comes in preparations that are sold as . So the heroin is contaminated with fentanyl and methamphetamine is contaminated with fentanyl. Therefore, if you have a patient who comes in with a methamphetamine intoxication, and they tell you, 'I have just done meth, I haven't done anything else I would tell you Doc,' you still give them with the commercial name of Narcan or some other form or Naloxone in case their methamphetamine was mixed in with the fentanyl, with opioids.

23:16 Alright, so we have crystal, we have sex. And the third partner is technology. Crystal, sex, and technology make an explosive combination, where it's very easy to get crystal and sex through sites and apps. It's pretty much a click away. Most of us feel that this is a matter of access. And so making it so accessible results in greater use of crystal methamphetamine and greater sexual encounters. A friend of mine by the name of Steve Leer, wonderful psychiatrist here in New York, proposed the Variable Intermittent idea, he never wrote about it. He talked about it, I wish I could have a reference for you, but he basically said the following he

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said, 'it is not that you have so much access to through the apps and the sites, it's actually the opposite. If you decide to date on the apps, your life is one of constant rejection. You constantly reject people and you constantly get rejected, only occasionally and intermittently and infrequently and unexpectedly, pretty much, you have an event where actually something happens.' And back from psychology 101, this is the best way to perpetuate that behavior. This is the best way to avoid extinction of a behavior. This is how we get hooked on things, if you think about internet gaming and all kinds of other technological , very very careful as to how to give you the little pellets of reward so that they can keep you hooked up. So, I don't know, it's another possibility of the beast. Of course Grindr being the granddaddy of the apps where people hook up, I'm sure like, everybody knows what a Grindr is. But if there's one or two people in the audience who may not, it is a GPS based app that tells you where somebody else who is also on Grindr is around you, you can send them pictures, you can send them all kinds of information, and then get information back and see where you go from there. You can just walk down Eighth Avenue in New York City, and find somebody right there and then. This is Joel, the founder of Grindr. This is his own page 16, kind of a timid one. He has since sold Grindr to a Chinese firm. And Grindr of course, doing very, very well. Blendr was the original lesbian app. It didn't take off, we're not quite sure why. And then Blendr switched to being everything, you know, gay, lesbian, bisexual, straight, and did well.

26:37 And in 2021, of course, we have very specific apps that cater and target specific populations, as you can imagine. Scruff, primarily for people who are attracted to people with facial . And what's interesting to me is towards the bottom there, the straight dating apps for gays, like for example, Tinder. Tinder is becoming more and more popular among gay men, who may be looking more for a combination of sex and romance, where some of the other ones may be more sexually focused. Just in case, anybody in the audience here thought that this was anything extreme or anything outside of mainstream, let me assure you absolutely not. As a matter of fact, the majority of lesbian, gay, bisexual people date on sites and apps. 55%, as you see down here, and this is 2020 data. 30% of US adults date on sites and apps. When it comes to LGB, then that jumps up to 55%. And as you can imagine, it is very much a generational issue, where the younger you are, the more people dating sites and apps. This is a picture I took in Manhattan, and it's an ad for a soft drink. And it says 'your taste buds will always swipe right,' a direct reference to these dating apps where when you swipe right you like somebody, when you swipe left you don't. So just want to make sure people recognize how mainstream this dating world is.

28:31 Okay, let's move on to some treatments focused on methamphetamine. First of all, that's way back. It kind of reminds us some of Nancy Reagan's campaign ',' I don't know if anybody really remembers here, but would have this idea that here's your brain and here's your brain on drugs, and it had some eggs and then they had the eggs being fried. And once you fry your your brain, then you're a goner, and you're done. And that was the idea. Well, we've come a long way since then. And it's not that you fry your brain on the drugs, with protracted abstinence from the drug, in this particular case, 12 month abstinence on the bottom panel, the colors of life come back both literally and figuratively. So there is certainly hope and we're

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amazed by how much our body is forgiving, and how much it restores itself. Not completely. And depending on the drug, , for example, may not be quite as forgiving as let's say cocaine. If you don't get a , if you don't have the heart attack from cocaine, it doesn't eat up your tissues the same way that let's say alcohol does or as we saw last time with ecstasy and by extension, the methamphetamine.

30:15 So with treatment, what treatments do we offer? Nothing in terms of medications. This is the common theme among all stimulants that we do get things that are promising and encouraging and then they fizzle out. Similarly for crystal methamphetamine, but psychosocial treatments have been quite effective. The most celebrated model is the Matrix Model. And there have been other ones that are based on the same concept. So essentially, the Matrix Model is the kitchen sink, everything that we know that has worked in addiction treatment, we put them all together and hope for the best. No, it does work quite well, individual psychotherapy, group psychotherapy, family , Crystal Methamphetamine Anonymous. Let me just stop at the Crystal Methamphetamine Anonymous for a second. As with all 12 step programs, its quality is very geographically dependent, very geographically dependent. AA is very big in New York and very consistent and very strong, Anonymous NA not quite as much. You go down to Florida and Narcotics Anonymous is huge over there and very well organized, and you ask them to come and hold the group in your facility and they will. Which you know, it's kind of a little bit dicey here in New York, I'm not bad mouthing anybody, but this is my experience. So it does depend on where you are and how well organized and how consistent some of these programs are. Again, my experience with Crystal Methamphetamine Anonymous in the city of New York has been mixed. Some people got some great results from it. Other people address the other groups as more of a hookup places, rather than actually doing the work of recovery. So Crystal Methamphetamine Anonymous, I do recommend to my patients, but I keep an eye on it. And I do ask my patients what their experience has been with CMA. And of course, treatment of co- occurring disorders, psychiatric and other medical disorders. What I left out is and I left it out for very good reason. Because contingency management has been the underappreciated, underused treatment for stimulant use disorders. It's a wonderful treatment, it has changed people's lives around and is not used quite as much. What is contingency management, otherwise known as vouchers. Classic addiction treatment of the 20th century was like this, you use use use use use, you come to me for treatment, and the moment you come to me for treatment I fully expect that you're going to stop using. If I catch you with a positive urine toxicology examination, there'll be consequences. I may ask you to go to more groups and more hard chairs and more things that drive you crazy. And if I catch you for a second time with a positive urine, there will be even more severe rules applied to you. And if I catch you for a third time with a positive urine boom, you're out of the clinic, you're discharged. That was all the thinking. Contingency management turns this whole thing to it's head and says the following, you use use use use use, you come to me for treatment, and the moment you come to me for treatment, I fully expect that you're going to continue to use. If at some point, I find that you have a negative urine, that's when I'm gonna reward you. That's where you get the vouchers, that's where you get the goodies. And if you're able to string together several negative urines, you get even a bigger reward. And that has been shown to be very effective treatment, both for people who need the money and the people who do not need the money. It

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cuts across socioeconomic strata, it is the gold star that you've done something right. That is the active ingredient in the intervention.

34:42 Okay, something that we've worked with, in terms of psychotherapy, with our gay male populations, and that's one way to think about it. Of course, there are all kinds of different sexualities, but if you want to simplify things in gay and straight, you can think of four different dyads, four different permutations there between a patient and a clinician. The discordant ones are pretty straightforward. You have a gay clinician with a straight patient, or a gay patient with straight clinician. And there is an issue of, you know, can we understand each other? Are we on the same page? That's understandable. What is a little more confusing or a little more challenging sometimes is what happens when you have a gay clinician with a gay patient. I'm very openly gay, people Google me right away, people know that, people come to see me, you know me as a gay psychiatrist. So there's been no questions about my sexuality and a gay patient usually would be very open about that as well. Now, of course there is a rapport, there's something good about that, we feel that would come from the same culture and that's a good thing. But we're also subject to what is often called as bright spots, as bright spots, and that is when we may take shortcuts in psychotherapy because we feel that we know each other, and therefore, you can bypass some issues. For example, coming out, our patient may start talking about coming out and it's tempting for me to shake my big head and say, 'yes, I know exactly what you mean, you know, I had to come out myself. You know, of course I know what you mean, let's move on.' Meanwhile, my patients coming out experience can be dramatically different than my coming out experience, and we miss an opportunity to really explore my patients individual circumstances by these bright spots. You can think about a straight patient with straight clinician having some blind spots, where homoerotic material may be showing up in psychotherapy through dreaming or through bromances, through all kinds of ways, and both the patient and the clinician may be shying away from having a blind spot to any kind of homoerotic material that may be coming up.

37:11 Some ideas about what themes come up in psychotherapy. And finally, some ideas about again in psychotherapy, this is an analysis of the research data in terms of sexual attraction. On the y axis, we have a measure of substance use disorders. And on the x axis, we'll have a Kinsey like down of the of sexual attraction. The shape of the curve is very similar among men and women. So let's just stick here with women. Green is totally gay, or lesbian in this particular case. Yellow, totally straight. Red is bisexual. And then we'll have these very interesting areas here, where people are almost gay but not entirely, or almost straight but not entirely. And it seems that these people who are almost straight but not entirely, or almost gay but not entirely, may be at the highest risk of substance use disorders, in which case, psychodynamically oriented psychotherapy unpacks these internal models and this internal sexual states may be most helpful to these people decreasing stress, and therefore decreasing the need of drugs. We are not sure if that's really the case, but this is something that we're working with.

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Okay. Prevention. This is our attempt to primary prevention, it is essentially scare tactics where we went out there and we told people don't use crystal meth because you're gonna end up like this guy. And it was pretty successful, people kind of took to these ads, and that was great. And then we went on to a secondary prevention campaign, where we, essentially, secondary prevention doesn't address, the general public addresses people who are already using and essentially tries to prevent progression of the illness to the more severe form. So we said, 'okay, if you're using crystal methamphetamine, come to us, we'll give you this wonderful treatment, and you will end up crystal free and sexy,' Terrible idea, absolutely terrible idea. The community was up in arms against us, and they were absolutely right. Why? Because when you launch a campaign like this, you think that you're only targeting people who are already using crystal meth. But in fact, you're really addressing the entire population. And there are a lot of young people who look at an ad like this and say 'what this tells me is that I can use all the crystal methamphetamine in the world that I want, and if it ever gets a little too much, no big deal, I'll go to the good doctor Levounis and his program, and he's going to make me crystal free, and I will emerge on the other side and I'm going to be rich, and famous, and sexy and beautiful, and all the wonderful things in life are gonna come my way.' Terrible idea. That's exactly why we don't allow celebrities to go to high schools, and say things like, 'I've used so much cocaine when I was young, and now I stopped and I'm very, very happy.' These used to happen like 10-20 years ago, we used to have Darryl Strawberry and other celebrities go into high schools and tell their own story, and try to tell the kids not to use drugs. Terrible idea. All the kids would see is somebody who's successful and healthy and had a drug history, and therefore the path to this kind of success is through drug use.

41:02 Alright. Let's move on to bath salts. I'm looking at the time here a little bit, but crystal meth is the main thing I wanted to cover today. Here it is. Yet another white powder, bath salts have nothing to do with bath, very little to do with salt, just a marketing ploy to make it sound as if it is something that is very benign for you. Meanwhile, they're not benign at all. They give you what crystal methamphetamine does, actually gives you more what ecstasy does, plus a lot of sexual arousal on top of that kind of placidity that we saw with with ecstasy. Okay, here's the molecule, I hope that you recognize right away. This is the one of the first bath salts of came the , the phenethylamine, and all we had was stuck a keto group on the beta carbon. The other way of calling bath salts is derivatives. I had a picture of cathinone, this is the cathinone, the original molecule. And if you start playing with the molecule and changing a few things, here or there, these are called cathinone derivatives. What is common among all bath salts is that they have this here, this keto group on the beta carbon. is the original original original molecule. It's naturally found in Ethiopia and Saudi Arabia. It is here, it's a leaf that people chew, and they get high from it. People who have watched Captain Phillips, the movie, they may remember the pirates, that they're constantly chewing those leaves. This is khat, which is a version of bath salt. And if you remember, towards the end of the movie, that supply of khat is cut, and therefore they're going to withdraw. And that has consequences on how the movie ends. And I don't want to give it out, but they are pretty miserable as they were withdrawing from the bath salts.

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What are we seeing intoxication. 'Hey, I just mentioned this is crazy, but I'm on bath salts and your face looks tasty.' Whenever you see on the internet, those clips where people go absolutely bezerk with drugs and on some occasions, you know, kind of cannibalized other humans and all that. Bath salts, cathinone derivatives, are often behind it. So very dangerous chemicals. Here is the British experience. It's a complicated slide, but I want to point a couple of things. It compares the bath salt with cocaine and ecstasy. So what we see here in terms of the pleasurable effects, the bath salt is as good as ecstasy and better than cocaine. In terms of strengths of effects, it is as good as ecstasy and better than cocaine. Value for money, as good as ecstasy and better than cocaine. But when it comes to urge to use, which is another way of saying how addictive they are, the bath salts are as addictive as cocaine and much more so than ecstasy. So the way to think about a bath salt is that it gives you all the pleasurable and fun and relatedness of ecstasy, plus the addictiveness and the urge to use of cocaine. And of course, the chemists can go wild, if you remember this is ecstasy here and then you stick this keto group on the beta carbon and you make this chemetic molecules. This is . Very popular in the US. This is Methylenedioxypyrovalerone, which is another one probably the most popular one, MDPV. You get these chemists and they start doing all kinds of crazy things.

45:18 And here's a couple of words about the beyond part. There is a Russian chemist by the name of Sasha Shulgin, who he and his wife manufactured, synthesised, and tried all kinds of phenethylamines, these molecules that we have been talking about today, and they published a big book sold on Amazon. If you like it, with a title of Pihkal, stands for 'Phenethylamines I Have Known and Loved,' and gives you the recipes of how to make them and it gives you a description of what you should expect from them. So there are a whole arrays of molecules that can be built on these phenethylamines. There is a wonderful documentary on Netflix called Dirty Pictures, and this is the life of Dr. Shulgin, here he is in his lab manufacturing all kinds of analogs, as they're often called, of methamphetamine.

46:28 Alright, so we came to the end. And here are the five things that we'd like you to remember from the two parts, the didactic parts of the sequence. For caffeine, remember that it's an antagonist to adenosine which is a drowsiness master of the brain. So by antagonizing the drowsiness master, then you end up getting the pep and the excitement of caffeine. Cocaine, the prototypical drug, this is the one that floods the brain with dopamine by blocking the reuptake of dopamine in the synaptic cleft. Best way to think about ecstasy as half a mild stimulant and half a mild , not as high as cocaine, not as hallucinogenic as LSD, but somewhere in between. On the other end, you think about crystal methamphetamine as the turbo cocaine, it does what cocaine does only bigger. The high is higher, the low is lower. The high lasts longer, the low lasts longer. Everything's bigger with crystal methamphetamine. And finally, in terms of bath salts, the cathinone derivatives, the best way to think about them is that they're as pleasurable as ecstasy, but as addictive as cocaine. Alright, and with that, I want to thank you, I think we'll have about 10 minutes for some questions.

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Great. Thanks, Dr. Levounis. We do have a question here in the chat. And then I just want to encourage all participants to feel free to type in their questions. So it says people who use IV heroin and cocaine, this affects their brain and cognitive impairment, right? It's a question. And then she wants to know those who stop and get and stay clean, twenty years later, is there a legacy effect so that the effects on the brain of cognitive impairment persist?

48:34 Okay, I'm just make a general comment about drugs of abuse, and then I'm going to talk specifically about stimulants. Think about the effects of drugs on the brain in two major categories. One is the addictiveness of the drug, of how permanent the addiction stays in the brain for how long the propensity to roll back to using stays in our brain. And the other one is the direct toxic effect of the drugs in different tissues of the brain, how much they chew up different axons and different parts of the brain. In general, in 2021, we are very impressed by how much longer the addictive effects are on the brain. And we are also quite impressed by how less permanent the toxic effects are on the brain, as a general rule. Now specifically about the stimulants, think about them in terms of cocaine versus methamphetamine. With cocaine, what cocaine does in the brain essentially, it constricts those arteries. So it may give you a stroke. When you have an overdose from cocaine, you can absolutely get a stroke and you know have very significant consequences from that. You can also get , you can get status epilepticus when you go into seizures, and you can have very significant consequences from that. But it doesn't have chewing effects in the brain, meaning that it doesn't have toxicity that dissolves particular parts of the brain, you either get the stroke or you don't. You either get the status epilepticus or you don't. And if you don't, then the long term effects to the brain due to cocaine are not quite as pronounced, most likely, you're not going to have much in terms of attention or cognitive dysfunction as the question suggested. On the other hand, with amphetamines, we do think that because of that second mechanism of action of directly releasing the chemical in the synaptic cleft, they may have a significantly higher direct neurotoxic effect.

50:51 Thank you, Dr. Levounis, we have two more questions coming up in the chat. And the first is how does mixing meth with fentanyl change the experience of crystal meth? Will it change how often a person needs/wants to use?

51:07 Okay. I mean, you want to get high. If you want to get high, why would you put like an into the mix to cut down your high essentially, when obviously, opioids makes you mellow, make you kind of take the anger away, take the volume of the world down. It seems like you know, you're posing to different things. Well, what the opioids do in the stimulant preparation is they cut down the jitteriness of the stimulants, you get high with any of the stimulants and you feel a little kind of buzzed, you feel a little jittery, you feel like a little bit out of your skin. And if you have a little bit of an opioid into the mix, it's a much smoother, it's a much sweeter experience than just be the stimulant alone. I don't know if people remember or have seen in dance floors, when people get high on ecstasy and they sometimes vomit. They have a projectile vomiting on the dance floor. And people you know thought originally that this was a direct effect of ecstasy, it

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is not, it is most likely the effect of opioids that were mixed into the ecstasy pills. And of course, opioid intoxication in opioid naive people would have a projectile vomiting effect. So this is what the dealers do. They're very, very smart. And they're very clever, I should say, and they try to make the product as appealing as possible.

52:44 Another question in the chat, Dr. Levounis. It says what is the best treatment for bath salt intoxication in an acute setting?

52:53 Okay, what we do want to avoid there is medications. We avoid primarily because of the risk of seizures. As you know, the antipsychotic medications lower that threshold. So, we don't want to do that. So do use , we do use a lot of Lorazepam. We do use Clonazepam, we do use these kind of medications to cool people down. In fact, when we need to give massive dose of benzodiazepines to patients to calm them down, either from or from bath salts these days, we always have a syringe full of flumazenil next to the bedside in case we overdo it, in case we suppress the respiratory system so much with high dose benzodiazepines that we need to reverse the the overdose, the overdose with the flumazenil. I've never used it. I've never seen it used. I've never seen flumazenil used to reverse too much benzodiazepine to treat bath salt intoxication, but I've certainly seen it stand by their bedside in emergency medicine settings.

54:14 Right, we have two more questions that I think we can tackle in our minutes left. Someone mentions that they read research that states the urge to use cocaine last 10 years after cessation. Is this true? And do timelines like this exist for other stimulants?

54:36 Great question, a very important question. We don't know how long the urge to use a particular drug stays with us after cessation of use of the drug. Some people, including myself, think that the majority of people will end up keeping this increased vulnerability to go back to using pretty much for that rest of their lives. Even you know, when you haven't used cigarettes for 40 years, you're not at the same level of addictive potential, of addictive risk, as somebody who has never smoked cigarettes before in her or his life. It's a controversial issue. Some people feel that actually with extended sobriety, with extended abstinence, you may bring back your brain to exactly the same state as you were before you used the drug at all, controversial topic. But what we are sure about is that it's not a matter of months, it is not a matter of years. It is going to be a matter of decades, if ever, your brain goes back to having exactly the same addiction risk, as if you haven't used the drug at all. In my mind, again, I don't have that much evidence to support it, but the hijacking of the pleasure reward pathways of the brain is quite permanent in your brain. It gets better and better and better and better, but maybe never go to exactly the same as if you haven't used the drug.

56:07 And our last question is, why is fentanyl getting mixed in other drugs?

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56:14 I think we've just addressed that, it's to cool down the jittery effect of too much stimulant. Just so that you know, there are medications in in research and development right now, where if you use cocaine and you're on that particular medication, disulfiram, more specifically, you get too much dopamine in your brain, you get so much dopamine that it becomes unpleasant to use the cocaine and therefore you stop using cocaine. So there is something to using too much stimulant and getting people in a state of when they are not particularly happy with it.

56:50 Great, thank you, Dr. Levounis. Thank you. Take care and have a great day.

56:55 Bye, everyone.

[End]

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