It's nice to see you. I know it's the end of the conference. We got kind of in the last few slots here, but we are so happy you came. We're interested in this topic. You look great. You all look great. Thank you. So we're going to talk about nootropics, which are a huge family of drugs. And we're going to talk about some of the challenges and addictive potential of these things. And if there are words you don't recognize in these slides and what we're talking about, then we've done our job. Because these are the weirdest chemicals. These are the hidden chemicals. These are the things that pop up in the drug supply we know nothing about. And these are the things our patients are buying online that we know nothing about. So I'm Jeremy Welliffe, addiction psychiatrist, instructor, and public psychiatry fellow at Yale. We have a panel here. The chair, Akila Nand, program director at Case Western UH Cleveland Clinic, addiction fellowship, medicine and psychiatry. And Julian Refool, addiction psychiatry fellow at Vanderbilt. And we have no disclosures, but we're open to them. I think this is ripe for a documentary or something. Anyway, I hope you have fun. I passed it around. There's a survey associated with this. It's totally anonymous. It's really quick. I see a bunch of you doing it already. Thank you. It's just because no one knows. These have been out of the light of addiction psychiatrists and other people's eyes. We just want your opinions, what you know about these things, how you feel about them, should they be regulated more or less, and some of the conflicts there. We also want this to be practical for you. So we're going to talk about the pharmacological aspects of these. So if you're a master psychopharmacologist, I hope you have fun. We're going to talk about the psychological reasons people use them and their effects. The three, we're going to talk about Phenibut, Tyneptine, Kratom. You may have heard of, you may not have. You might have patients on it that told you. You probably have patients on it that didn't. And we'll talk about all of that. They have consequences. We'll talk about those. I hope you leave with the practical guidance you need to be screening for herbal supplements, dietary supplements, things on the clear web, things on the dark web, and have a better understanding of what those are and what those mean. So. Being an astronaut is probably the most difficult job. The physical and psychological stresses put on the body go unmatched, probably within a few seconds. I can't imagine the pressure of being launched into space and the adrenaline and G-forces felt. But, you know, and there's a long history of space exploration and many important events. Some even more important than the Apollo 11 here. And one of those most catalyzing events of the space race was the acts of this gentleman. This is Yuri Alexeyevich Gagarin, who was famous for being the Soviet cosmonaut who was the first human in outer space. And this ignited the space race. This was JFK's great speech. And everything came after this, right? So this is 61. This is his capsule that he did it in. The Vostok 1, 108 minute orbit around the Earth in this little thing. Few people know it, but this was a cosmonaut supply kit that apparently they carried with them on these missions. Packed with a pistol for fighting off extraterrestrial life forms. All of the medical supplies and other things you would need to survive out there. And as the story goes, one of the most important items in this kit was a medication called Phenibut. And I don't know if that's actually the case. I don't know if that's a true story, but that's how it goes. And I don't know if Yuri had this with him on the Vostok 1. And I don't know if any Soviet cosmonaut actually had it or if they had actually taken it. But that doesn't matter. Because this is the story being used online to sell Phenibut. The mother of all marketing ploys. And they're selling the hell out of it. It is advertised with dietary supplements and body building. And it is in this very loose family of nootropics or smart drugs. And these are claimed to enhance all of human physical, mental, cognitive capabilities. And it is amazingly convenient to get. It is as easy as putting a search, going on Google, doing a search, picking your favorite supplement provider, mine's Paradigm Peptides. I have no disclosures again. And putting it in your cart and checking out. And that's how easy it is to get. And of course, people would be driven to these things. Life is hard. Life is particularly hard in 2023. And there are a lot of demands put on us. Internal and external demands. There are many things we do. Modern life is difficult. And so whether it's the physical demands or the cognitive demands or the mental, emotional demands of today, of course, people would take these things. They want to feel better. That's why they come to us in the first place. Maybe we're not the most accessible. Google is definitely accessible, right? I need something now. Phenobut is interesting for those reasons. But it's also interesting because it still is prescribed in Russia and some post-Soviet Eastern Bloc countries today with indications ranging from alcohol withdrawal, insomnia, and anxiety. So it comes not only with the approval of the cosmonauts, but with other regulatory agencies. And it's a really interesting chemical. And you don't have to be a master psychopharmacologist to see its similarity to medications we use. So this is GABA and GABApentin. Based off that GABA backbone. This is Baclofen. And that's Phenobut. And Phenobut is much, much, much like Baclofen. It's a GABA-B agonist. It has a little bit of GABA-A activity. And it hits dopamine. So it's a perfect addiction chemical. This is excellent. This is a perfect combination. At higher doses, it causes euphoria. People rapidly develop tolerance to it. And it's difficult to treat rebound anxiety and withdrawal. And we'll go into all the details of that. But just kind of keep that in the back of your head that it doesn't come without risks. And as you look across the case reports, you have everybody using this. You have a huge group of college students looking to ace their exams, of course. You have the older adults looking to stave off cognitive decline and be functional and physical and happy into their later, later, later years. To the neonate, who had a difficult withdrawal syndrome after her mother was unknowingly taking Phenobut. So across the entire lifespan, you see these. So college age, newborn, college age, older adults. We have problems with addiction, adverse events, falls, all these sort of things. We'll go and overdose and toxicity deaths. And we'll go over all the details of these. And Phenobut isn't the only one. We're going to talk about Kratom. If you haven't seen patients with Kratom already, we'll teach you all about that. Tyeneptine, which is another extremely interesting chemical. Similar story to Phenobut, where it's prescription in France and some other countries. It's a TCA with mu-opioid properties. Again, what a great combo. And what do you do when someone... Oh, the great thing about this one is you can buy it at gas stations. So, in America. So it's, again, perfect. Just perfect. This is the tip of the iceberg. These are available on the ClearWeb and gas stations and these sort of things. We have this huge underbelly of the dark web that you can't just Google. But some of our patients definitely know how to get on the dark web. These are things where designer benzodiazepines live and designer stimulants and all these other novel psychoactive substances live, etc. Of course, you all know this. I'm not going to belabor this. The opioid epidemic is really, really bad. I don't know if maybe that's the point. But in the group where these have really spiked, of course, are those with synthetic opioids. Synthetic psychostimulants and other stimulants. And in that group is the novel psychoactive substances. And everything from Etazolam, which has been in that toxic drug supply for many years, is a benzodiazepine from Italy, Japan, etc. These exist. Other medications that look similar to ones we would prescribe, like Flubromazepam and other mouthfuls, designer benzodiazepine that never was tested, was never made it onto the... never met regulatory requirements, found in the supply here as early as 2012. This one's fun because it has a half-life of over 100 hours. So you're detoxing people, and they're using these things, and what do you do with a benzo that's lasting that long? Luckily, this is the one thing I thank the pharmaceutical companies for, is that benzos, stimulants, and opioids, we have ones that do everything. We have short-acting ones, and we have long-acting ones. And so you can mix and match to find your right balance. So you can treat this stuff. The nidazines, if you haven't heard of them yet, they're going to be the next ones in the news. They're starting to pop up there. These are synthetic opioids. These are in the supply, etc. All of these names, just under the surface, the pentolones, synthetic stimulants. Your patients are already taking these. That's the message here. And we need to be asking about, screening for, and knowledgeable about them. And also have the data ready, or the treatment guidelines in place for them. So, Phenibut. I'm going to go over Phenibut, and then the guys here will do Tyneptine and Kratom. We'll talk about the regulatory aspects. We'll talk about practical aspects. Some of this stuff I've already gone over. All of the data that I'm going to talk about, our little group did a systematic review of all of the published cases of Phenibut that were in the literature. So this is a summary of all of that. This is the most up-to-date guidance on who is taking this stuff, why are they taking it, what their withdrawals look like, because that's fun, and how to treat it. So Phenibut, half-life about six hours, onset's about two, three hours. It's typically taken, like you saw, you can buy the tablets, but it often comes as a powder or fine crystals. So people will buy it, mix it in their drinks, mix it in other things, and take it that way. So dosing can be really tricky for our patients. It is prescribed 0.25 to 0.5 TID. So that's a 1.5 grams a day total. So remember that, 1.5 grams a day total is what the Russians have said is safety, with relatively low adverse event rates amongst the randomized clinical trials for this. So GABA-B receptor agonist, why is it appealing? You'll find a lot of reports of this. People will be using it to kind of self-medicate social anxiety is what people commonly say. They get a little bit of relaxation from it, etc. Others will say they're using it for insomnia. At the higher doses, you get that sedation. But many folks find it, in trying to balance this GABA system with alcohol and benzodiazepines and etc., will go over a case of that where it gets really muddy really fast. People say there's a dose-dependent effect. So at lower doses, they find more stimulation with it. They're more tuned in. That's where the kind of pro-cognitive smart drug sort of thing might come in. And then at higher, you get the anti-insomnia stuff. Nootropics are a very loose family of drugs. And some are like amino acids and supplements. And then all of these other things, if you want to learn everything about them, David Thoman is the self-proclaimed Nootropics expert. He will send you almost daily updates. And I subscribe because it's a blast. And there's about 102 chemicals he's listed on his website. And there's a great holiday deal. Again, no disclosures. There's a great holiday deal to get like your personalized assessment for which ones might be right for you, etc. So this is what's out there. This is what our patients are seeing. You can get it easily. The other important note, we'll note this with the demographics, but it's also the bodybuilding crowd. So because it's in the dietary supplement world, there's this rumor that the GABA, you use GABA and you get more muscle. I don't work out. You build muscle. That's what it is. And so that's also in the rumors and in the story of this. So watch out for that group also particularly because they might be advertised or reading about this sort of stuff. These are some very clear definitions just so everybody, just so we have a similar knowledge. So the surface web or the clear web, that's stuff that's Google-able. The deep web is that funny space where like government documents live and your electronic medical record lives. So it's sort of connected, but it's really hard to access or behind all these like million logins and passwords that change every couple months and it's really terrible. Anyway, and you have the dark web, which is this, all the bad stuff happens that the news writes about. So this is the place you can go on there and there's drug retailers that can just, you order it and they ship it to your house right away and sex trafficking and child stuff and all that other bad stuff. That's where that space happens. That requires a level of technological skill that many young people may have that maybe older generations won't, but things to be watching out for amongst them. Systematic review, like I've kind of hinted at a few times. The group most reported on are males with an average age of 30.9 years. And most people get it online. So about 87% of these case reports published are online. That's where people are getting it. Case here that I hope you enjoy, which is on the other end of that spectrum. So Mr. R was a 68-year-old guy we had on our detox unit who had substance use in his early 20s. He was binge drinking when he was in the army and at times there was some everyday drinking and problematic stuff. And then he had this really, really big period of sobriety, essentially natural recovery. He had this period of sobriety without much assistance, kind of just family pressure and getting married. And he was in non-abstinence remission for a while. In 2016, he sought psychiatric treatment for depression, anxiety, and insomnia. There was quite political tension in his family around that time and political disagreements. That was part of it that was in there. Psychiatrist, he ended up on paroxetine, lorazepam, and temazepam, and quickly developed tolerance, requiring higher doses, needing benzodiazepines to sleep. You can kind of see the pattern. He then adds alcohol, again, long period of sobriety. He starts adding alcohol to treat his symptoms. He goes to a naturalist and he gets a sleeping pill for his insomnia. It turns out that of the ingredients in this sleeping pill, this natural medicine, was phenibut. He looks it up and he figures out that it's phenibut and he starts buying it online. Just as simply as I showed you and Googled it. He was using it, didn't tell his psychiatrist, didn't tell anybody about it, etc. I think when we saw him, he was on this great regimen of like 100 of diphenidramine, a bottle of wine, 3 milligrams of lorazepam, 15 to 30 of temazepam, and 3 grams of phenibut. So double the highest Russian typical dose. So that's kind of where he's at. This is hitting that GABA-B. He's getting everything, right? Anxiety, insomnia, GABA regulation. That's what he's using it for, just trying to keep that regular. He stops phenibut. There's pressure on him to stop using this. He has a panic attack. He has withdrawal symptoms, etc. He returns to use on and off. His use escalates to 7 grams daily. I think probably as he was taking away other things or not drinking. It's all very difficult. His family notes behavioral changes, cognitive changes, a lot of memory problems, irritability, anxiety. He's hiding phenibut powder in the basement stairs, down in the basement. His family has an intervention. They bring him to detox, and that's when we saw him. Pretty classic picture. Pretty much looks like alcohol withdrawal, course tremor. He had some other mochas on there. We ended up repeating a mocha, which is fine, and there's no cognitive. This is really just the benzos and GABA modulation and phenibut and everything going on. He had an MRI, which was normal. When you look at the data about what phenibut withdrawals look like, these are case reports, but almost 95% of them were using medications to manage the stuff. Most people were using phenibut for about 11 months. The shortest time from start of use to having withdrawals was about 10 days of use, so this is quick. This is the rapid development of tolerance and withdrawal, and use escalates in that very quick pattern with phenibut. The average daily dose is 10.5 grams in the case reports, the highest being 34.5. I think there was a recent case that just beat that record, so people escalate quickly. People will dose multiple times a day. That's also a risk factor just to look out for in general. This is about... The bottom here is what I want you to focus on. This is the withdrawal. I mentioned a little bit about the dopamine and this serotonergic and norepinephrine, this adrenergic rebound. The one thing about phenibut that might stick out, if you have a complicated toxicity in which you do not know what is going on, watch out for movement disorders like this. One thing that you should walk away with is, what does baclofen do? We use it as an antispasmodic, etc. Phenibut is doing the same thing. When you pull it away, 54% of the withdrawal cases were having tremors, dystonia, stereotypes, myoclonus, rigidity, catatonia, and MS, and these sort of things. Look out for those, these physical signs. There's also a pretty high rate of psychotic symptoms being noted in the reports. That I don't really have much of an explanation for. Dopamine, dopamine, something, something. But I don't know. But they're high. And visual auditory hallucinations were pretty common, which is surprising. Because I don't think we see that with baclofen. So anyway, when you're stuck, think about these, is what I'm getting to, right? We detoxed him. He had four days in the hospital. We can talk a lot about management, but we used baclofen, phenobarb, diazepam, and lorazepam as adjuncts and as needed within there. Having a lot of trouble with insomnia. We kind of did this naughty thing where we gave him catepine, got it to 100. It helped. It kind of just took care of that. We had to get something on board that wasn't playing with this GABA system all the time, we felt. Got him on escitalopram, got him on naltrexone for AUD slash phenobute use disorder, right? This is a use disorder. He has a lot of comorbid substance use disorders and everything, but we really felt pretty confident this is a phenobute use disorder. You see this in the case reports that are out there. 60% with a concomitant substance use and phenobute. Benzos, alcohol, opioids pretty high, and kratom, which we'll talk about more. About 50% of these have a substance use disorder also, so this is a high-risk group, I think. We should have, as addictionologists, when you have alcohol or benzodiazepine use disorders, etc., be watching out for this. Long-term in the management of phenobute withdrawal, baclofen, all this sort of stuff, right? The GABA-B agonism. Everybody's using benzodiazepines. Antipsychotics. People are intubated a lot, about 50% are intubated. These are very serious toxicities. NMS, one case of death, an overdose we captured. There's a couple more in the international literature. It's serious. Most need ICU care in these reports. Length of stay in the hospital, five or so to seven. We worry about our older adults, just like Mr. R, right? They are at risk. I am encouraging you to ask, routinely ask your patients about these things. Many know how easy it is to get it. The herbal and supplement market is massive, right? This is an $8 billion to $14 billion industry, and only growing. We don't ask our patients enough. That's what all the data shows in all these reports. I'm just going to skip them, because I think we're going to hammer this home. There are large online discussion boards about Phenobut. Reddit slash R Phenobut has an updated guide where they give people specific guidance, which is not that much different than from ours. I went to school for a long time. And it's really kind of fun. And the counterbalance to that is there is a reddit.com slash R quitting Phenobut. And it is recognized in the community, the natural history of this, that this is dangerous. And there are self-help groups and thousands of posts of people trying to help each other print on here. It says print this and give it to your doctor. This is what they need to know about Phenobut in order to treat you. There is a really great community. There is also this community knowledge. The title of this one is when you're a substance abuser and decide to try Phenobut anyway. People know that there is this overlap and this risk. This is just community knowledge. I think that's almost better than what I'm showing you. Other reports. Yeah, this guy was using 40 grams a day, so he beat the record. This is the one I'm going to leave you with. Doctor looked up Phenobut. So I saw the doctor today and he had never heard of Phenobut before, but he graciously looked it up. He seemed quite intrigued by it. I mentioned the gabapentin. He prescribed it based on his search. It was cathartic to come clean about how the substance has insidiously affected my life and how awful getting off it is. Listen to your patients. Look these things up. Find our report. No, cite us. No, just kidding. But the info is out there and you can treat these things, but you're never going to treat them if you're not asking. They're going under the radar. We know they're going under the radar. We'll talk about regulatory stuff at the end. I'll leave it up to you. Julian. Thank you, Jeremy. For those who are coming in, we have the survey that we would like you to complete. Totally anonymous. Part of our study and analysis of the knowledge base behind nootropics. I'm Julian Rafoul. I'm an addiction psychiatry fellow at Vanderbilt. I encourage all trainees that are here to talk to each other. That's how I met Jeremy last December and Dr. Anand. We started working together and we're having a good time behind this, so here we are with our presentation. The substance I'm talking about is tineptine. It's actually a medication. An atypical tricyclic discovered in France in the 60s. It's marketed as Coaxil or Stablon. Some may have heard of this medicine before. It is not FDA approved in the US for prescription use. Interestingly, it's still available online. Like we saw how Phenibut is purchased. You can put in tineptine and I'll talk a little bit about the different names it comes under. Three countries have made it a controlled substance due to the issues I'll mention. In the United States, there are regulations in nine states. I think it's now 12 monthly. It's growing because of the public outcry about patients or people, peers that are taking these substances or this particular medication within an adulterated supplement that Akhil will talk about. The CDC, about five years ago, said that this is an emerging public health risk because of the way that tineptine is available in the US. If you put into Google, you search gas station dope or gas station heroin, you'll find out the words Zaza or Tiana red or Tiana gold or silver, I believe as well. They're substances that are actually, I don't even know what they are. I have a picture here. I'll just flip through the label that says the facts, that are in there. It's like alpha GPC, CDP choline, tineptine, and I can't even pronounce the first line, cornbratum quadrangular leaf. I was curious. I have a background in nutrition and I called the company at the bottom, 888-254-0924, for anyone who wants to call them. And they basically hung up on me because I was pushing to ask questions about the contents, like how much tineptine is in there because you can see on the label, it's not reported. And this is important because as we see here for the pharmacology, the dosing range that is prescribed in Europe is between 12.5 to 50 milligrams per day. And then phenibut and tineptine and kratom, there's Reddit sites that show. And the literature has also shown that patients can take up to five grams per day. And we're currently conducting a systematic review on this. And we've seen up to 10 grams per day, 10 grams versus 50 milligrams. And think about being prescribed surgically in our Zoloft, 50 milligrams, and then you take like five grams to 10 grams of it. And the thought of that, it's just astounding. And then the half-life of this medication is two to three hours. Sometimes patients, when they take it before they're actually feeling the effect of it, they're starting to feel withdrawal symptoms from this medicine, which is why they end up presenting to us. And it's structurally a tricyclic antidepressant. It has an atypical structure. I don't remember much of my organic chemistry days, but there's the structure if you want to take a look at it compared to the nortriptyline or amitriptyline or doxepin. Some of the medicines that we don't usually prescribe first line for patients when they come in, but then TNF team patients are taking like mega doses of this on their own. It's metabolized in the liver. It's renally cleared. It is purported to have an anxiolytic or mood enhancing effect. It's known to have opioid agonist effects. Studies have shown that and possible euphoria at high doses. And that's how patients, when they're self-treating and they look up online different substances to take, then this is something that comes up as could be helpful for them. Some of the side effects that they start to feel when they take too much of it, because they're not taking 12.5 or 50 milligrams, and they don't really know how much they're taking because if they're buying it in the supplements, we don't know what's in there. One pill might have a gram. One pill might have 10 milligrams. We don't know. So they'll come in having some wide reaching complaints like abdominal pain, constipation, dizziness. They might have some dry mouth. Ultimately, they do get addicted to this and they start to have symptoms that are more serious like arrhythmias or liver toxicity. There have been reports of patients succumbing to this. I think about two or three case reports of deaths and calls to the National Poison Control have steadily been increasing, which has led to the public outcry if a loved one has died from an over-the-counter supplement. How is this possible to be bought at a gas station? That's what's led local politicians to ramp it up. It's at the state level, not at the federal level. There is no lethal dose that's established. Again, as I've mentioned, the dosing in the supplements is unknown. Within a week, patients can develop tolerance because of that short half-life. They can have withdrawal symptoms when they present that's similar to an opioid use disorder. It'll be described in the case that I'm about to talk about. They have symptoms where they're not hungry. They have loose stools. Sometimes they have fever, muscle spasms, myalgia, rhinorrhea. They can feel very angry, agitated, hostile, restless. Some get really sad and have tension. The medications that we use to treat them initially are similar to the opioid use medications that I'll mention right here. With this particular case example, I like to highlight this case because in our systematic review, we've reviewed the literature. I have a case series, but this particular patient I see in clinic longitudinally. I've been following her for about two years now. She has signed a waiver for me to talk about her case in more detail. She's 39 years old. She's single, works as a nurse at Vanderbilt. She's had a history of cervical cancer, has struggled with her weight, some body image issues that manifest as anxiety, lots of depressive episodes, not necessarily depressive disorders. She's had some trauma in the past due to unstable relationships. Historically, from her cervical cancer diagnosis, had been taking opioids, developed opioid use disorder, but then had successfully weaned off of the opioids, but had taken Suboxone historically back in the day. That's not how she had presented to us now. She was also known to misuse stimulants in the past. There's a reported history of some attention issues, but not meeting criteria for ADHD. She smokes and has always had a negative UDS every time she would present to clinic, but there's one time she presented and had these opioid use withdrawal symptoms. With her opioid use disorder history, she was very sensitive to being diagnosed with that as active. The UDS was negative. She didn't take any opioids, but had these symptoms. Just based on talking to her and having a good relationship, you end up finding that she's taken an over-the-counter supplement that her current relationship told her would help her with her mood issues. It would help her focus. It would help calm her down and help her do better at work. The substance that she took was Zaza. The bottle that we saw looks like this. Her boyfriend had presented it to her. She would take a couple of pills and feel a little bit better. Take a couple of more pills, feel a little bit better. Then before you know it, she was taking up to a bottle a day. The bottle is not cheap. Their prices vary. I think it's about 50 bucks per bottle. She's taken it for more energy, to feel calm. It helped her focus, but then she started having the withdrawal symptoms really quick. Then within a week or two, she was feeling like, I need to take more and more and more. When she had come for treatment, I listed here a lot of PRNs that we use for patients that come in with opioid withdrawal. We give very standard medicines in the inpatient setting. This could also be prescribed to outpatient like Clonidine, Hydroxyzine, Cyclobenzaprine, Requip or Rapenerof or Restless Legs, Zofran, Bentol, Liperamide, Trazodone, Seroquel, etc. These are all PRNs. They're not scheduled for her, but they were PRNs to help her through the withdrawal symptoms. After we did some research and figured out what she took, I looked up on PubMed and saw that TENeptine misuse or use disorder can be treated with Suboxone. We had another patient that we tried treating with Naltrexone. These are FDA approved medications for opioid use disorder. We're using this because TENeptine has the opioid agonist effect. Naltrexone failed in one particular patient and he was lost to follow up. With this particular patient, she was successfully induced on Suboxone and she had been taking 8 milligrams twice a day for the past 18 months, maybe a little less than 18 months. We did a slower induction with her and she would still have the cravings even on 8 milligrams, but we found 12 to 16 just like OUD was helpful for her. The published reports that I was reviewing when I was starting to follow this patient was this one by Trowbridge and Wally that published in 2019, the use of Buprenorphine Naloxone and the treatment of TENeptine use disorder. Then there was a follow-up study published last year about microdose induction of someone who was coming in with TENeptine use disorder. Just like Jeremy was presenting on Phenibut, you can use TENeptine or Zaza with other stuff. They're not just coming in using pure TENeptine isolated by Pfizer that handed it to them through a doctor. They're buying some random stuff online that could be adulterated with anything or they'll combine it with benzos or alcohol or other polysubstances. This is basically what we're reviewing right now in more detail so that we can understand exactly what the literature is showing in detail and how to treat that so we can provide the community with some algorithmic approaches to treatment for this and our current data extraction is in process. Overall, we are trying to press the message that we must ask our patients about over-the-counter use of anything. Historically, in your past medical history, review of medications, etc., just say do you use anything over-the-counter to help self-medicate or self-treat some of your symptoms or do you purchase anything online because there is no immunoassay or point-of-care testing for these substances and the confirmatory tests are expensive. I'm not going to send the blood sample to do LC mass spec on a patient and if I did, I'd probably get a rejected reimbursement. The patient would be like, why do I have a $500 test and then somebody would end up getting lost to follow up. You know how it goes. Then the studies on the maintenance treatment, we want you to be comfortable to consider naltrexone or extended release naltrexone, consider buprenorphine and there's one report of methadone being used and as I mentioned, we'll be putting together a paper soon to help guide you in your treatment algorithm. And again, survey please, if you will, and I'll pass it on to Akhil. Thank you. Hi guys, so my name is Akhil Anand. I'm an addiction psychiatrist at Cleveland Clinic. I'm also the program director of University Hospitals Citywide Addiction Psychiatry Fellowship Program and I'm a clinical assistant professor at Case Western School of Medicine. Can you hear me? Yeah. Okay. Sorry. So good. That was just my titles. So has, does anybody watch TV here? I love TV. I like documentaries. So this is from the title sequence of The White Lotus. It's one of my favorite TV shows and just like Dr. Welliff and Dr. Rufu, I'm going to talk about a case and I called it the case of the White Mangda. Has anybody feel familiar with White Mangda? Have anybody heard it before? I see a nod. Okay. And so this is a case that I actually did during my fellowship and we did end up publishing it. So I'm going to share it with you guys. So this is Mr. A. He's a 29 year old married unemployed veteran that presented to ED for suicidal ideations. He was hospitalized in our VA psych unit. He has a history of bipolar disorder, PTSD, ADHD, and chronic back pain. At admission, he was adherent to his Abilify Prozac and was also receiving Atarax PRN. He was on therapeutic doses, low doses. So I think Abilify 10 milligrams and Prozac 20. He has also had a long history of substance use disorders. So that's opioid use disorder, tobacco use disorder, and stimulant use disorder. Very severe history, actually has a history of multiple opiate overdoses, and he was currently serving a two-year probation for a drug-related offense. At admission, he reported for the last three months he was using Kratom to address back pain, enhance his mood, to pep him up, and to evade probation-related drug screens. He began using Kratom after completing a court-ordered residential program. He was told by other residents there how it goes undetected in standard urine drug screens and how easy it is to obtain online. After trial and error, the patient reported that he enjoyed the white mangosteen. He initially was using every other day, approximately five grams three times a day, but this would increase over time quite quickly, actually, where he was using every day 30 grams three times a day. His continuous use affected his mood, negatively endorsing anhedonia, amotivation, poor concentration, fatigue, and social isolation. He tried to quit but could not. He endorsed cravings and withdrawal symptoms. Whenever he stopped using, so withdrawal symptoms included insomnia, anorexia, diarrhea, restlessness, worsening mood, worsening anxiety, and thoughts of self-harm, and that eventually brought him to the ED. At admission, he was immediately placed on CALS, started on Clonidine and Hydroxyzine as needed for withdrawal management. Within three days, he was stabilized and discharged home. He was referred to the VA Substance Use Disorder Intensive Outpatient Program for Kratom Use Disorder. At IOP intake assessment, he endorsed depressed mood and still cravings for his Kratom. We increased his Prozac to 40 milligrams daily to address his irritability and depressed mood. He was offered Naltrexone for relapse prevention but he declined. At the end of IOP, we did a LC-MS confirmatory test and we uncovered that both Mitragynin and 7-hydroxymitragynin were still in the system. Those are both the active alkaloids in Kratom. They were in his urine and which conflicted with the patient's self-report that he was Kratom abstinent for six weeks. Sad story. How many of you guys have patients that use Kratom? I follow a dozen patients longitudinally. I also have the opportunity to work on a detox unit, so I get to see a lot of patients over a year and I'm seeing at least seven to ten presentations of Kratom a month. It's become very, very common. Kratom originally originates in Southeast Asia. If you go to Malaysia or Indonesia and you say Kratom, they don't understand because that's not the word they use there. They call it either Ketam, Biak Bak, or Kratom. Primarily, it's found in Thailand and Malaysia originally, but it's really expanded all of Southeast Asia. It's part of the plant called Mitragyno spiosa, which is actually a very tall tree and it grows everywhere. It even grows in water. It goes up to 25 meters in height and has a gray bark. What's really well known is this oval-like leaf, which is actually where the active alkaloids are. It's got this beautiful yellow flower. It's really pretty, but it grows everywhere over there. Particularly, the three countries we're talking about is Malaysia, Thailand, and Indonesia. Bear with me, there's a very interesting history of Kratom in all three of these countries. Malaysia, it's been banned for a long time, so you can't import, export, dispense. You can't use it. I will say because it's everywhere, depending on the region in Malaysia, people are using it, particularly in the North and East Malaysia. Thailand has also an interesting history. It was initially banned in the 1940s because in Thailand, what they were doing was actually selling, the government was selling opium and opiates to everybody and they were taxing it. Individuals were like, you know, we can get our opioid-like substitute that's cheaper, so they banned Kratom. It was a governmental operation. In the 1970s, they made it a Schedule 5 drug, which was still a controlled substance, but it had a lot more leeway. It was like cannabis over there. Now, finally, in 2021, they've now made it fully legal and are now looking at seeing how they can take advantage of us Americans as an economic opportunity. In Indonesia, right now, it's currently legal, but it's going to be banned in 2024. Why that's important is because about 70% of our Kratom is coming from Indonesia. So, folks use it for all kinds of reasons over there, for opioid withdrawal, pain relief, stimulant effects, and as an aphrodisiac. It's really part of, depending on what parts of the countries you're looking at, it's really part of their culture. So, they'll wake up in the morning, they'll take two leaves and oftentimes, they'll either chew it, but most often, they'll boil it and make a tea out of it. It'll start them up at the day, sort of like their coffee, and then they may let the tea cool for a while and then take it to work with them. They'll have it again in the lunchtime so they can get through the afternoon. And on Friday night, they may combine it with some alcohol and Coca-Cola to get a good buzz. But it's really... I want to explain that the Kratom that they're using over in the Southeast Asia is very, very different than what we're using here. It's really part of their traditions and the potency is very, very different. We are using it here as a legal high. The first reports of Kratom were in the 1980s, but really, it's peaked up in the early 2000s. The DEA, for a second, had actually temporarily banned Kratom. They made it a Schedule I drug, but because of lobby groups, American Kratom Association and politicians, that ban was lifted very quickly. It's illegal in Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin. So you can't sell it over there, but like we've all been talking about, it's very easily obtainable online. According to the American Kratom Association, 11 to 15 million folks in America are consuming Kratom. I will say also there was a study that came out in 2019 that showed that monthly 2,000 metric tons of Kratom are coming into the country. So there's a lot of Kratom. And because it's not regulated, we'll talk a little bit about that later, it's often adulterated or contaminated and there's some misrepresentation happening by companies. So my patient liked white mangda. And the question is, what's in a name? So essentially the color is the venation. So you can have a red, white, there's yellow, gold, different types of the stem, the color. And then mangda or sandai or katapang, those are the regions where they're from. And what companies have done, knowing this, giving them this beautiful title name, they've kind of classified these different Kratoms into different effects. They're telling consumers that, for example, white mangda has a stimulant-like effect and will help you get through the day, whereas red sandai has like an opioid-like effect, can help you with your pain. The question is, is it true? So a really nice paper was published by Hussain and colleagues in 2023, like this year. And what they found was that, what they did was really clever. They actually, they tag-teamed with the Kratom producer, the company, and they reached out to their consumers and they sent out a survey. And the respondents actually kind of agreed with the company pitch. They did agree that, yeah, the white mangda was giving me stimulant-like effects, was helping me with my energy levels, and the red sandai would help me with my opioid-like effects. After that, what they did was they analyzed all the products. And what they found out was that the actual alkaloid composition of these places, despite them being from different regions, may have been slightly different, but not clinically significant. So it's like an example of how foolish consumers we can be, and how driven we are by the media, or the businesses. So pharmacologically, Kratom is actually in literature called an atypical opioid, which I like a lot because it does have opioid-like properties, but it's more than that. Dose-dependently, if you give one to five grams at one time, it's more like a stimulant-like effect. Anything higher, you're looking at opioid-like effects. So my patient, for example, initially he was using at a dose that would cause stimulant, but over time he used more and more. And that's something that I have often seen with my patients. If you really like talk to them about how their Kratom use escalated, they will tell you that. They will tell you that, originally, Doc, I was using it to increase my energy levels, but then I later realized that it was helping me with my sleep. And that tells me that the patient has developed dependence. In that leaf, only two percent of that leaf has active alkaloids. So it's very different from what we're using here in America, which is all processed. It's a hundred percent mitragynine and 7-hydroxymitragynine. Only in the leaf is very little. There's over 40 active alkaloids. The most prevalent one is mitragynine, which makes up of 66% of that 2% of alkaloids, okay? And this is an interesting one. It's a partial agonist at the mu-opioid receptor. It's an antagonist at the delta and the kappa-opioid receptors. It activates the alpha-2 system, blocks calcium channels, works on the serotonin systems, dopamine. What's really interesting about mitragynine, and this is what I'll go back, I'll talk a little bit later about its therapeutic potential, it doesn't recruit beta-arrestin. Beta-arrestin is a protein in the beta-arrestin pathway. We see this with opioids. This is the pathway that leads to respiratory depression. So mitragynine does not recruit this. Another drug that we use very often in our practice is buprenorphine also does not recruit beta-arrestin. So there might be some safety utility here. 7-hydroxymitragynine is its metabolite and also it originates on its own. It's a partial agonist at the mu-opioid receptor. It has a higher binding affinity than mitragynine and even morphine. Preclinical studies have shown that it causes tolerance and dependence in animals and studies are mixed whether or not it can recruit beta-arrestin. Kratom in general has a Tmax of about 45 to 60 minutes and has a half-life of about 24 hours. It's metabolized in the liver by the CYP3A4 enzyme. So you guys will probably remember this from medical school. I have actually a couple of patients that if you take Kratom, I'm not gonna ask if you guys have taken it before, but it has a very tangy taste and I have a couple of patients that will take Kratom with grapefruit juice to enhance the effects. I don't know why but it's that sounds disgusting but they will do that. It inhibits CYP2D6, CYP1A2, and CYP2C9. Being an addiction psychiatrist, I really have learned to appreciate my patients' drugs of choice and I've realized that there's two sides to every coin, so to speak. There's been some questions on whether or not Kratom is actually very, there's some therapeutic benefits for it. I will say clinical studies for this has been very limited. I looked it up through clinicaltrials.gov. Right now I think there's three trials happening on Kratom and it's not happening on with Kratom so as much there's a there's a drug that they've kind of synthesized that has a makeup of Kratom called ocrilidine that they're looking at. But in general, human clinical studies are pretty, pretty bad, relatively. Preclinical studies have shown a reduction in heroin self-administration and I believe because of its effects on the alpha-2 system, it may have some benefits with precipitated opiate withdrawal, which are encouraging, and it may have some antidepressant effects. Again, all preclinically. Most of the clinical studies are more epidemiological. People have gone to Southeast Asia and interviewed and surveyed folks. We've obviously had multiple surveys that have been produced online and they have shown some benefits with mood enhancing. The two citations here are great. They were based over in Southeast Asia and they said that folks were using less illicit opioids, less methamphetamine in Southeast Asia thanks to Kratom, and it increases pain tolerance. So it's, there are maybe some potential here. So what do people say that here in America, and I love these two studies just because they're just fun. I've never seen people do this before, but one group of folks looked at YouTube videos and then there was another one that looked using Amazon crowdsourcing surveys, and the YouTube video found that most folks are using it here in America for opioid dependence, addiction, pain, lack of energy, anxiety, depression, other use disorders, mood elevation, and then nootropic effects. Folks in crowdsourcing, there's actually was pretty impressive. They surveyed a lot of people that were just, they just mass surveyed folks, and they found that 13.4% reported lifetime Kratom use, two-thirds after 2015. So really a huge shift in this use. 11% according to the survey met the criteria of a Kratom use disorder. I will say from other studies, I've seen 2%, so this was pretty high. Kratom users had significantly poor psychiatric health and quality of life. They did all sorts of different tests. Kratom users had higher proportion of substance use disorders, and as Dr. Will have talked about, poly-sub is the majority with these patients. Whenever I talk to my trainees, I always talk about, you know, does, is this drug actually, because we see a lot of patients misuse drugs. I've seen folks have issues with the lanzapine and avilify and benadryl, and I always think of, does the drug actually increase dopamine in the nucleus accumbens? Right now, I couldn't find anything that suggests that, but 7-hydroxymitragine seems to show some, in preclinical studies, conditions place preference. I will say for sure, for 7-hydroxymitragynin, mitragynin, the studies have been mixed. So there has to be some type of rewarding profits, and seeing my patient, the one that I gave you an example, seeing others, there has to be some form of true addiction there. Kratom withdrawal. So depending on a lot of factors, most likely the daily use and how much someone is using, patients will develop withdrawal. I have seen patients that use regularly, and they do not develop any withdrawals, but typically if someone's using more than 14 to 40 grams per day, they're going to develop withdrawals. Withdrawals begin at 12 hours out of stopping use, and they can last 7 to 10 days, and this is acute withdrawal. Protracted withdrawal can linger even longer. Typically, if you look at kratom alone, it causes milder opiate withdrawals, but because of the poly sub, most of these folks are using alcohol, opioids, benzos, etc., phenibut, the withdrawals are not so easy to differentiate, but if you had to, you would say that they're milder than opiate withdrawals. We have case reports. That's just one. That's the original case report from a Canadian journal, but there's been multiple case reports at this point that show that kratom can cause neonatal withdrawal syndrome. There's no formal guidelines on how to treat kratom withdrawal. It's basically symptomatic treatment, using an agonist maybe, and I always try to emphasize this. There's so many receptors involved. It's not just classic mu receptors, so you have to bear in mind that it can be a little bit more. That's why I think they have a little bit more of an unpleasant but milder symptoms for a little longer, and yet classic opiate withdrawal symptoms, you see them with kratom. Adverse effects. So overdose and death. Animal studies have failed to find a lethal dose of kratom, and I couldn't find anything that suggested kratom on its own is lethal. However, and I think that's because of the partial agonism and the fact that it doesn't recruit beta arrestin, the primary active alkaloid, but there have been kratom-related deaths, and that's because of combined with CNS depressants. There's been multiple studies that have come out with folks buying kratom and actually buying unfortunately adulterated kratom. Kratom with phenylethylamine in it, kratom with other opioids, kratom products with very high 7-hydroxymitrogene, that's abnormal. There was a huge uproar in the mid-2010s in Sweden where there were people dying and they were taking something called krypton, and krypton was a combination of kratom with O-desmethyltramidol, and yeah, and what happened was that kratom actually inhibits CYP2D6, and so it had very lethal doses of the O-desmethyltramidol, which led to respiratory depression and death. And because of its mu-like properties, if you were to have an overdose on this, theoretically you could use Narcan. Being from Ohio, I did also my inquiry work, and I called our poison control folks, and between 2017 and 2021, poison control was called about 205 times regarding kratom use, and there was three deaths. My county is 32 during that time. Other acute adverse effects. So kratom is not, and this includes mitragynine, is not good for the heart. It causes all kinds of ventricle dysrhythmias like ventricle tachycardia, and that's because mitragynine blocks the potassium channel causing QTC prolongation. We don't know exactly how, but it causes seizures. My understanding is it because it can block calcium channels. Subacute and chronic.

nootropics

Phenibut

Tyneptine

Kratom

cognitive enhancement

addictive potential

GABA-B agonist

dopamine activity

social anxiety

insomnia