Thug Drugs: Psychedelic Studies | Pain Pod

Psychedelics, hallucinogens, natural medicines, you name it, if it has been, is, or will be in a clinical trial, we’re covering it on this episode of the Pain Pod folks! We’ll chat through all types of psychedelics including LSD, MDMA, Psilocybin, DMT, and Ketamine and beyond. No trippin’ just learnin’! You’re not going to want to miss this one! Come one, come all, to the Pain Pod!!! TzrIckmic7Yeigg0uagt

• 0:05Speaker 00

  You are listening to the global network of podcasters dedicated to the pharmacy profession. Welcome to the pharmacy podcast network.

• 0:34Speaker 01

  Welcome to the pain pod. The podcast for all things pain management. Hosted by the pain guy, Dr. Mark Grofely.

• 0:48Speaker 01

  We'll be collaborating with numerous pain management experts talking about substance usage disorders, the latest treatment modalities, and most important, focusing on the pain of our patients as leading providers of pain care.

• 1:05Speaker 01

  And now here's our host, a man wanted in all 50 states, a suburban city like mountain man. Without the beard. From the hills of West Virginia and certified in weapons of mass destruction response. It's Dr. Mark Grofely.

• 1:31Speaker 02

  Welcome back everyone to the pain pod. So yours truly, of course, Mark pain guy Grofely here on the mic as usual. And well, today we have a well, a little situation of a follow-up episode here for the pain pod. Alas, if you did not tune in, listen in or download the last episode of the pain pod that went over our mini series of thug drugs concentrating on psychedelics. If you haven't listened to it yet, no worries, just, you know, download it, it'll be your homework for next time, I guess. That's where we basically went into, you know, a review of the, the substances themselves, the classes, classifications, the groups, you name it. You know, in the big picture there.

• 2:16Speaker 02

  I will say, although perhaps a little bias, maybe a little fun and learning. But what else would you expect from the pain pod, right? But here today, we're going to be going over, you know, continuing our thug drugs mini series and reviewing psychedelic studies. Hey, just kind of rolls off the tongue. But, you know, the big picture is there's been an uptick in the, you know, the bandwidth, the number of psychedelic substances being studied for FDA approval, actually. And, you know, it's one of those classic cases where how many folks actually read the articles, right? You know, not to be the nerd in the room or anything, but it kind of helps out, right?

• 2:58Speaker 02

  And I know my student pharmacist self back in days thinking, oh my goodness, what happened to him? But folks, you gotta read the article. So it was a famous guy back in the eighties, nineties that said it too, with a, you know, a couple of picture books and all that, but it actually is important. So, you know, here though, I fully realize that everybody's time is valuable and not everyone has the time to dedicate to reading every study on the planet, even though some we wonder how that get published and others are like, wow, it's about time that this gets published, right? But in the realm of psychedelic studies, there's a lot of hubbub, right? A lot of perceived to be debatable things. So let's, you know, clear the fog here. To do so though, okay, first off, I'm just gonna spend like maybe two minutes or so,

• 3:43Speaker 02

  very brief succinct review here of, you know, psychedelics, also known as hallucinogens, of course. So, you know, it turns out, you know, as a pharmacist, my usual equation that I came up with of, you know, how, how we operate, how a pharmacist rolls, the things we consider. Okay, how's it work? The mechanism and how much? The dosage, right? Those things lead to safety and efficacy. That's my pharmacist equation, okay, or pharmacology for that matter, you name it. Okay. So when we're talking about psychedelics or hallucinogens, you know, they got some aliases here and some street names we went over last time, right? But, you know, when you think about how they work, you know, the bottom line nutshell

• 4:27Speaker 02

  to review is that, you know, being agonists, generally speaking at dopamine and selective serotonin receptors, getting nitty gritty granular, usually serotonin subtype two and other things. Okay, but that's like the core. And we got to remember that that's basically the exact opposite, but same ballpark as our second generation atypical antipsychotics. You know, that escalated quickly, right? So what we mean there is that the second generation atypical antipsychotics, just say that one, I'm, I'm just going to say it once, one and done. Okay. Those gents are antagonists at dopamine and serotonin, usually subtype two. And again, they have other attributes as far as mechanisms as well, but generally speaking.

• 5:12Speaker 02

  So when you're looking at those, I'm breaking my rule, I'm saying it again, second generation atypical antipsychotics, you know, they're, they add on that serotoninergic action compared to the first generation, which would be antagonist only at dopamine. But those are working as antagonists in the same ballpark where psychedelics come in as agonists. Okay. So it's the age old, you know, Yankee fan at Fenway Park. Ooh, that's not, that's gonna be a rough weekend, right? Well, what about when the, you know, the Sox fan goes to the Bronx? That's a rough weekend too, right? And hopefully some fun along the way. And whatever other rivalry you want to do out there, right? I'll pull up my own where, you know, I went to Pitt, I work at the W, you're thinking, good golly, is there psychedelic utilization around there? Nope, nope, nope.

• 5:56Speaker 02

  That's just the backyard brawl for your East Coast football, basketball fans and any other sport you can think of these days. Cause that has resurged, right? But anyways, the bottom line is psychedelics hallucinogens are, you know, in the same ballpark, that dopamine and serotoninergic receptors, but they're working as agonists, whereas the atypical antipsychotics are the antagonists there. Okay. And very briefly, you know, we covered, well, yours truly is own classification of psychedelics. You know, but nothing, you know, like rocket science here, you know, just classifying as, you know, how they're working, where they come from, things like that. We had our belladonna alkaloids, things like nightshade, mandrake root, Jimson weed, got

• 6:38Speaker 02

  lots of stories with those, like, you know, Harry Potter group, you name it, or a plant that was growing even in my backyard at a contractor thinking that we were growing hallucinogens. When it turns out it was just something that grew with the rest of the weeds, not weed, but weeds. Okay. Then we have, of course, as far as psychedelics go, the dissociative anesthetics, things like special K or ketamine, PCP, Mexi or methoxetamine. Then we are tryptamines are serotonin like, they were thinking like, you know, Thanksgiving turkey dinner, kind of LSD, psilocybin, you're going to hear a bunch here today in a succinct episode, but a bunch regarding psilocybin as far as studies go.

• 7:22Speaker 02

  Dimethyltryptamine or DMT businessman special, aihuaska, you think of, well, a bunch of celebrities that have done a rant about that recently. The next classification we had was phenethylamines. Those are dopamine like, so we had some, well, interesting things named bromo dragonfly, mescaline, what's another, 2CB N-bomb, that one rolls right off the tongue. Things like, you know, even our substituted amphetamines like methylene, dioxymethamphetamine or ecstasy, cathinones, and even nutmeg because of the merestison within it, certainly needing that, remember how does it work? And then how much? A little bit more of a dose that's in an average pantry regardless of the time of year.

• 8:06Speaker 02

  And finally, there was the piperazine, the benzyl and phenyl piperazine. So that's the five groups of psychedelics overall. That's our, it probably took me more than two minutes, my apologies, but that's the quick down and dirty when it goes, the, the most basic components of what we want to prime this conversation for psychedelics today. So let's jump into the studies. Okay. What we're going to do here is go over the past and then kind of some recommendations reflective from the FDA and then the present slash future. Okay. A little hot tub time machine as usual, but in this accord, it's psychedelic studies. Okay. So one place to look, you know, when you're thinking about the previous studies that are

• 8:46Speaker 02

  out there, there is, there was a review article back in 2022, it was from curious. It basically just, you know, taking a snapshot, like what's the landscape look like? In that particular review article of psychedelic clinical trials, they found that there was over a hundred trials. It was actually just over a hundred, I believe a hundred and five, but just over a hundred. The tricky part was that like half of them were cannabis. And that brings up this little conundrum of like, do people classify cannabis as a psychedelic or hallucinogen? Or is it its own little group? Or is it, you know, sedative with properties, you know, like the psychoactive components of THC? It's got a lot going on, right?

• 9:29Speaker 02

  In fact, we've got multiple episodes of the pain pod, even dedicated to thug drugs and cannabis and the whole gang overall. Okay. But, you know, one thing when you say, oh, there's over, there was over a hundred trials. Well, if half of them are cannabis and if folks are saying, well, that's kind of its own thing and not necessarily in the psychedelic grouping, well, that kind of downplays the number a little bit, right? And about 70% of those were actually in our country, United States of America. It involved things like substance use disorder, addiction, PTSD, depression, pain, you name it. Okay. So that was basically the landscape. Okay.

• 10:06Speaker 02

  In the big picture. Now, if you go a little bit more granular and what I'd like to do here is kind of go into, you know, pick a substance or two, a psychedelic or two, to go a little bit more granular from some of those studies that were reviewed. Okay. So we're going to start with psilocybin. I gave it the little drum roll earlier, of course. But again, back in about 2022, there was a New England Journal of Medicine published study, you know, regarding psilocybin utilization for treatment resistant major depression. Okay. The, you know, what they were looking for would be appreciable decreases in that said depression. And then they're going to assess adverse events as well. So safety and efficacy, right?

• 10:50Speaker 02

  Lo and behold, in that study, the higher the dose, the incremental increase in the percentage of participants with side effects. I'm sure most would have guessed that. And you guessed it as well, headache, nausea, business fatigue, everything you hear on a DTC direct to consumer commercial these days, right? There was also a little bit more granular information as for suicidal ideation, but you know, not huge takeaway pearls overall.

• 11:18Speaker 02

  There were other clinical trials as well for psilocybin. Even back in 2022, same thing, there was a little bit over two dozen patients that were in a trial that was in the Journal of Psychopharmacology, in case you checked that one out recently. Really looking at major depressive disorder. And then there was actually, or I guess I should say is, all the way back in 2014, so well over a decade ago now, the ongoing trials at the University of Wisconsin-Madison. There was actually four clinical trials. There's the Hootie One, the Primus, the Poesis, and then Enhance, I guess we'll call it. So four, in case, I just mentioned them in case you ever want to look them up or whatnot.

• 12:02Speaker 02

  I could always provide things in the show notes, of course, but the big picture there was really looking at the grander picture that, again, more studies on psilocybin, right? And that's an important thing to keep in mind. So much so that psilocybin actually was granted breakthrough designation by the FDA, okay? And that was to a specific formulation, of course, it was CYB003. Boy, that rolled off the tongue more than I thought, it was from Cybin. It's basically a deuterated psilocybin analog. So no one was eating mushrooms, let's just start there, right? And it was being studied for major depressive disorder.

• 12:42Speaker 02

  So what's this, as a little reminder, maybe original learning, but that BTD breakthrough therapy designation, basically the FDA gets involved in the phase three studies followed by an expedited review process. It's not necessarily that it speeds things up, although that is inherent, it gets, you know, involvement, so the reviews are a little bit more, you know, granular and along the way, okay? All right, now, let's jump over, we touched on psilocybin in the past, how about MDMA or ecstasy? That, of course, being studied for PTSD. This, this is gonna, this is gonna get hot and heavy pretty quick, folks, but, so there were two phase three clinical trials that had about, almost like 200 patients, they

• 13:27Speaker 02

  were looking to treat moderate to severe PTSD, okay? Both trials involved MDMA, a form of ecstasy, it was midomethadine, given in three eight-hour therapy sessions, and they were four weeks apart. So, you know, not just your usual pill a day, right? Participants also had shorter talk therapy sessions before and after getting the medicine, or even before or after the placebo as well, too, of course. The authors concluded that the MDMA product works better than a placebo in reducing the severity of PTSD symptoms, okay? Then what, though? Well, then the FDA's gonna review things, right?

• 14:05Speaker 02

  So back in December of 2023, that, you know, there was, basically, the NDA was, the new drug application, was submitted to the FDA as MDMA-assisted therapy, because there were those talk sessions as well, for the treatment of PTSD. The panel evaluated and voted on both safety and efficacy. They voted nine to two against for safety, and voted 10 to one against for efficacy. Whoa, that doesn't gel with what the author said, right? That being said, there was actually a quote, "The panel chair said, 'I'm not convinced at all that this drug,' I usually would say medication, 'is effective based on the data I saw.'"

• 14:47Speaker 02

  Okay, so the FDA advisory panel declined to recommend MDMA for PTSD. Now, that's a panel, though, so then, you know, it goes to the actual FDA leadership to make those decisions, so. A little bit extra info came, and this is where, if you're not on the edge of the seat, scoochy forward, folks, okay? And this is public information, okay? I'm not just pulling this from the internets and the whole misinformation thing, this is public substantiated information, okay? So the, that panel brought up that there was blinding and sexual misconduct concerns within the trial. And if I don't have your attention yet, well, pay attention now, okay?

• 15:29Speaker 02

  So the FDA panel stated that Lycos Pharmaceuticals' trial data was marred by inconsistencies, poor study design, and allegations of misconduct. Interesting. All of a sudden, we're all on board for doing a journal club, right? Due to profound alterations in mood sensations, suggestibility, and cognition, most of the trial participants were able to accurately guess which treatment they had received after this study ended, which resulted in the study being nearly impossible to blind. And if you think about it, that's not to one company, that's, that's just a concern in general, you know, you know, the actual facts, right, on the psychological side. So the FDA panelists raised concerns about the case of a female trial patient who, in

• 16:10Speaker 02

  2015, said that she was sexually abused by a male therapist during a trial treatment session. That patient actually testified via surrogate in June 2024, almost a decade later, pointing to a publicly available video of her session, which showed the therapist pinning her down and then cuddling and stroking her. Sometimes I can't believe what I read, and, and this would be one of those times, of course. Now, certainly feel free to dive deeper in there, but, boy, that's, that's not what we typically see when we're going over, you know, recommendations from an FDA panel, or, you know, doing a quote-unquote journal club for an article, okay? So what comes from that, okay?

• 16:52Speaker 02

  In general, not just that situation, but, you know, remember our overall timeline here today, kind of gonna go over the past ones, relatively recent, then FDA recommendations, and going forward, okay? So the FDA actually published some clinical trial recommendations when it comes to psychedelic substances, okay? There's a decent laundry list, I'll go through them here, but, you know, basically they want the pharmacokinetics and pharmacodynamics, the PK and PD should be adequately characterized in silico, meaning virtual, you know, on the computer, in vitro, in the glass, and in vivo, in life, that's in us, you know, animals, humans, right? They also said that there should be two monitors, okay?

• 17:35Speaker 02

  That'd be, that would be the people, so someone, you know, grad-level healthcare provider with experience, and then someone else along the way. The FDA also said there should be inner placebo alternatives, including other psychedelics or low, mid, or even high dose and placebo controls put in place. Being able to distinguish that, you know, some, a participant, a patient, not knowing inherently which treatment they got, okay, or which option. Also must justify treatment psychotherapy inclusion, because that can certainly affect the efficacy results, is it, you know, chicken or the egg? The serotonin receptor subtypes binding evaluation is recommended, in fact, they must include serotonin subtype 2B. And they should characterize the durability of response, you know, is it more than three

• 18:20Speaker 02

  months? Dosage intervals, and repeat dose safety and efficacy. Now, by now, you might be thinking, well, you know, this list is growing, but it is pretty basic things for getting a, you know, medication FDA-approved, right? Should be able to determine dose-response relationships for both safety and efficacy, of course. They also want folks to evaluate the effect of a high-fat meal, when you're talking about oral dosages, that gets pretty specific, but it's, you know, to the tune of concerns that have been observed. There's also the, you know, physical dependence, abuse potential assessment data, along with a proposed controlled substance classification scheduling, okay? And all in all, the FDA may consider the public health effects of the drug as part

• 19:03Speaker 02

  of the overall benefit-risk assessment, basically saying, even if you do all of this, we have to look at the big picture overall, okay? Now, there's one, that's kind of the culminating recommendation or statement, really, but one other thing was, you know, the evaluation of drug-drug interactions, and obviously that's where, you know, us pharmacists hear us roar, right? But the potential concerns that the FDA said for any psychedelic trials and studies, you know, to definitively evaluate, would be your serotonergic subtype 2A antagonists, things like trazodone, buprenazone, risperidone, you name it, also dopamine antagonists, we

• 19:41Speaker 02

  got a bunch of those, of course, SSRIs, MAOIs, TCA's, lithium, riserpine, pendolol specifically, and even niacin, which vitamin B3 is that? Hmm, let's see, I think I, somebody came up with the, remembering, you know, 1, 2, 3, and 6, and so on, the registered nurse P is PC, so niacin being vitamin B3, right, TRN, N is the third one, vitamin B3. Oh, P1s, you're welcome, or the rest of us, you're thinking, where did that come from? Anyways, we're on a psychedelic trial journey here, okay? What I wanted to highlight, though, is that the FDA went very granular on assessing drug-drug

• 20:23Speaker 02

  interactions as a recommendation for psychedelic clinical trials. Speaking of those trials, let's jump into, well, things that are more recent and current along the way, okay? So we've got, of course, that synthetic psilocybin, so again, not the mushroom, it's synthetic. And there's a Cybin phase three trial, in of which trial participants can continue their current antidepressants, previous studies didn't allow that, and there's a longer three-month blinded period, you know, to really maximize the number of patients that remain blinded along the way. In addition, there's another company that has two phase three trials out there, it's

• 21:05Speaker 02

  Comp 005 and Comp 006, the C-O-M-P, as I'm saying. So Comp 005 had three main parts proposed, anyway, part A, I believe that's already concluded easily, where, you know, was blinding through six weeks for looking at synthetic psilocybin, so again, a synthetic product. Then the second part, part B, per se, continued that blinding through week 26, I believe that's actually already been done, and then part C, the third part, was proposed for, you know, open-label treatment going to the rest of an entire year, 52 weeks, okay? So that's a big time to know.

• 21:45Speaker 02

  Then the counterpart there, Comp 006, because the previous one was ended with five, that had the three, you know, proposed parts as well, blinding through nine weeks, and then blinding through 26 weeks, so half a year, and then the final part being, you know, open-label for the final six months of the year overall. You know, hundreds of patients involved, and really distinguishing dosages along the way as well, too. So TBD, to be determined for published results, you know, for all parts inherently coming through here, but again, big picture, we're looking, like all of these scenarios, it's synthetic along the way.

• 22:25Speaker 02

  Speaking of which, let's jump to another synthetic, synthetic LSD. There's a D-Tartrate that also got the breakthrough, BTD designation from the FDA. So it's in this trial case, there's a single dose synthetic LSD, D-Tartrate. It's known as MM120 from MindMed. And that's being trialed and studied for GAD, generalized anxiety disorder. It's actually the fifth psychedelic to receive that breakthrough designation. Just weeks, actually, after psilocybin products. All right, so there's the Phase IIb trial, and that's MMED008.

• 23:07Speaker 02

  And that was really assessing the dose response for generalized anxiety disorder, looking at basically four different doses, all micrograms and placebo. And what was found there was that the single 100-microgram dose showed significant durable anxiety reduction for up to three months with high remission rates. There were side effects, though, of course, visual effects, nausea, increasing with the dosage. Then we also have, well, a couple there. There's at least three other, there'll be more. Phase III trials for synthetic LSD. There's the Voyage Study, that's MM120-301. That's actually the first Phase III trial for generalized anxiety disorder. It started at the end of 2024.

• 23:52Speaker 02

  And then there's also the Panorama Study, labeled as MM120-302. So just one in addition to the other one. Basically, another Phase III generalized anxiety disorder trial, started in the first half of 2025. And then the Emerge Study is also a Phase III trial for major depressive disorders. So we see all these clinical trials really honing in on the mental health aspects, the psychological side, whether depression, anxiety, different designations and diagnoses along the way. All right, one more, folks. How about Special K, ketamine, right? There's the More Care Study. So that's actually a Phase III in the United Kingdom, currently recruiting to test infusion ketamine for alcohol use disorder.

• 24:36Speaker 02

  So I kind of lined that up where a lot of the, you know, the previous studies were for different, you know, collective genres of care. But this More Care Study is basically a follow-up to a Phase I study that had a little bit over two dozen people in it, and a Phase II study of a proprietary sublingual S-ketamine, one of the mirror images, for alcohol use disorder. So more to come on that. Bottom line, folks, that's a lot of studies, right? And some big points, though, when you're thinking about it. At no point did I say that folks were ingesting a mushroom, or a cactus, or anything, just directly out of the ground. These things that are being studied are actually synthetic. And if you think about that, we've been down this road before for things like cannabis.

• 25:19Speaker 02

  We've talked about this in the Pain Pod before, where, you know, we've had for decades, we've had FDA-approved cannabinoids, things like Dronabinol, you name it along the way, right? And then more recently, even natural CBD epidilex. It's extracted naturally, right? So, you know, we see that as a potential here for psychedelic studies, future medications, potentially, as well. But so far, we're really looking at a lot of synthetics along the way. And that's an important thing to bring up, of course, because, you know, if you want the conversation to continue, you got to go over the basic facts along the way. And I hope that this, you know, relatively rapid review here of psychedelic studies helps along the way with that for you.

• 26:03Speaker 02

  So, you know, I'd be remiss to say, well, like, where do we fit in as pharmacists, of course, right? So you got to keep in mind, we touched on the last episode, there are FDA-approved medications that are a form of psychedelics, like ketamine, of course, you know, on the WHO list of should be in every hospital, you know, whether anesthesiology, or pain management, you name it. But also, the S-ketamine is an FDA-approved product, along the way, the nasal spray. Also, you know, as pharmacists, we want to appreciate the difference between clinical trial synthetics and natural products. It's not saying thumbs up, thumbs down to either of those. It's just a reality that's out there, right? And always, just as the FDA recommended, but it's one of our specialties,

• 26:47Speaker 02

  review for drug-drug interactions when a patient shares current utilization of psychedelics. Not even in the trials, but if somebody's sharing that information for you, now we have some pretty granular recommendations for what to look for for drug interactions, right? And, you know, also, being a trusted source of ongoing psychedelic clinical trial data, keeping up with these things along the way. Perhaps even future episodes of the Pain Pod, right? It's a lot of information that's out there, a lot to digest, but we're all in it together, folks. And as always, I really want to thank you for your time here today. I hope it was worth your time for a rather rapid rundown of multiple, if not many, psychedelic clinical trials and studies that are out there.

• 27:28Speaker 02

  So I hope you enjoyed our Bug Drugs mini-series continuation here with psychedelic studies. And I certainly look forward to, well, doing the next episode of the Pain Pod, of course. But as always, I want to thank you for your time. As far as I'm concerned, it's our most valuable resource. And of course, I want to wish you a great day, every day.

• 27:47Speaker 01

  If you'd like to join Mark on the Pain Pod, send us an email to [email protected]. And make sure to share the show and subscribe on your favorite podcast directory. Thanks for listening.