Thug Drugs: Psychedelic Studies | Pain Pod

0:00You are listening to the Global Network of Podcasters dedicated to the Pharmacy profession. Welcome to the Pharmacy Podcast Network. Welcome to the Pain Pod. The podcast for all things Pain Management hosted by the Pain Guy. Dr. Mark Grofully. 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

1:01as leading providers of pain care. 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, insertified in, weapons of mass destruction response. Yes, Dr. Mark Grofully. Welcome back everyone to the Pain Pod. So yours truly of course, Mark, the Pain Guy Grofully here on the mic as usual. And well today we have a little situation of a follow-up episode here for the Pain Pod. Alas, if you did not tune in listening or download the last episode of the Pain Pod that went over our many series of thug drugs, concentrating on psychedelics, if you haven't listened to it yet, no worries, just download it, it'll be your homework for next time I guess.

2:04That's where we basically went into a review of the substance themselves, the classes, classifications, the groups, you name it. You know, in the big picture there. 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 many series and reviewing psychedelic studies. Okay, 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? Yeah, not to be the nerd in the room or anything, but it kind of helps out, right? And I know my student pharmacists self back in days thinking, oh my goodness, what happened to them? But folks, you got read the articles.

3:06So it was a famous guy back in the 80s, 90s that said it too with a, you know, a couple picture books and all that, but it actually is important. So, you know, here though, I fully realized that everybody's time is valuable. And not everyone has the time to dedicate to reading every study on the planet, even those some we wonder how that can publish. 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 up, I'm just going to spend like maybe two minutes or so. Very brief succinct review here of, you know, psychedelics. Also known as hallucinogens, of course. So you know, 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 does it work, the mechanism, and how much?

4:07The 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, through 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 escalating quickly, right? So what we mean there is that the second generation atypical antipsychotics, just saying that one, I'm just going to say it once, one and done, okay? Those gents are antagonists at dopamine and serotonin, usually subtype two.

5:07And again, they have other attributes as far as mechanisms as well, but generally speaking. So when you're looking at those, I break up my rule, I'm saying again, second generation atypical antipsychotics, you know, they're, they add on that serotonergic action compared to the first generation, which would be antagonists 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. Who that's not? That's going to be a rough weekend, right? Well, what about when the, you know, the socks fan goes to the Bronx? That's a rough weekend too, right? And hopefully some fun along the way. And whatever other rival you want to do out there, right? I'll pull up my own where, you know, I went to Pitt, I work at the WU, you're thinking, golly, is there psychedelic utilization around there? Nope, nope, nope, that's just a backyard broth here. I'm not going to be a risk host football basketball fans and any other sport you can think of these days, because that has researched, right? But anyways, the bottom line is psychedelics, hallucinogens are, you know, in the sand ball

6:09park, that dopamine is serotonergic 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, 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 Belodon alcaloids, things like nightshade, Mandrake root, Gymson weed, got lots of stories with those, like, you know, Harry Potter, Groot, you name it, our plant that was growing even in my backyard, and 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, okay? Then we have, of course, as far as psychedelics go, the dissociative anesthetics, things like special care, your ketamine, PCP, mexy or methoxetamine, then we are triptomines, there are serotonin like, there we're thinking like, you know, Thanksgiving turkey dinner, kind of LSD,

7:13psilocybin, you're going to hear a bunch here today, in a succinct episode, but a bunch regarding psilocybin, as far as studies go, diomethyl triptamine or DMT, business man, special, ayuasca, you can think of a, well, a bunch of celebrities that have gone around to about that recently. The next classification we had was phenythelomines, those are dopamine lakes, so we had some, well, interesting things named bromo dragonfly, mescaline, what's a two CB end bomb, that one rolls right off the tongue, and things like, you know, even our substituted amphetamines, like methylene, dioxymenthemphetamine or ecstasy, cathodones, and even nutmeg, because the meristisin 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 the year. And finally, there was the paparizines, the benzolyne, paparizines, so that's the five groups of psychedelics overall. That's our, it probably took me more than two minutes, my apologies,

8:16but that's the quick down and dirty when it goes, 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 is 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 out there, there was a review article back in 2022, was from curious, basically just, you know, taking a snapshot, like what's the landscape look like, and that particular review article of psychedelic clinical trials, they found that there was over 100 trials, it was actually just over 100, I believe 105, but just over 100, 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

9:22know, sedative with properties, you know, like the psychoactive components of THC, it's got a lot going on, right. In fact, we've got multiple episodes of the pain potty 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 100, we were was over 100 trials, well, half of the market 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, and involved things like substance use disorder addiction, PTSD, depression, pain, you name it, okay. So that was basically the landscape, okay. 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

10:28Journal of Medicine published study, you know, regarding psilocybin, utilization for treatment, resistant major depression, okay. The, you know, what they were looking for were be appreciable decreases in that said depression. And then they're going to assess adverse events as well. So safety and efficacy, right. Loan behold, in that study, the higher the dose, the incremental increase in the percentage of participants with sign effects. I'm sure most would have guessed that. And you guessed it as well. Hedic, nausea, disnice, 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. There were other clinical trials as well for psilocybin, even back in 2022. Same thing. There was a little bit over 2,000 patients that were in a trial

11:29that was in the Journal of Psychopharmacology. In case you check 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 Houdy-1, the primus, the poesis, and then enhance. I guess we'll call it. So four, in case, I just mentioned, in case you ever want to look them up or whatnot, 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. And that's an important thing to keep in mind. So much so that psilocybin actually was granted breakthrough designation by the FDA. And that was to a specific formulation, of course. It was C-Y-B-003. Boy, that rolled off the tongue more than I thought. It was from psilocybin. It was

12:31basically deuterated psilocybin analogue. So no one was eating mushrooms. Let's just start there. And it was being studied for major depressive disorder. So what's this little reminder? Maybe a regional loan learning. But that BTT 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 involvement. So the reviews are a little bit more granular and along the way. Now, let's jump over. We touched on psilocybin in the past about MDMA or ecstasy. That, of course, being studied for PTSD. This is going to get hot and heavy pretty quick folks. So there were two phase three clinical trials that had about almost like 200 patients. They were looking to treat motor to severe PTSD. Both trials involved MDMA. A form of ecstasy was

13:35middle-mephytane, given in three eight hour therapy sessions, and there were four weeks apart. So not just your usual pill a day. Participants also had shorter talk therapy sessions before and after getting the medicine or even before after the placebo as well, too. The authors concluded that the MDMA product works better than a placebo in reducing the severity of PTSD symptoms. Then what, though? Well, then the FDA's going to review things. So back in December of 2023, that was basically the NDA was the new drug application was submitted to the FDA as MDMA assisted there 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 9-2 against for safety and voted 10-1 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

14:41convinced at all that this drug, I usually would say medication, is effective based on the data I saw. So the FDA advisory panel declined to recommend MDMA for PTSD. Now that's a panel, though. So then it goes to the actual FDA leadership to make those decisions. So a little bit extra info came. This is where if you're not in the edge of the seat, scoochy forward folks. And this is public information. I'm not just pulling this from the internet and the whole misinformation thing. This is public, substantiated information. So that panel brought up that there was a blinding and sexual misconduct concerns within the trial. And if I don't have your attention yet, well, pay attention now. So the FDA panel stated that Lycos Pharmaceuticals trial data was marred by inconsistencies, poor cell design, and allegations of misconduct. Interesting. All of a sudden we're all on board for doing a journal club, right?

15:42Due to the profound alterations and mood sensations, suggestibility and cognition, most of the trial participants were able to accurately guess which treatment they had received after this study ended. It resulted in the study being nearly impossible to blind. And if you think about it, that's not to one company that's just a concern in general. You know, the actual effects on the psychological side. So the FDA panel has raised concerns about the case of a female trial patient who in 2015 said that she was sexually abused by a male therapist during a trial treatment session. That patient actually testified via a 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 this would be one of those times, of course. Now, certainly feel free to dive deeper in there, but boy, that's not what we typically see when we're going over recommendations from an FDA panel

16:45or doing a quote-unquote journal club for an article. Okay. So what comes from that? Okay. In general, not just that situation, but you remember, overall timeline here today, can I go over the past ones, relatively recent, and FDA recommendations, and going forward? So the FDA actually published some clinical trial recommendations when it comes to psychedelic substances. There's a desilangilist. I'll go through him here, but basically they want the pharmacokinetics and pharmacodynamics. The PKPD should be adequately characterized. In silico, meaning virtual, the computer, in vitro, in the glass, and in vivo, in life, that's in us, animals, humans. Right. They also said that there should be two monitors. 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 inter-plicable alternatives, including other psychedelics or low mid or even high dose and placebo controls put in place.

17:52Being able to distinguish that, you know, some 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 months? Dosis generables and repeat dose safety 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 to, 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,

18:53along 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 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 a 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, as far as this here is raw, 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, or Promasine, Respiridone, you name it, also dopamine antagonists, we got a bunch of those, of course, SSRIs, MAOIS, TCA, Zolythium, Resurping, Pindalol, specifically, and even NICEN, which vitamin B3 is that? Hmm,

19:53let's see, I think I, somebody came up with the, remember, bring, you know, 1, 2, 3, and 6, and so on, the register nurse P is PC. So NICEN being vitamin B3, right, TRN, and 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 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 civil sibon. So again, not the mushroom, it's synthetic. And there's a sibon phase 3 trial, in, in of which, trial participants can continue their current and endoprescent, 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.

20:58In addition, there's another company that has a two phase 3 trials out there. It's Comp 005 and Comp 006, the CLMP, 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, continue 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. Then the counterpart there, Comp 006, because the previous one was ended with five, that had the three proposed parts as well, blinding through nine weeks, and then blinding through 26 weeks, so half a year. And then the final part being open label for the final six months of the year

22:04overall. Hundreds of patients involved and really distinguishing dosages along the way as well too. So TBD, TBD determined for published results, you know, for all parts inherently coming through here. But again, big picture we're looking at like all of these scenarios, it's synthetic along the way. Speaking of which, let's jump to another synthetic synthetic LSD. There's a D-Tartrate that else, you know, 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 Mind Dement. And that's being trialled 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 2B trial, and that's MMED008, and that was really assessing the

23:08dose 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, synosium, increasing with the dosage. Then we also have, well, a couple there, there's at least three other, there'll be more, Phase 3 trials for synthetic LSD. There's the voyage study, that's MM120-301. That's actually the first Phase 3 trial for generalized anxiety disorder. It started at the end of 2024. And then there's also the panorama study from labeled as MM120-302, so just one in addition to the other one. Basically another Phase 3 generalized anxiety disorder trial started in the first half of 2025. And then the merge study is also a Phase 3 trial for major depressive disorders. So we see

24:12all these clinical trials really honing in on the mental health aspects, the psychological side, whether depressure 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 3 in the United Kingdom, currently recruiting to test infusion ketamine for alcohol use disorder. So I kind of lined that up where a lot of the previous studies were for different collective genres of care. But this more care study is basically a follow-up to a Phase 1 study that had a little bit over 2,000 people in it, and a Phase 2 study of a proprietary sublingual S ketamine, one of the mere images for alcohol use disorder. It's a 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.

25:16And if you think about that, we've been down this road before for things like cannabis. We've talked about this in the pain pod before, where we've had four decades. We've had FDA-approved cannabinoids, things like drew an avidol, you name it along the way, right? And then more recently, even natural CBD epidialyx, it's extracted naturally, right? So 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 if you want the conversation to continue, you got to go over the basic facts along the way. And I hope that this, relatively rapid review here of psychedelic studies helps along the way with that for you. So I'd be remiss to say, well, where are we fitting as pharmacists, of course, right? So you've 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, on the who list of should be in every hospital,

26:20whether anesthesiology or pain management, you name it, but also the S-ketamine is an FDA-approved product along the way the nasal spray. Also, 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, 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

27:27that are out there. So I hope you enjoyed our drug-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 you to wish you a great day, every day. If you'd like to join Mark on the pain pod, send us an email to publish your at pharmacypodcast.com and make sure to share the show and subscribe on your favorite podcast directory. Thanks for listening.