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Dr. Kelan Thomas on Psychedelics, Serotonin, and Heart Health

Exploring a potential side effect of microdosing on cardiovascular well-being

Dear listeners,

I am thrilled to share with you my recent interview with Dr. Kelan Thomas, a renowned psychiatric pharmacist and psychopharmacology researcher. Dr. Thomas holds a PharmD, MS, and BCPP, and is dedicated to improving mental health care through clinical pharmacy and research.

In this episode, we continue to cast a bright light on the adverse effects of psychedelics, and in particular, concerns around the potential heart risks associated with chronic microdosing of the classic serotonergic psychedelics such as LSD and psilocybin. Dr. Thomas shared insights into the binding affinities of psychedelic compounds and their effects on serotonin receptors, specifically the 5-HT2B receptor.

Kelan Thomas, PharmD, MS, BCPS, BCPP

“My primary concern is how many people have been continuously microdosing for three months, six months, or even a year without taking any breaks,” he says.

He believes that microdosing twice-weekly for several months, for example, can lead to valvular heart disease. This is a known side effect of a whole class of drugs with high binding affinity at the 2B receptor. According to FDA regulatory reviews, about one in four people develop this issue while taking these drugs.

“However,” he notes, “this hasn't been specifically shown with LSD microdosing; it's an extrapolation from other substances.”

Those of us who were around in the 1960s remember the campaigns that demonized LSD. The media and government conspired to spread misinformation, falsely linking LSD with chromosomal breaks and making other fictitious claims. We must be cautious not to blindly believe every finding, but we should also remain open to the possibility of the unknown unknowns.

Fortunately, we are now emerging from the era of suppression of research. Studies can now be conducted on individuals who are actively engaged in microdosing, enabling more accurate data collection. If you are currently microdosing, considering it, or know someone who is, be sure to share this important broadcast, along with the links to Dr. Thomas's work below.

Golden light,

Dr. Richard Louis Miller

Links and Resources

Seeking Psychedelic Testimonials: The Good, the Bad, and the Ugly.

We are currently looking for first-hand accounts of adverse effects of psychedelics—from ‘bad trips,’ to unwanted physiological complications, to abusive practices by guides, therapists, and shamans.

The interviews from this series will go into a forthcoming book on the topic—perhaps the first book its kind.

Please contact me if you would like to be interviewed. You can also leave us a voice message to share your story. We will keep your information anonymous unless you tell us otherwise.

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Mind Body Health & Politics is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.

NOTE: The podcast is always freely available thanks to our paid subscribers. Please share this post to show your support for transparency. The following transcript distills the key points from this show into a condensed form. It is meant as a reference - listen to the full episode for an accurate rendition of the conversation.

Transcript


00:00 - Introduction

  • Dr. Miller introduces the podcast's mission.

  • He discusses the tribal, cooperative nature of humans.

Dr. Richard Miller (0:00): Welcome to MindBody Health and Politics. I'm your host, Dr. Richard Louis Miller. The mission of MindBody Health and Politics is to enhance your physical and emotional well-being and encourage community. I say encourage community because I believe that living in community is the most effective and healthiest way for human beings to live. I believe we are tribal animals. And when we hang out together, in tribes, which is the way we began, we support one another, we collaborate with one another. And we basically live in peace. Human beings are basically tribal, cooperative, collaborative animals. We love doing things together, all kinds of things, whether it's throwing a ball, reading books together, watching an event together, a sewing circle, playing poker, playing golf, or eating. We love eating together. Human beings love sitting around in a circle, having something to eat and share, and breaking bread. That's who we are. However, there are also a very small percentage of us who are very different. This group are predators. This is the group when we came out of the cave, who used the big stick to get somebody else to do what they wanted. As soon as they got somebody else to do what they wanted, that was the beginning of what we now have as armies, or cartels, because two people working together could get a third and then a fourth, and then a fifth, always remembering that the person who started had the big club, and that was the predator, who eventually became tribal leaders, kings, then dictators. We've seen them all through history, the small predator group, who would rather have us be subjects than citizens. It was our founders, who after thousands of years of nothing but kings who could cut off anybody's head with a stroke of their finger, overthrew a king, King George, and overthrew the Pope, by whom King George ruled by divine right. Because if you went against the king, you then went against God. And nobody wanted to do that. But our founders took us out from under that, and we became citizens. And that's who we are today. But citizenship, and a democracy and a republic that they created is a fragile thing. And those of us who are collaborators and cooperators, the over 95% of us, we must stay awake, awake, we must vote. And I know saying to people, you must stay awake and vote and be involved in this is particularly hard right now, when 60% of us are struggling to put food on the table and pay the rent and have warmth, a shelter for our families. It's a hard time to be asking everybody to do that. But we still must do it. Because better to be poor, in an experiment in democracy and Republic than poor in a dictatorship, or poor under a king, or poor under a cartel leader. Hang with me, folks. Stay awake. Let's keep our democracy and our Republic. In the words of one of my great heroes, Thomas Jefferson: "Eternal vigilance is the price of liberty."

04:00 - The Predator Group and Preserving Democracy

  • Dr. Miller contrasts cooperators with power-seeking predators.

  • He emphasizes the fragility of democracy.

Dr. Richard Miller (4:00): One scientist who's maintaining an eternal vigilance is with us today, Dr. Kelan Thomas. He's maintaining a vigilance on a renaissance that's happening, or at least it's been referred to as happening within psychedelic science. After over 50 years of government suppression and obstacles, we are being allowed to do a certain amount of research into what's called psychedelic substances. And so people all over the country are trying them, some with professionals helping them, some on their own. We have a lot to learn. And although so much of the news is so good with regard to reducing PTSD, anxiety, depression, and many other aspects of life that are troublesome to so many of us, while so much of that news is good, we must also, in all transparency, bring to everybody's attention any negative effects, what are called side effects, by the pharmaceutical companies trying to sanitize their negative effects by referring to them as side effects as if it's just a little something that happens on the side. But they don't happen on the side. Negative effects happen to the entire being. And it's our job as scientists to be honest. And we have today, a man who's working on being honest. Welcome to Mind, Body, Health, and Politics, Kelan.

Kelan Thomas (5:35): Thank you for having me.

Dr. Richard Miller (5:37): Kelan, you've been working on the very topic that I've been talking about in my introduction. And it's the topic of a book that I'm in contract to work on, called Psychedelic Medicine: Adverse Effects. Where would you like to begin in sharing with us your scientific discoveries?

Kelan Thomas (5:58): Yeah, so regarding adverse effects, you know, we're starting to collect new modern datasets from looking at these clinical trials where we can try to parse out what's happening with the active drug or medication versus placebo, or in some cases, even using another active comparator to see how it compares to the standard of care. And within the context of those studies, I think a lot of people are pretty familiar with most of the adverse effects. Well, we may start to learn about some of the long-term effects more by studying this. And so one of my particular areas of concern, in particular areas that I've been the most worried about with my research and writing, is this potential risk of a novel utilization for psychedelics with microdosing, that may, in fact, have this risk. And I'm starting to hear anecdotal reports of people developing something called valvular heart disease. And this is something that's well known in the pharmaceutical industry. So pharmaceutical companies have known this for decades now that people taking medications with this specific pharmacologic property of activity at the serotonin 2B receptor, and their affinity at that receptor, the FDA toxicology regulatory groups have agreed that this is a potential problem for any medications that are supposed to be dosed routinely.

07:32 - The Renaissance in Psychedelic Science

  • Dr. Miller introduces Dr. Kealan Thomas.

  • Dr. Thomas researches adverse effects of psychedelics.

Dr. Richard Miller (07:32): But what's promising for me is that most of the research is focused on the so-called macro dosing. All of our evidence that we have so far, that's in things like phase two, and phase three clinical trials that are heading very close to FDA approval, are being investigated in a similar way to any other medication that's been approved. And in these intermittent doses, we're seeing really strong beneficial effects with minimizing the adverse effects because you're essentially only taking the drug one or two times, as opposed to having to take it every other day or every third day. Okay, let me be clear on this. And by the way, I want our listeners to know that you're speaking as a professor of psychiatric pharmacy, you're not just another guy on the street who has an opinion on this. So that's important in terms of establishing who's talking here. And given that so much of the research has been suppressed for so long, how do you get research to look at when you're doing your research, looking at research? Where is it? Like, for example, LSD, let's use LSD because LSD has the most baggage from the 60s, the most fear about it, people jumping out of windows, looking at the sun until they got blind, and so on. All that, how do you dig in and get some scientific reality? Tell us.

Kelan Thomas (08:59): Yeah, so this has been important to me for the book chapters and publications in journals that I've written, where I really do go back and look at some of this literature from the 50s and 60s, which wouldn't be up to the same level of analysis that you need to get a drug through something like the FDA right now. But it still provides a lot of information and a lot of clues in context about what types of adverse effects we should be looking for. And to your point, the statements or stories and media sensationalism around things like you'll go blind or it'll break your chromosomes, all of this was false. All the evidence of times that all that was false and completely fabricated. And essentially, they were just making things up out of thin air. They didn't really have any scientific basis in the medical literature.

Dr. Richard Miller (09:56): Some of that made-up stuff was surely published, wasn't it?

10:00 - Dr. Kealan Thomas on Psychedelic Adverse Effects

  • Dr. Thomas analyzes clinical trial datasets.

  • He expresses microdosing concerns regarding heart valves.

Kelan Thomas (10:02): Oh, not to my knowledge. And I think with some of the chromosome papers, they would say, yeah, there were differences. But there were differences with everything. So then people would just grab one aspect of it. And the same goes with the blindness. That was essentially someone just put that story out there. And there was really no medical literature or journal article.

Dr. Richard Miller (10:27): But didn't a scientist at Johns Hopkins, I believe, named Riccardi publish some papers on the neurotoxicity of MDMA? And it turned out, right. And it turned out that he had not given his subjects MDMA, but he had in fact, given them, I believe, methamphetamine.

Kelan Thomas (10:49): That's correct. Yeah, that's a famous failure of the peer review process. And then there had been a track record of questions around where you were getting your supply from. Those data were later retracted. But the damage was done, right. Some of those messages got out to the media. And then they perpetuated this story that was factually inaccurate, because the animal models had been dosed with methamphetamine and not in fact, MDMA.

Dr. Richard Miller (11:18): Tell me as a scientist, how do you react when you read that a prominent scientist at a very prominent university publishes a document. And it's completely bogus. Because the substance that he claims he's writing about was not the substance that the subjects were given? How do you deal with that? As a scientist? What did it tell me?

Kelan Thomas (11:50): It's upsetting. It's a breach of scientific etiquette and the scientific method to do that. But there again, as you brought up, there's always bad actors, right?

Dr. Richard Miller (12:05): For what reason? How does he benefit? As a person benefit financially by taking a position that a particular molecule is dangerous, and he's doing it erroneously? How does he benefit?

Kelan Thomas (12:24): So to me, I think the way that you benefit is that grant funding is quite competitive to do research projects. And just by virtue of one of our earliest governmental agencies being called the National Institute of Drug Abuse, not drugs, facts, not drug information, but abuse. You have incentivized someone to claim these drugs are bad, they're drugs of abuse. NIDA basically has already biased the scientific funding, showing a negative outcome. And so to keep your funding going, that's how you benefit.

Dr. Richard Miller (13:05): That's an astute point. Thank you for that. Okay, let's come back to take them one substance at a time. Talk to us about LSD. What you're saying is, there were studies done on larger doses. And now you're doing research on this new trend of what's called microdosing. What kind of numbers in micrograms are we really talking about? Now let's talk so that because people are understanding micrograms when they are listening to this program.

Kelan Thomas (13:44): Yeah. So traditionally, whether it was LSD or psilocybin, about 10% of a typical dosage range was considered a quote-unquote microdose. So in the case of LSD, I think the most frequently used if you consider like most tabs had been about 100 micrograms, some up to 200 micrograms, so around 10 to 20 micrograms, I would consider that within the microdose range, and probably 10 is the most consistently used and one that actually has some randomized controlled trial data on it now, the 10 microgram LSD dose.

14:45 - The Challenges of Psychedelic Research

  • They discuss past suppression and fraudulent psychedelic claims.

  • Dr. Thomas explains how this enabled false narratives.

Kelan Thomas (14:29): My research has primarily focused on psilocybin macro dosing. However, upon reviewing the medical literature, I've identified a potential risk associated with both psilocybin and LSD due to their long-term, repeated stimulation caused by their strong binding affinity. This is not only at the 2A receptor, which is believed to be responsible for many of the psychedelic and beneficial effects, but also due to off-target pharmacology at the serotonin 2B receptor, which is expressed in heart valves. Medications like fenfluramine and pergolide, the latter having a structure somewhat similar to ergolines, have been shown to cause valvular heart disease in long-term studies over about a year. Many drugs were removed from the FDA marketplace following post-marketing surveillance that identified these issues. My warning has been particularly focused on the risks of continuous micro dosing for extended periods, such as six months to a year, which I believe could lead to an increase in valvular heart disease cases.

Dr. Richard Miller (15:57): Are we seeing them yet?

Kelan Thomas (16:01): Since publishing an article on this topic in the media, someone has come forward, and I'm currently working on a case report of microdosing-induced valvular heart disease.

Dr. Richard Miller (16:12): One case, but I would imagine there are tens of thousands, if not more, people microdosing. It's become a major phenomenon.

Kelan Thomas (16:23): Yes, my primary concern is how many people have been continuously microdosing for three months, six months, or even a year without taking any breaks.

Dr. Richard Miller (16:36): When you say continuously, what exactly do you mean?

Kelan Thomas (16:42): By continuous, I mean without any breaks. For example, if you're following the Fadiman protocol of taking it every third day, instead of just doing it for the 30-day cycle, you never stop.

Dr. Richard Miller (16:59): Like Paul Austin, who started The Third Wave and told me he took it for nine months following that protocol, which would be twice a week.

Kelan Thomas (17:14): Yes, that's an example of what I consider long-term microdosing. I believe there are potential risks for developing valvular heart disease. Intriguingly, when looking at larger datasets for drugs with high binding affinity at the 2B receptor, about one in four people develop this issue, according to FDA regulatory reviews. However, this hasn't been specifically shown with LSD microdosing; it's an extrapolation from other substances.

Dr. Richard Miller (17:43): So, they haven't shown it with LSD microdosing but with other substances, and they're generalizing to LSD microdosing, correct?

Kelan Thomas (17:54): That's correct. We don't have any data for 2B agonist drugs with strong affinity that have not shown valvular heart disease. It's a bit of a catch-22 since the absence of information doesn't prove safety, especially when symptoms of valvular heart disease can be asymptomatic or go unrecognized by those microdosing. This issue is about the repetition and long-term window of exposure. The Fadiman protocol and other microdosing guidelines typically recommend periods of dosing followed by breaks, which I believe is a safer model than continuous dosing without breaks.

Dr. Richard Miller (19:03): Do we know which heart valves are affected?

Kelan Thomas (19:09): The disease often appears in the aortic and mitral valves, leading to thickening in these areas. It's about stimulating this tissue expression, causing the valve tissue to overgrow, which can lead to complications like arrhythmias and, in the worst-case scenario, sudden cardiac death.

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19:15 - Adverse Effects of Specific Psychedelics

  • LSD, psilocybin, ayahuasca, ketamine, and MDMA effects.

Dr. Richard Miller (19:36): Because the valve gets too stiff, and it can thicken and doesn't close properly, having flexibility is key.

Kelan Thomas (19:46): Exactly. And it's very different from the effects of amphetamines, alcohol, or smoking, which can cause heart damage but don't affect the valve in the same way. For instance, the heart beating too quickly can lead to left ventricular hypertrophy, which is essentially a toughening or strengthening of the heart's muscle wall. However, this is very different. We're talking about a clear pharmacological effect on a specific receptor that leads to fibroblast proliferation in the valve's cellular matrix.

Dr. Richard Miller (20:28): So, what guidance can we offer to people who are microdosing, given they're unlikely to stop? Let's not revert to the ineffective 'just say no' approach.

Kelan Thomas (20:42): Absolutely. The key isn't to discourage it outright but to study it further. If anyone is collecting data, like through apps from Third Wave or other microdosing platforms, it would be beneficial to inquire about symptoms such as shortness of breath or heart palpitations. This way, individuals can report if they're experiencing these signs. Moreover, those who haven't yet should consider getting an echocardiogram from their cardiologist. This can confirm the presence or absence of valve issues. From a harm reduction perspective, it's advised to microdose for four to eight weeks, followed by a break of two to four weeks. This interval could potentially help reset the triggering of the 5-HT2B receptor.

Dr. Richard Miller (21:47): Another aspect to consider is what people are seeking by microdosing so frequently. What's the goal here?

Kelan Thomas (22:02): That's an excellent question.

Dr. Richard Miller (22:04): The objective with larger doses is clearer, such as seeking a psychotherapeutic breakthrough or enhancing creativity. However, with a proper microdose, you shouldn't feel anything since it's below the threshold of sensation. If you do feel something, it's no longer a microdose.

Kelan Thomas (22:46): Exactly. Some individuals report feeling more irritable or anxious with their microdose, which, in my view, indicates they've taken too much. It's not a full trip but an in-between state that can lead to what feels like anxiety due to the excess energy, similar to having too much coffee.

Dr. Richard Miller (22:52): Yes, and shifting focus to psilocybin, what insights can you share based on your research?

Kelan Thomas (23:43): Psilocybin carries similar risks to LSD, even in microdoses. A major challenge with psilocybin is the variability in dosing. Studies have shown up to tenfold differences in psilocybin and psilocin content in mushrooms from the same region. This makes it difficult to know the exact dose you're getting, which is a particular concern for microdosing. LSD and psilocybin share similar adverse effects in larger doses, such as increased anxiety, paranoia, headaches, and nausea. However, these effects are generally manageable within the duration of the dose and tend to dissipate within 24 hours.

Dr. Richard Miller (25:50): Indeed, the precision of dosing with laboratory-made psilocybin is significantly higher than with mushrooms. The latter introduces much uncertainty regarding the strain and active ingredient content.

Kelan Thomas (26:28): Precisely. The lack of precision with mushrooms contrasts with regulated settings, like those recently introduced in Oregon, where psilocybin services must specify the exact concentration. This is a step towards more reliable dosing, but generally, the variability with mushrooms remains a challenge.

Dr. Richard Miller (27:06): Notably, we don't see large numbers of emergency room visits from psychedelic use, unlike with substances like cocaine during its epidemic phases. This observation is intriguing, especially considering some risky behaviors associated with psychedelic use.

Kelan Thomas (28:34): While there are emergency room visits linked to psychedelics, their frequency is significantly lower compared to other substances. This discrepancy partly reflects the lower percentage of psychedelic users in the population. However, the overall lower incidence of emergency room visits speaks to the relative safety of these substances when used responsibly.

29:15 - Public Health Considerations

  • Dr. Thomas emphasizes harm reduction strategies.

  • Dr. Miller questions MDMA's impact on sexual vulnerability.

Kelan Thomas (29:15): But secondly, it doesn't have the so-called addiction potential. When you look at things like an eight-factor analysis of what would make people more dependent, or get into a substance use disorder with hallucinogens, that is incredibly rare, whereas things like cocaine, methamphetamine, opioids, those rates are much higher. People get opioid use disorders because they want sort of the more of the euphoric effect. The way I describe it to my clients, I work with anything that makes you feel really good really fast, and that feeling disappears quickly. That is a potentially addictive substance, behavior, whatever the case may be, and that is not what you see with something like psilocybin or LSD. If anything, you ask the person, "Do you want to take that again tomorrow?" They'll usually say, "No, that's too much. I'm good for now. I don't want to take it again tomorrow." Right. So yeah, very different experiential process too, but but.

Dr. Richard Miller (30:13): I do think we're being told something by the lack of emergency room admissions because, even though the percentage, as you say, is small, the numbers are very large. Because, I read recently that the number of people experimenting with psilocybin went up from 3% of the country to 6%. In one year, we're talking 15 million people. Hmm.

Kelan Thomas (30:41): Yeah, no, I mean, and we've seen, as all these, you know, Oakland was quick to decriminalize. I gave some testimony at the safety committee hearings in Oakland City Center. And now, yeah, I mean, there's a lot more access than there's ever been. There's, you know, people selling them online, making chocolates, Colorado, Oregon. So yeah, it's out there. You're right. I mean, there's been a huge increase, I would argue, in the past year or two, in accessibility, and then there's ever been, and we are hearing some reports of bad outcomes, but not at the volume that we'd see as a percentage of some other substance. Exactly.

Dr. Richard Miller (31:22): So that says something in and of itself about what you might call relative safety. Yes, doesn't it?

Kelan Thomas (31:30): Yes, from a physiologic standpoint, something like LSD or psilocybin are very safe in terms of the acute physiologic effects.

Dr. Richard Miller (31:43): Let's move on to another substance, Ayahuasca. We've got people getting on planes and going to South America, and taking Ayahuasca in the jungles. We've got people all over the United States sitting in Ayahuasca circles. Anybody who's taken it knows, it's as powerful as a full dose of LSD. But again, it's hard to tell with Ayahuasca what the dose is, because you don't know the vine it came from, and you don't know the mixing. People know very little about it, in terms of it being what they're eating, one gulp or two gulps? What does your research tell you that you can share with us?

Kelan Thomas (32:35): Yeah, the interesting thing is, there have been some labs in Brazil that have started to really do sort of modern randomized controlled trials with Ayahuasca. And what they do is they look at, you know, different churches or indigenous use. And actually, like I said, figure out the concentration. So they would say, "We're doing this experiment, but we know it's this amount of DMT for 'em this amount of harmine or harmaline." So they're identifying all the compounds in the brew that we think have these psychoactive effects and quantifying them and getting a sense of, okay, well, if we do that, well, how do you see people's depression symptoms improved, for example?

33:30 - Toad Venom (5-MeO-DMT)

  • They discuss 5-MeO-DMT's popularity.

  • Dr. Thomas explains receptor binding variations.

Kelan Thomas (33:30): So, that's been a very interesting study, the first RCT by Pohon and Vaughn Tez, down in Brazil. I think we're starting to see people also research Ayahuasca, not as much in the US in terms of medical research going on, but in Brazil, there's a pretty robust network of research that's been ongoing. I think this gives us a sense, and in terms of adverse effects, I believe that adverse effects often—and again, this is something you could go either way on—because the purging effects, some people get a lot of therapeutic benefit out of it. In terms of risk during the ceremony, if you're having so much excessive nausea and vomiting, that is certainly at a much higher frequency than LSD or psilocybin. People could get into electrolyte disturbances if they've been fasting before, which could lead to certain nutrition shifts and electrolyte changes. So, there are some risks associated with Ayahuasca, but still not so much more than any other substance people are taking.

Dr. Richard Miller (34:30): We're not seeing people post Ayahuasca journeys, showing up much in emergency rooms, are we?

Kelan Thomas (34:39): No, I think one of the beneficial things is they're often in group contexts, which I think creates a safer container if people are there to help each other in a group. Versus, I think the times you do see psilocybin or LSD cases, they tend to be someone doing it on their own or with no one around, and then people get into a lot of paranoia or get very anxious. And then they feel like they need to go to an emergency room, for example.

Dr. Richard Miller (35:08): If the local guides can help them, look at what it is that's scaring them and turn it into something positive. Hopefully.

Kelan Thomas (35:14): That's right. That's right. Yeah.

Dr. Richard Miller (35:18): By the way, even though I'm a clinical psychologist, I don't think the purging from Ayahuasca is getting rid of internal demons and bad vibes. I think it's because people have eaten an emetic. And I think you, as a pharmacist, know that Ayahuasca is an emetic. Yeah, absolutely. Absolutely. And so, what happens when you eat an emetic is you throw up. And I think the shaman and a whole bunch of other people made this whole big story up about how it's beneficial, psychologically, to be throwing all that bad juju at the ecosystem. And I don't—I've never bought it. I still don't.

36:00 - Drug Interactions and Serotonin Toxicity

  • Cautions against combining SSRIs with ayahuasca.

  • No interaction risks combining SSRIs with other psychedelics.

Kelan Thomas (36:01): Yeah, I don't know for sure. But I've also heard stories where people say things like, they felt like they got rid of some burden through it. That's true. So, if it has meaning-making to them, you know, that could be possible too. So, there really could go multiple ways. But yeah, statistically, I don't think there's some actual benefit from purging for sure. Right?

Dr. Richard Miller (36:24): But I'm with you. If somebody says they got benefit, as my grandmother would say, "Go in good health." So, ketamine, talk to us about ketamine adverse effects.

Kelan Thomas (36:39): Yeah, ketamine adverse effects. In terms of the sessions, for a while, there had been concern about increases in heart rate and blood pressure, just like LSD and psilocybin, which had also been monitored. They have pretty low effects on blood pressure, unless there are some people that are more susceptible. One particular area that has been in the modern version of the S-ketamine approval is people with arteriovenous malformations, for example. So, they have some underlying vascular problem. They might be someone at risk from ketamine in terms of the acute effects, but in general, if people are fit to exercise and don't have any other restrictions, it's a very safe molecule, particularly at the dose range being given. It's another drug where people often don't understand the huge range in dosing. So, if you're doing things like procedural anesthesia, you might be giving doses at or above five milligrams per kilogram. In all these depression trials, they're using 0.5 milligram per kilogram. So again, we're talking about a huge range of dosing that's been studied with ketamine for many, many years. Very good safety profile. One of the risks emerging now is that, I think, compared to other psychedelics, there does seem to be more likelihood of people developing ketamine use disorder. So, we had seen that in the rave days in the UK and Hong Kong, where some people coming out of these club scenes were developing ketamine use disorders, where they would take too much at a time, they would sort of lose track of what they were doing. And then you can get into a lot more accidents if there's that sort of pattern of consistent use for hours and days at a time.

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38:30 - Microdosing Effectiveness and Future Research Implications

  • Explores the evidence regarding the effectiveness of microdosing psychedelics, mentioning recent randomized controlled trials (RCTs) that have not demonstrated significant effects on mood, cognition, or pro-cognitive benefits. Discusses the limitations and variability in individual responses to microdosing.

  • Highlights the need for continued research into the therapeutic uses of psychedelics and discusses the potential impact of this research on future health policies. Emphasizes the importance of informed regulation based on scientific findings.

Dr. Richard Miller (38:41): And then with ketamine, we have something similar, but even more so than psilocybin, in that there are so many ways to administer it. Right? So true, you can take it as a massage, you can get it into your muscle, you can get it in your bloodstream, and people are snorting it nasally, which is probably the common way for people to take it when they're getting addicted to it.

Kelan Thomas (39:07): Yes, I think that's the most common way. But it raises another point. Regarding the variation in terms of dosing ranges, when you add the layer of different routes of administration, whether that's insufflation, oral consumption, sublingual lozenge, intramuscular injection, or an IV infusion, all these methods have various pharmacokinetic profiles in terms of the drug concentrations entering the body and subsequently the brain, so they can have slightly different effects. They're not equivalent. I've actually put out a dose equivalence guide based on the bioavailability of the compounds. This provides at least some estimation of this milligram versus that milligram based on the route of administration. However, it also can have differences because of how it's administered, whether it's given over an hour in an IV infusion or taken in a sublingual lozenge. The milligrams don't exactly match up because they're going to have different peaks and changes in the way that the concentration enters and exits the body. So, those are all important factors to consider when thinking about the risks of dosing and administration.

Dr. Richard Miller (40:31): What's your view of ketamine as a psychotherapeutic agent?

Kelan Thomas (40:37): I mean, right now, it's all we have in controlled medical clinic settings. I have seen it have some benefit for people. But again, it mostly seems to dissipate after about two to four weeks. Sometimes, you might hear cases of people only needing infusions every couple of months, but it does tend to rise. Over time, we see a drop-off. That doesn't seem to be happening from the preliminary data we have for things like MDMA and psilocybin in clinical trials, where the symptom benefits seem to persist much longer, six months, nine months, 12 months, etc. So, one of the downsides of ketamine is you might need more consistent treatment with ketamine than you might with other psychedelics.

Dr. Richard Miller (41:32): When we take other medicines, we take them for the effect that they have on us. So, if I have a headache, I take two aspirin, I'm saying to that aspirin, remove my headache. Do these psychedelic substances, in your opinion, have a therapeutic effect in and of themselves, the way an aspirin takes away a headache by reducing inflammation and the various things it does? Or are the psychedelic medicines making us amenable to getting a benefit from some other source, such as verbal therapy or activity or something?

Kelan Thomas (42:27): I think it's both. There's emerging preclinical data for things like BDNF, neuroplasticity, changes in neural network states that have been associated with changes in people's inner experience of psychological thoughts. But if you're doing it without the psychotherapy, I think you're missing out on a lot of the benefits and the meaning-making from the experiential component. There are people who think we're going to make therapeutics that act like psychedelics but don't have any subjective experience. I don't think they're going to be as effective. So, there is a pure biological effect, but there's also a psychological effect at the same time.

Dr. Richard Miller (43:18): I want to come back to LSD just for a minute because I missed something that I wanted to ask you about. I had a spinal surgery yesterday, very high tech, radiofrequency ablation of nerves. And I was chatting with the surgeon, and he was asking me about the books I've written about psychedelic medicine. He asked me if I use the substances. And I said, I've tried everything I can possibly try, in the tradition of scientists using themselves as their safest subject rather than another human being that you might hurt. And he said, Well, when you use it for yourself, like microdosing, or other amounts of LSD, what are you seeking? What are you looking for? He wanted to know, particularly with the microdosing he wanted to know, because with the larger doses, the answer is more obvious. And what I said to him, and this is what I want your opinion on. When I saw Amanda Feilding's, the MRIs she published, of a brain on LSD, and a brain that's not on LSD. It appeared that the brain that was on LSD was more activated. There was so much more going on, firing, if you will, neurotransmissions. I see you shaking your head. Yes, that you agree. So my answer to him was that if these medicines can get more of my brain activated, that's to my benefit, because I will have more brain to work with.

Kelan Thomas (45:23): Yeah, and that's kind of what a lot of the neuroimaging data has shown thus far. Even in the absence of any drug, when you have hyperconnectivity in this default mode network, between certain regions, like the posterior cingulate cortex and the anterior cingulate cortex, which have been well described to relate to things like rumination, depression severity, if you can get out of those constrained thought patterns and allow more synergy. A lot of those charts and things show that you're having more cross-connections between various regions and networks of your brain. Why would you not want to, you know, shake up the snow globe, as some people say, and get some new connections or have some new ability to form new patterns or thoughts? If you're a curious person, it seems like you'd be very interested in psychedelics.

Dr. Richard Miller (46:21): But you'd also want to be listening to Dr. Thomas, who's saying, if you're trying to get more of your brain talking to each other, do it in moderation. Do it in a way that you don't pay in another way by getting a problem with a heart valve, if that's possibly the case. We're not sure of it yet, but you're giving a possible warning. Right, right.

46:55 - Exploring MDMA's Impact and Regulatory Challenges

  • Dr. Richard Miller reflects on his initial experiences with MDMA, emphasizing its profound impact and the prolonged struggle for FDA approval.

  • Discussion on the scientific community's response to MDMA's potential neurotoxicity and the subsequent legislative actions affecting its research and use.\

Dr. Richard Miller (46:55): So we talked about LSD and psilocybin, ketamine, Ayahuasca, let's talk about MDMA, the couple's heart drug. When I first took MDMA in my doctor's office while it was legal, man, I thought it was the greatest thing since chopped liver. And I still feel that way. I'm so sorry that it's taken Rick 35 years to get this close to FDA approval. And I was in shock because I heard Riccardi when he presented his paper on neurotoxicity. I was scared at the time, and that was a long time ago. And of course, Congress got a hold of that paper too. What do we know about adverse effects of MDMA that are definitive with real science?

Kelan Thomas (47:53): Yeah, it's similar to the other issues that I brought up.

Dr. Richard Miller (47:58): It doesn't go to the same receptors. No,

Kelan Thomas (48:01): It doesn't. That's another important point. So ketamine, for example, that we just talked about works on the NMDA glutamate receptor system. And MDMA, instead of working on the serotonin 2A, like we discussed with DMT, from Ayahuasca, LSD, and psilocybin, we all think that's mostly working through the serotonin 2A receptor. In the case of MDMA, it actually goes inside of the presynaptic terminal and releases neurotransmitters, more preferentially serotonin. And we think that the way that is being triggered, Google Dolan has written a lot on this, it opens this sort of social reward learning critical window, where people are more open to experiences, they feel more calm, they feel able to remember past memories that might not be so pleasant, and be able to sort of work with that material. And that leads to, you know, abilities to relearn like we're seeing in things like the PTSD, clinical trials that have been done so far. So from an adverse effect, it's really just the short term blood pressure and heart rate things. It's slightly higher with MDMA, but not much a couple of beats per minute more a couple of millimeters of mercury in blood pressure. It's not extensively more, particularly at the 80 milligram dose that's been studied in the phase three trials right now. And yeah, these neurotoxicity issues and things to me either, there's nothing really there in a therapeutic clinical trial. We're not seeing people overheat. We're not seeing people get serotonin toxicity or seizures, like we have seen in club environments. Because you have all these other factors. People are dehydrated, they're overexerting themselves, their temperatures are rising. So that's where we've seen some bad outcomes in those contexts, but in a therapeutic setting, none of those have been issues thus far in the clinical trials from a physiological standpoint.

Dr. Richard Miller (50:09): So when with a little piece of paper that gets printed up, that's going to be attached to the bottle of MDMA pills that the doctor is going to prescribe, if it happens that way. And you open up that little piece of paper. What's it if it was written right now by you? What would it say about adverse effects? Because those little pieces of paper always have some adverse effects written on them.

Kelan Thomas (50:40): Sure, it would say dizziness, do not operate heavy equipment or machinery while under the influence. That's pretty much the major things they would warn someone about on a prescription bottle like that.

Dr. Richard Miller (50:55): How seriously do you think we can get the public to take don't drive a vehicle under the influence of these substances, particularly like MDMA?

Kelan Thomas (51:06): I hope, I mean, with alcohol and cannabis, you know, people have raised this issue of don't drive while impaired. I think that's going to be an important messaging to get out for people that are self-experimenting with any psychedelic medications. So yeah, all the medications we discussed, I would want to have the window of its duration effects where you're not getting in cars and driving anywhere.

Dr. Richard Miller (51:33): Do you think MDMA leads people to do things, perhaps against their better judgment that they wouldn't do ordinarily, because of the nature of this particular medicine?

Kelan Thomas (51:51): I mean, I think maybe it depending on the context of use, you may be more open to suggestion from other people. But I think in general, that, you know, it's not completely changing your personality, I would say, but I think it does leave people open to being more susceptible to suggestion by people, if you're in that sort of loving state, or you're not being critical. Maybe you're feeling a little drowsy or woozy with some of the dizziness, maybe you're not making all the best decisions, moment to moment. But I think it's very useful from the context of having more introspection, and being able to sort of sit with ideas and have conversations about your emotions. That's what it's really useful for.

Dr. Richard Miller (52:40): Well, it is, it that no question it really lowers defenses, and makes us feel more compassionate. But I'm wondering also, to what extent, it makes women more open to predators sexually, for example.

Kelan Thomas (52:55): I think that's a real potential risk. I think that's a possible risk depending on the environment and context of use.

Dr. Richard Miller (53:02): With MDMA particularly. Yeah,

Kelan Thomas (53:05): Well, I think any psychedelics, really, but I think MDMA is in that category,

Dr. Richard Miller (53:11): Because of the open feeling. Yeah. Toad venom, what an interesting thing. People are eating Toad Venom, 5-MeO-DMT. But before we go into the toad venom, because there's something related to it that we need to talk about, you have been talking about receptors. And you know what a receptor is. And you know what a receptor does. But that doesn't mean all the rest of us know what a receptor is and what it does. And you've made the point that methamphetamine and fentanyl touch a particular receptor. And that receptor is known for creating valve problems. So therefore, other things that touch that receptor, we have to look out for the possibility of also creating valve problems. Tell us about this receptor. What the heck is a receptor? What does it do? And where is it and what does it look like?

Kelan Thomas (54:24): Yeah, receptors are everywhere in your body. For a variety, but some of the main ways that we have sort of chemical messaging throughout the body to change and regulate and have shifts in your mental state, your physiological state, you have adrenergic receptors that are often the things that are affected by stimulant type drugs. Dopamine receptors, also affected by stimulant type drugs. Then you have opioids like fentanyl or oxycodone, that's the mu opioid receptor

. So there's all these different receptors that each drug is binding into different pockets to cause these sorts of effects on transcription, on second messengers, on neuropeptides. So it's a lot of complexity once you get beyond the receptor level into second messenger systems. And that's where a lot of the science is right now, is looking at what's going on inside the cell, as techniques have ever improved to try to figure that out. But yeah, anytime you think of a drug, you know, my first instinct as a pharmacologist and a pharmacist is, what's the mechanism of action? Where's that molecule attaching in the body to cause whatever physiological effect we know that might cause? And so that's essentially what a receptor is in the body. Where do they live? Everywhere. Where are they expressed? Everywhere. Yeah, they're expressed everywhere, on the heart and the brain, in the blood vessels, in your gut, and digestive tract.

Dr. Richard Miller (56:04): They're all over the place. They're everywhere in your body. Yep. Yep. Okay, so I'm thinking now, we got these receptors, they're everywhere in the body. And I take a particular substance, X, the substance is now distributed, it suddenly gets distributed all over the body. And it's seeking out different receptors. And this particular X happens to find its way to the receptor that takes it in, right? Not all receptors will take in X, only certain ones, only certain ones, right? Yep. Okay. So we have a receptor, that if you mess with it, it sends a bad message to a heart valve. Right?

Kelan Thomas (56:55): Yep. It does. It's vital for the development of the heart valve and growth of the heart valves. And so it's vital to human development to have this receptor, but not triggered in the context of an external drug repeatedly seems to be

Dr. Richard Miller (57:12): Oh, that's the key. You want that receptor to do that building of that heart valve. But you don't want to do something to that receptor, that sends a message that instead of putting four wheels on that car, you put 12 on that. Right now your car can't drive because it's too many wheels. Yep,

Kelan Thomas (57:34): That's right. That's a good way to put it.

Dr. Richard Miller (57:39): Well, I want us all to understand what this is about as much as possible. Because that's our job as public scientists, Kelan, to make our language accessible to everybody. Right? Because we have that, that's exactly because these little things like 5-MeO. And so this is basically shorthand that we all use amongst ourselves. But it's our job to also let the public know what the longhand is when you pull this stuff apart, what it means, what it does,

Kelan Thomas (58:12): Yeah, yeah, that. I keep trying to come up with new ways to describe it. But another way that I described this potential risk of heart valve is that people understand about their muscles. As if you lift weights every day, over time you build muscle mass. If you lift weights for a couple of weeks and stop, you don't see that continued growth of muscle mass, for example. So that's sort of one way for to help people think about what might be going on with this 5-HT2B receptor. It's really all about total exposure over time, consistent exposure with no breaks. That's what we know from the other molecules that have this similar 5-HT2B receptor binding affinity.

Dr. Richard Miller (58:56): Well, the heart is a mystery to me, in that, we want to avoid the heart getting what's called too muscular, because then it's not pliant enough to do the pushing of the blood. And I have a hard time understanding how certain things can make the heart too muscular, and at the same time, the heart is more active than any other part of the body and it's constantly exercising, and you would think it would build giant muscles just by its exercising. But it doesn't.

Kelan Thomas (59:39): No, now the body is incredibly resilient in terms of homeostasis. It's only if you introduce new things. It's never seen all the time that we start to get into potential problems. But you,

Dr. Richard Miller (59:54): Understand my point. If you move almost any muscle in the body, even a fraction of how much the heart moves, you would build up a big muscle. Right? A really big muscle, but his heart that's beating 72 times a minute.

Kelan Thomas (1:00:12): That's a lot else it doesn't have resistance to. So a lot of like you can get tone a little bit, right muscle tone if you're not doing resistance. But most of our muscle building is also there's an additive resistance in addition to the pumping part.

Dr. Richard Miller (1:00:27): Yes, I do understand that. And that's why there is a condition called athlete's heart, where they exercise at a great, you know, great amount of heartbeats, and they build up muscles that way. All right, the frog venom. Why? To begin with, everything has a name, psilocybin has a name. Ketamine has a name, but the frog venom gets 5-MeO-DMT. Everybody on the street even calls it 5-MeO. Tell us about that.

Kelan Thomas (1:01:00): Yeah, so I mean, again, like when we think of all these molecules, why they didn't pick a specific sort of chemical name versus that. So Dimethyltryptamine, which is the DMT found in the Ayahuasca brew, then we have 4-hydroxy DMT, which is the psilocybin active metabolite. And then we have in the case of this, now we have a 5-methoxy functional group. So a 5-methoxy is just a different functional group on the edge of the DMT molecule. So anytime you make a little bit of a functional change, or add this hydroxyl group on to DMT, or add this 5-methoxy functional group on to a molecule, it can really change how it binds in the receptor pocket. So the receptor is a three-dimensional structure. And as the molecule comes in, David Nichols has done a lot of work on this, it attaches within this pocket, and that creates a certain conformation that leads to the signaling that happens intracellularly from there on in. So it really each molecule has a slightly different effect in a slightly different way. Even though they're working on the 2A receptor, they all trigger that 2A receptor just slightly differently.

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01:02:23 - Psychedelic Drug Interactions and Serotonin Toxicity

  • Cautions against combining SSRIs with ayahuasca due to risks of serotonin toxicity.

  • Clarifies that combining SSRIs with other psychedelics like LSD, psilocybin, or MDMA does not pose significant interaction risks, but may reduce the efficacy of the psychedelics.

Dr. Richard Miller (1:02:23): Do you think the public should be aware of the risks associated with taking psychedelics while also on an SSRI, a selective serotonin reuptake inhibitor, which inhibits certain neural sites?

Kelan Thomas (1:02:46): Yes, SSRIs and medications that inhibit serotonin reuptake, or certain substances like MDMA and other phenethylamines that increase serotonin release from the presynaptic neuron, pose significant risks. The most dangerous combinations involve Ayahuasca because it contains DMT and beta-carboline harmala compounds, which are monoamine oxidase inhibitors. This results in increased serotonin levels without adequate breakdown, leading to a risk of serotonin toxicity. MAOIs, once commonly used for depression, are less favored now due to their safety and tolerability profile, though they're still prescribed. The critical concern is mixing SSRIs, SNRIs, MDMA, or other phenethylamines like 2C-B with Ayahuasca, as this can dangerously elevate serotonin levels. Conversely, with MDMA, psilocybin, or LSD, the risk of serotonin toxicity isn't apparent; however, the psychedelic effects might be less intense for those on SSRIs, without posing additional safety concerns. The primary danger lies with Ayahuasca and its interaction with other serotonin-affecting substances.

Dr. Richard Miller (1:05:15): Regarding the administration of psilocybin and MDMA, do you have any warnings or advice on this combination?

Kelan Thomas (1:05:30): There's no significant increased risk with combining LSD and MDMA, as studies have shown. This combination might offer a benefit by alleviating the overwhelming influx of thoughts or feelings associated with classic psychedelics like LSD or psilocybin, making the experience more manageable with the empathogenic effects of MDMA. There's no clear evidence of adverse drug interactions with this combination.

Dr. Richard Miller (1:06:09): I've heard that the irritability associated with LSD and psilocybin can be mitigated by correctly timing MDMA intake. This seems to smooth out the initial challenging phases of the experience.

Kelan Thomas (1:06:32): That aligns with pharmacological expectations, indicating a potentially beneficial combination for managing the effects of psychedelics.

Dr. Richard Miller (1:06:39): Kelan, thank you for joining us today on MindBody Health & Politics. Your insights have been invaluable.

Kelan Thomas (1:06:46): Thank you for having me. I appreciate it.

Dr. Richard Miller (1:06:50): Let's reconvene in six months to a year to discuss new developments. And to our listeners, thank you for tuning in to MindBody Health & Politics. Remember, our archives are freely available at mindbodyhealthpolitics.org, featuring some of the finest minds on the planet. Also, my latest book, "Freeing Sexuality," has just been released and might be of interest. Until next time, remember that good health is worth fighting for as it's essential for life, liberty, and the pursuit of happiness.

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Mind Body Health & Politics
Mind Body Health & Politics
Dr. Richard Louis Miller is an American Clinical Psychologist, Founder of Wilbur Hot Springs Health Sanctuary, and broadcaster who hosts the Mind Body Health & Politics talk radio program from Mendocino County, California. Dr. Miller was also Founder and chief clinician of the nationally acclaimed, pioneering, Cokenders Alcohol and Drug Program. Dr. Miller’s new book, Psychedelic Medicine, is based on his interviews with the most acclaimed experts on the topic. Mind Body Health & Politics radio broadcast is known for its wide ranging discussions on political issues and health. The program’s format includes guest interviews with prominent national authorities, scientists, best-selling authors, and listener call-ins. The programs offer a forum and soundboard for listeners to interact with the show and its guests. We invite you to listen to the latest broadcasts below or visit our many archived programs. We’d love to hear from you on political and health issues!