Delve into the World of Psychedelic Research and Ethical Inquiry

About this episode:

Join WCG Talks Trials podcast host Kelly Fitzgerald, PhD, in a riveting dialogue with guest expert Currien MacDonald, MD, as they unravel the nuances of “Psychedelics in Research: Ethical and Medical Perspectives.”

Dr. MacDonald, with a solid foundation in family medicine and clinical trials administration, guides listeners through a grounded exploration of psychedelic substances. In this episode, they demystify the realm of psychedelics, encompassing both dissociative and classic varieties, such as LSD and MDMA.

As the conversation delves into ongoing research, the potential applications of these compounds in treating mental health challenges like depression, anxiety, and post-traumatic stress disorder come to the fore. The dialogue doesn’t shy away from probing the ethical dimensions surrounding psychedelic research, addressing concerns about study design, potential abuse, and the intricate balance between benefits and risks. This insightful podcast offers an engaging journey into the evolving field of psychedelic research, shedding light on its medical potential and the ethical considerations that guide its path.

Speakers:

• Kelly Fitzgerald, PhD, IRB Executive Chair and VP IBC Affairs
• Currien MacDonald, MD, CIP, IRB Chair, WCG IRB

Episode Transcript

Kelly: I’m here today speaking with Dr. Currian McDonald. We’re going to be speaking about psychedelics and research today. After graduating top of his class from the University of Minnesota Medical School, Dr. McDonald completed a family medicine residency program as chief resident. He then delivered primary care for five years in San Diego, California.

After that period, he served as a medical consultant to the University of California, San Diego, on a groundbreaking prisoner health care reform project. He has been with WCG for over 10 years, and he has completed certification programs and clinical trials administration and medical acupuncture. He’s also a certified IRB professional with Primer, the National Organization for the Protection of Human Subjects in Research.

In addition, Dr. McDonald’s a member of the American Academy of Family Physicians, the American Medical Association, and the American Medical Writers Association.

We’re here today to talk about clinical research with psychedelic drugs. FDA published its first draft guidance on this topic in June in response to an increasing interest in clinical trials of psychedelic drugs to treat a range of diseases. So, Currien, when we hear someone say psychedelics, what types of drugs are they talking about?

Currien: It’s a great question, Kelly, and really important when we start to look into this to be clear about what we’re talking about. In the kind of general term, psychedelics are anything that produce this psycho emotional or dissociative state, kind of your hallucinogen is another term that’s commonly gone with it.

However, that’s not the best scientific term. There’s a number of terms that are better and psychedelics are ones that go with. A either disassociative or an increased associative emotional state, sometimes enacted genes or pathogens are used with these because they have someone connect more deeply with themselves and more deeply with someone else.

They act in a certain place in the brain rather. Dr scientific key. And that’s why they’re kind of lumped together. However, the mechanism of actions and. The specific drugs being studied mechanisms are different enough to think that this is not one thing, but actually very multiple things with the multiple different kinds of mechanisms and things to worry about.

For right now, since it’s rather the infancy of their being studied, calling them psychedelics as anything kind of that produces these states and is on the classes that we know about of either classic psychedelics like LSD. Or a classic antigen like M D M A are kind of good places to talk about them.

At first, I’ll leave dissociative drugs as kind of on the borderline. Those are important because there are known drugs that we currently are using that are very much like psychedelics in our arm, our arm medical armamentarium, the drugs that doctors commonly use. For current things you can think of general anesthesia, for example, as being something that’s used in this or.

Something used for a medical procedure. Okay.

Kelly: All right. So, have any of these psychedelic drugs been approved for treatments of disease yet?

Currien: That’s a great question, and that goes to, again, what do you call a psychedelic? Because we have dissociative drugs that we use very commonly some classic drugs that have been used in these areas.

So, for example, you can even think of propofol drug. It’s rather just an amnestic. So it’s dissociating you from yourself or you have the classic one, which is ketamine, which on the street is special case. So it kind of goes more towards a classic psychedelic. That’s approved both for anesthesia and also has been recently approved for depression in that specific way.

So depending on which you use, you use it for, it might be more psychedelic or less psychedelic, depending on how you’re using. It’s a very interesting question. Okay, and so sorry to answer your question directly ketamine and as ketamine are approved for anesthesia or depression treatments, respectively.

However, many people use ketamine off label because it is an approved drug and it’s cheaper than as ketamine, which is approved for that other indication, but it’s the same drug basically.

Kelly: And are they using it off label for these purposes or other purposes in addition?

Currien: Great question. Off label for the treatment of depression, which would be acceptable medically, generally medically, and off label uses are acceptable medically.

You can use it off label for a lot of other things. You can use it without a prescription if you happen to get it illegally for recreational use as well. And that is an abuse sidetrack that probably will come up later as we talk about these terms.

Kelly: Okay, and do you know what types of studies are currently underway for new therapeutic indications for these types of drugs?

Currien: This is a huge and such a great question. It depends on what you mean by studies and therapeutic indications. These drugs are very old. They’re used in a lot of kind of cultural experiences as well, and they have been around for a while illegally and have been brought into hard for a while. They’re being researched for kind of I want to actually now publish and let people know they can use it or perhaps get approval to use these drugs in a regular way is where the studies are going now, and the potential from these drugs is absolutely astronomical.

It is a new kind of way to get into the very powerful area of the human brain and includes things like major depressive disorder. We already mentioned with the approved drug, but the abuses, it’s kind of somewhat ironic to think of these drugs as being very good against alcohol abuse and tobacco addiction research.

I think they Actually gave a grant for these drugs to be used in tobacco addiction research, because it’s that you think that ones should be kind of simple, and it’s still not. But these seem to work well in that area. Cancer related anxiety, depression, kind of a coming to group with the end of life is another area that is a huge need, but.

Nothing else really can go there. Obsessive compulsive disorder is another one that is just not pharmacologically able to be treated right now, but this has a way to perhaps bridge that gap again. Eating disorders, very similarly, very large unmet need with no medical intervention. And even something as simple as post traumatic stress disorder, which has some drugs that kind of work and some therapy aspects that kind of work, but it’s still really very drastically unmet need.

The part of the reason the question is so interesting is because. We don’t understand the drugs and we don’t understand the brain. And so there’s this untapped potential that really is huge for something that needs study, desperately needs study.

Kelly: And so what are the hypotheses about why these particular drugs would be useful in treating these challenging diseases?

Currien: Again, I hate to say brilliant question all the time, but you’re just brilliant. These questions are brilliant. The idea is that because of their unique mechanism of action, it’s not terribly unique. They go through a pathway that we know works in, for example, depressions, and a lot of the run of the mill We know they work kinds of serotonin drugs in depression.

These work through a lot of them are through a similar pathway. Recently, we found out that the way we thought they work. These classic depression bugs is not the way they work, but they still work. We know that for sure. So it really calls in a. Brings to for the idea that we’re not exactly sure how all of these things go together to think your brain is as simple as kind of on off switch or simple things like that is obviously not true.

What makes them so unique and so potentially powerful as they work in a different way. That is this disassociative or associative actions. We know the. Mental process that produces it. We know the anatomical structures that go to it. We have an understanding of some of the chemical compounds that are in it.

And so it’s an area that we could understand if we researched it and have a theory to drive a hypothesis that would drive in a clinical outcome. Right now, we just aren’t touching at all. And so that’s why they’re extremely exciting is because they’re like a new class of drug, like a new antibiotic that goes and kills bacteria in a way.

We’ve never seen before. That’s why kind of it’s exciting.

Kelly: Okay. So there’s a lot of potential here, but it would take controlled clinical trials to get at these mechanisms as opposed to doing sort of natural history studies of people who are already using them and then seeing how they respond.

Currien: Absolutely. Absolutely.

Kelly: What characteristics of psychedelics make them particularly risky in these types of environments?

Currien: And that is the flip side of power is power is dangerous. So anything that’s exciting and has a potential for really cracking open your brain and getting to a root cause is cracking open your brain and can have risks.

There’s several kinds of risks, especially for this kind of a drug, like an antibiotic. You’re not really worried about things such as abuse or dependency or them being taken. And like, Ketamine has a control. And esketamine has a control. Aspect to them, because they can be used as drugs of abuse.

Antibiotics don’t go that way. These certainly lend themselves to. We know that they have come out of a culture and have a history that goes with them of being used for recreational purposes and can be potentially abused. So there’s that part of it. The fact that if I know that the drug you prescribed for me works, and I can get it.

Without a prescription from my neighborhood dealer makes it also a different kind of a danger and having these kind of drugs available that then you have just the standard risks of side effects. We always talk about the side effects of abuse, but there’s also other ones to any chemical that works, works in different ways.

For example, the same kind of neural network in your brain is in your intestines. And so there’s a potential for these having kind of serious intestinal problems, especially when you start dealing with people who have intestinal disorders, then there’s the risk of on target effects. If they work really well for having you make close connections with your therapist and the drug wears off and you go home and getting a really bad Fight or car accident or something, then you’re going to have that same open connection to be available.

And so there may be problems with that and telling someone. Well, we’re going to give you this medicine. Then you’re going to stay in my clinic for 5 hours. That doesn’t really work. That’s a risk for use of. Well, maybe we can do it over the phone and that’s good enough. Maybe again. Need a lot of more study about this, how, what dose is appropriate, et cetera.

And then the last risk that goes with that are regulatory risks, kind of the flip side of back to the front of all right, these are potentially now becoming legal. There’s a problem with that, especially when I’m saying, okay, this thing is a drug, but it’s being used in ceremonial aspects right now without any regulation.

And to be clear that we’re not trying to regulate. This culture ceremonies, we’re just trying to regulate the abuse of this drug, which happens to be the same thing that y’all use. And that’s another really important thing to consider. I consider it a risk as something just to be aware of. Again, we’re kind of dovetailing on that, the power and the risk.

It’s not something to be afraid of. It’s something to be aware of so we can appropriately study it, learn how to minimize risks and maximize benefits, get the best from the power that we have. Same way that we do for electricity, right? It’s a very powerful thing, but don’t let it just wiggle around in your street in the rainstorm.

Kelly: All right, so we know there’s a potential for abuse because these are drugs that are used for recreational purposes. How much do we know about their abuse potential compared to other drugs such as oxycodone or and how would we study that? How would we do a good study?

Currien: I’m not going to say brilliant question. I won’t. It’s a very good question. However, we don’t know very well. FDA does have pretty clear general guidelines about what they would want to see for ensuring that the abuse potential of whatever is being studied is studied appropriately. That is in their job to ensure that drugs are safe and effective when used in general.

They’re going to want to have labeling and restrictions on them to maximize them. The benefits and minimize the risk. So they do have some guidance in there right now. I think we’re starting with. I would say nothing because it’s so mixed. Regular users say there’s very little to zero abuse potential while critics say there’s a very high abuse potential because.

Well, people get into trouble with them. It’s a little bit of a chicken egg because if they were legal and use, would you get into trouble with them anymore? Because that’s not trouble to be using them at the same time. They’re very different drugs than oxycodone. However, there’s also good theory to support that looking at any drug as abuse.

Are abusable is neglecting that people are abusers and a personality type makes you susceptible to. Abusing something, coffee, work, like all the, what are those called aholics, all the aholics, you know, that’s a personality issue, and it’s not necessarily a drug issue. At the same time, I don’t think that detracts in any way from the need to have appropriately designed studies looking at the potential for this.

And we may find that, for example, just to use common names, LSD has almost zero abuse potential, while MDMA Or ecstasy or 1 of the MDs has a very high abuse potential, but only above 10 milligrams, but next to 0 at 2 milligrams was still effective at 2. So we just need a lot more data on it. I’m not saying a brilliant question, so these

Kelly: are the questions that we need answers to, and in order to get them, we need to do studies.

So what are some unique challenges to designing studies using psychedelics?

Currien: A list a whole litany unique challenges. I’ve hinted at some of them. The first one is making sure that we’re using the same thing. And FDA does know in their guidance on this kind of what prompted a lot of the attention on it that these could be considered botanicals or could not be.

So if my study product is a mushroom and I say take half a mushroom a day, well, that’s not very scientific, but that may be what we’ve had in the past to use. We haven’t had manufacturing plants trying to narrow down the specific chemical involved. And there may be good reasons for that. I’ve just read a recent study on my favorite mentally active compound on caffeine, that caffeine is not the same as coffee and coffee works a lot better to do the things that I want to do than caffeine alone.

So maybe we do need to study actually the mushroom. Complicated, though, because how do you grow a mushroom? How do you test it to make sure you’re getting the same mushroominess across everyone in your 100 person, 1000 person study as opposed to another chemical that I can just make? Using other things that are issues with this is the observational data.

And if it’s going to be such a regulatory issue, can I just say, well, I just want to study people who are already using this. And the question then becomes, is that controlled again? Are they taking mushrooms? Are they taking a compound that I know it can control? And once I start to control it, then who’s making it?

Well, it’s my mushroom grower. Does that work? It’s very, very difficult to do that. The other part that’s difficult, and FDA does note this is that we’d like to think of these drugs as take home, here’s a pill, call me in a week. You know, take your X milligrams of whatever you’re taking once or twice a day.

And they probably don’t work that way, especially when we’re looking at the way that people get through mental illness. Brilliant and terrible thing about the brain is it can’t observe itself. You can’t do therapy on yourself. You can think you can, but then you’re just thinking. So trying to get a mental illness, especially powerful mental illnesses, just by here’s a pill.

Take it home. Maybe a problem. Especially we’ve seen some of the. Studies out of the psychedelic research in PTSD that it is really the therapeutic alliance. I mean, that’s really difficult for FDA who regulates drugs and not therapy and not therapeutic alliances. So to build that into the study makes it okay.

Then how do I label this drug? What is the drug doing? There’s other things such as controls that if it’s their only drug, what would you use? Like, 0 control, is that ethical at that point? And there’s a bunch of issues that go with. Well, I have really good evidence that this might work, but I’m going to complete placebo control it.

And, you know, especially if it’s a disease that has, for example, suicidality or other issues that can negate exactly what you’re going for keeping people in a study. With mental illness, when it doesn’t work, it’s really, really hard. And so your study design, placebo control, powerful study design is problematic.

There may be others.

Kelly: Okay. Are there any issues with recruiting these populations? I mean, we’re talking about pretty vulnerable groups of people here who are struggling with mental illness. Does that also add to the complexity of doing studies with these populations?

Currien: Another great question. Not only the vulnerability, but the potential for the view of it as just an easy way to get high.

Come join my study and get high for a while. Yeah. Yeah. I’m suffering real bad from what disease did you say? Doc? I don’t think that would be actually the case. I think it’s more likely we’re going to have a hard time recruiting people into the study because they’ll be vulnerable and they’ll be perhaps targeted or feel bad.

I have this real bad disease, but I don’t want to just get high doc. Don’t you have anything? No, this really might work. I don’t know. And once you go into a trial thinking, I don’t think this is going to work, you have like a anti effect effect. I think that’s a nocebo effect. I’m not sure. But something like that going on.

So. I think recruiting for it is going to be really difficult. Recruiting and retaining is the other part. I think retaining is going to be another really challenging issue for well controlled designs. Anytime you introduce the therapist into it, recruiting from a therapist’s clinic is really hard because there’s bias.

And if you’re trying to control for that, then you generally want to have 1 or a set group of therapists. And so to have them go to someone external to start over with the therapeutic alliance would be a problem. I think some of those are easily overcome. For example, you could have therapists all following some sort of a script or a training program or something like that, which would help normalize it.

But these are all things to think about as you were designing the trials.

Kelly: Great. And are there any particular issues with after a trial is done? I mean, these are challenging diseases. Somebody might obtain relief through participating in the study from something that was causing them a lot of distress.

Are there issues with how they might access treatment after these trials and are those different issues with these types of drugs than with other drugs?

Currien: Yeah, that is a, especially for researchers and for people like us in the IRB, looking at what is the appropriate way to review these minimizing risks, maximizing benefits, and ensuring appropriate inclusions the vulnerability of people coming in can’t be overstated from just their aspect of having a serious disease that doesn’t have good treatment.

As well The ongoing consideration of them as a vulnerable population. What happens if, for example, they’re not responding. And what’s our duty to them, just kind of punt them out. The last part that you’re just bringing up is okay. Let’s say we get through all of that. And it’s actually is working.

We’re like, trials over do we want to, for example, with some cancer drugs, just say. If you’re getting benefit, we’re just going to let you continue on it. Personally, kind of makes sense in cancer. It doesn’t make sense here. That, I think, is still a big question mark. It’s not saving someone life like it is in cancer or is it.

Hard to say, maybe yes, maybe no. Similarly, if you just say, listen, this is all the supply I have and FDA says you’re done after this, or, you know, any 1 of those kind of situation. So this is it. The person again, like I alluded to earlier says, okay, that was working real well. I’ve never felt this normal in a long, long time.

Where can I get this? And you as the researcher say, or don’t say, I know where you can get it. Cause I know people who can get it. You can’t say that, but at the same time, they know. And at the same time, you don’t want them to just go buy it from some random on the street and you’re like, this is a reputable source.

This is safe product to use. I mean, those are really tough questions for people designing studies, running studies, trying to care for their participants in the best way that they can for reviewing bodies and saying what amount of care is necessary to ensure that people are exiting the study safely.

All those sorts of things are really difficult questions. I do not have great answers.

Kelly: Well, it sounds like, I mean, that’s why we, we want to see studies in this area. And it sounds like it’s a fruitful area to study with with potential benefits and also potential risks. So, which is it is this a revolution in treatment, or is it unsupported hype over the chance to legalize getting high?

Currien: It’s all of that and more and everything in between. It entirely depends upon the people doing the work, and there will be, and I guarantee that if the IRBs or the research community as a whole have not seen attempts to hype up And say that these drugs are perfectly safe, and we should legalize them.

There will be. And if we have not seen studies that say that this is an absolute revolution in treatment, then we will see that too pretty rare to have a revolution in treatment. And at the same time, you can have bad research in any field that you want. It doesn’t matter what drug it is, doesn’t matter what device you’re studying, it can be unsupported hype over the next best thing, because people want hope.

I think there is definitely some hope here. These are powerful drugs, unarguably powerful drugs. We wouldn’t be as either scared or excited by them if we didn’t recognize the power there. I think the power though, like any other power, any other drug with power, it is about how you use it. And I think leaving these drugs untapped power in areas that are such a sore clinical need, and leaving these poor people without any treatment whatsoever, is just a wrong.

That I can say it’s just not ethical at this point. Not arguing needs to be done right. I’m a little bit worried about both sides of the coin too much oversight too much regulation too close scrutiny and not enough. Just let’s do something at the same time knowing that when you just do something, it can be random and can lead to problems like a real bad study may sour it for everything when it was just a badly designed study.

So again, I think it’s all of those. I’m glad we’re having the conversation of starting the conversation about this.

Kelly: I am too. So thank you very much for your time today. I’m really glad that we had the chance to have this conversation and thanks to anybody who’s listening today. I hope you come back for another one of our podcasts from WCG.

Currien: Thank you very much. Hope you all have a great day.