Expert: Blinding in Clinical Trials Investigating Psychedelic Medicine Remains Difficult, Potentially Impacting Results

Pharmacy Times interviewed Jordan Sloshower, MD, MSc, a clinical instructor of psychiatry at the Yale Department of Psychiatry, a member of Chacruna's Council for the Protection of Sacred Plants, a clinical investigator in MAPS’ Expanded Access Program, a trainer with Usona Institute, co-director of West Rock Wellness, PLLC, and a member of the Board of Directors of the American Psychedelic Practitioners Association. Sloshower discusses his work serving as an investigator and therapist in several clinical trials investigating psilocybin-assisted therapy, and an upcoming course titled Critical Perspectives on Knowledge Production in Psychedelic Science at Chacruna Institute in which he will be addressing some of these issues.

Alana Hippensteele: Hi, I’m Alana Hippensteele with Pharmacy Times. Joining me is Jordan Sloshower, MD, MSc, a clinical instructor of psychiatry at the Yale Department of Psychiatry, where he co-founded the Yale Psychedelic Science Group and served as an investigator and therapist in several clinical trials investigating psilocybin-assisted therapy. Jordan is also a clinical investigator in MAPS’ Expanded Access Program for MDMA-assisted therapy of PTSD and serves as a trainer with Usona Institute’s psilocybin facilitator training program. He is also the co-director of West Rock Wellness, PLLC in New Haven, Connecticut. Most recently, he was elected to the Board of Directors of the American Psychedelic Practitioners Association.

Jordan will be teaching in a course titled Critical Perspectives on Knowledge Production in Psychedelic Science at Chacruna Institute that will offer CE credit for those interested. Could you tell me, Jordan, a bit more about this course at Chacruna and its focus?

Jordan Sloshower, MD, MSc: Recently, there's been a pretty big explosion of interest in psychedelics. A lot of different courses and training programs are popping up, the majority of them focused on kind of psychedelics 101, trying to convey some sort of basic information either about psychedelic drugs, their mechanisms of action, kind of the exciting neuroscience about them, as well as some of the nuts and bolts of clinical applications. And all of that stuff is also super interesting and exciting. However, that's sort of being done by other organizations. What's really unique about this course is that it's taking a critical perspective on all of the science that's being done in the psychedelic field, and especially bringing a social science and humanities lens to all of this body of research, which really hasn't been done to a full extent.

There has been increasing discussions about ethical issues in the psychedelic medicine space, as well as some of the challenges and problems with clinical trial design, and that is gaining traction and discourse is going to look at some of those issues. But to go beyond just the nuts and bolts, like the scientific problems of how do we blind psychedelics, which is more the area of clinical trials science, and actually sort of get under the hood inside the lab to understand how knowledge is being produced? What are some of the philosophical issues? What are the contextual issues, and actually look at how this is playing out across the globe, not just in North America. We have researchers presenting from different contexts around the world, we're looking at indigenous perspectives on psychedelic science. And we have the humanities perspectives, as well as other social scientists who are thinking deeply about some of the complexities of doing this kind of research and bringing it forward.

Hippensteele: In much of clinical trial research, the focus is FDA approval. How might this trial design impact or be impacted by the unique qualities of psychedelic medicine?

Sloshower: So I think clinical trials are grappling with how to fit psychedelics into standard clinical trials, especially psychedelic-assisted psychotherapy. Because on the one hand, the drugs themselves have extremely powerful subjective effects, which makes it very difficult to blind, which is a typical part of clinical trial design. And then the added pieces that these are in clinical use are combined with some amount of psychotherapy or psychotherapeutic support. And in the typical FDA model, as you mentioned, the focus is really about isolating the drug, the compound itself, it's not set up well to account for the complexities of psychotherapy and other factors. Then if you take away the blinding piece, then you're really left with a problem here. So many clinical trials are grappling with how to deal with those issues.

I think what we're looking at in the course is, well, how does that actually play out? How has that been playing out in the labs? What are the solutions that are being done, and what are some of the tradeoffs and risks and complications of these different techniques that are being done in the clinical trials? That's at least one of the things I will discuss in my lecture for the course.

There are other perspectives, another lecturer who will be discussing the challenges of placebo use, again, from more of a social science historical lens to actually pull out how these issues aren't actually totally unique with psychedelics. So we'll be looking at some of these problems from a few different lenses, and also how it's playing out in labs around the globe.

Hippensteele: Right. In your experience serving as an investigator and clinician in 2 recent trials of psilocybin therapy for major depression. What are some of the ways the studies address some of the challenges in investigating a psychedelic medicine like psilocybin?

Sloshower: Yeah, again, it's a good question, I could probably speak for at least half an hour just on that one topic, but a couple little snapshots, I guess, are one, the trials have to kind of standardize the non-drug components, right, and the drug components really, so that we can try at least from an FDA standpoint, we want to try to isolate the drug effect, which is kind of an artificial thing to do with psychedelics. Because number one, we know, through many years of experience that actually the set and setting also impact the effects of the drugs, with the set being more the mindset setting, being physical and social context, in which the experience happens, which can impact the actual result and experience of the medicine itself. And again, we have the psychotherapy, so one of the ways that the trials have dealt with this is trying to standardize those different components and standardize the psychotherapy component. In some cases, that actually means minimizing the therapy components, so that it's almost considered a non-factor or non-variable, which again, has some issues there as well. And then the other thing that the trials have done is tried to select different types of placebos and also try to create other techniques to minimize what we call expectancy effects, or people being able to kind of predict what they're going to get and then have preconceived notions of how that's going to affect them.

Hippensteele: How did differences in study design in these 2 clinical trials you participated in impact knowledge production and participant experience?

Sloshower: It has been such a rich experience to move through and be part of these 2 incredible trials that I was part of and work with these patients and learn so much about actually conducting the trials. So there's been a lot of learnings, I think. One of the points that I draw out with some nuanced discussion is that there's some inherent tensions between the purely scientific imperatives to sort of isolate that drug effect. And, in some cases, that means minimizing the therapeutic content. So a tension between those scientific imperatives, and actually the best interests of individual patients are the optimization of the actual therapy itself. And so, for instance, in the trial I was part of at Yale, we actually really tried to optimize the therapy and wanted to do that piece of it. But, in fact, in some ways that didn't actually favor isolating the so-called drug effect. And so the results of that trial are pretty nuanced in terms of trying to tease apart those different factors.

There were also differences in the blinding strategies across the different studies, and we had some sense of what may work better than others a lot of times in one of the studies using niacin, for instance, often in both cases, actually, it didn't feel like the blinding was overly successful. And so thinking a little bit about how that impacted patients and at least in the context of the Usona study, one difference between the 2 studies that was part of his one had only one dosing session and the other had 2, although in that one people only receive the active drug in one of those sessions. But there was a real difference in the expectancy and how patients moved through those trials. And when, again, these studies were being done with patients with moderate to severe depression, actually, both of the trials, it was a relatively ill population who are often coming to these trials as kind of a last resort and for many of them, so there's just huge amounts of disappointment when they don't receive the active medicine, and again, at least suspected or know or feel like, they know that they received the placebo, and they don't have a chance to receive the active drug. And, of course, in the current legal context, there being no legal mechanism to receive these therapies. So, in some ways, that's what I mean, when the trial design itself, although there's good clinical scientific reasons to only have that one dosing session, because it's a cleaner design, also, it really creates some challenges for those patients and the therapists in the trials. And it, in some ways, makes these trials high stakes for a lot of people and the clinician, so it's just getting into those types of nuances is where this course is going to shine. Because those are the complexities that often don't make it into published papers are not commonly explored thoroughly.

Hippensteele: So pharmacy professionals, who might be working in compounding psychedelic medicine, or who are involved in research and the clinical trials space, although potentially not directly correlative, how might a deeper understanding of knowledge production in psychedelic science help to potentially shed light or help to clarify aspects of its medicinal use and effect?

Sloshower: Yeah, I think there's a significant role for clinical pharmacists, especially in these trials, because and especially as the field continues to evolve with different psychedelic compounds. So I think having that perspective is key what will be, I think, useful for pharmacists in this course, is having a little bit more nuanced understanding, for instance, of how drugs’ set and setting are factors, how these types of trials look different from the trials, they may be used to in terms of combining the drug assisted psychotherapy model and understanding some of the nuances of that.

We have one class that actually discusses the entourage effect, which refers to how actually with certain especially botanicals, psychedelics, are naturally occurring psychedelics that contain more than one active compound, how does the interaction between those different active compounds affect the patient and the subjective experience as opposed to the usual isolating a single compound and testing it. And then the whole drug interaction piece is critical for working with our patients, understanding how we can wear them safely off of off of psychiatric medications, so they can participate in these trials. And that's evolving, and it differs from one medicine to the other. So again, some of those pieces actually won't be covered in this course, so particular pharmacological pieces, but I think for those who are interested in having a deeper understanding this area of research, it'll be a great opportunity to learn about the nuances and also again, about how the research may be looks in different settings.

Hippensteele: So there has been more research showing the efficacy, efficacy and safety of at home ketamine treatments for MDMA and psilocybin, which are behind ketamine on the track toward FDA approval and availability. Do you think the at home potential may be impacted due to differences in clinical trial design and outcomes?

Sloshower: Thanks for that question. So I'm familiar with working with compounding pharmacies to produce the oral form of ketamine or ketamine lozenges. In my practice, we do ketamine assisted psychotherapy, using the oral form as well as intramuscular form of generic ketamine. In both cases, however, we exclusively in my own practice, do those sessions in office under supervision so I'm less familiar with literature supporting the safety of at home use, and I think that still it’s potentially controversial area, I know it is being done.

Increasingly, however, at least from my own personal clinical perspective is that these medicines are extremely powerful and useful psycho-therapeutically. And so I wonder at least, and this is an ongoing debate in the field is when patients take this at home, and it's really just enabling them to sort of get the medicine medication into their body. Hopefully, they're doing that safely. But it's really more of a biological model, as opposed to doing the having these medication sessions in a supervised and supportive setting where they're able to on the spot and afterwards, process that experience, and sort of combine it with a psychotherapeutic process. So I'm personally more comfortable and in favor of the latter, and I believe with psilocybin and MDMA, certainly initially, there's really no possibility that they will be at home treatments. Again. The all the discussion now is for similarly to what I've shared is an in-office supervised model. Even in Oregon, where there's a legalized state initiative that is not a medical model is going to make psilocybin supervised psilocybin experiences available to the general public, even in that context, it's still not legal for just buying it and taking it home and using it, it's still within a supervised context with people who've undergone some amount of training and supervision to help increase the safety. I think, again, the question of general legalization, and whether people should be able to have experiences with these medications on their own is a separate policy and public health question. But at least for the medical model that we're mainly discussing here, in terms of using these medications, for the explicit purpose of treating mental disorders or other medical conditions, the model is really the supervised use supported model.

Hippensteele: That is really interesting. As psychedelic medicine continues to become more broadly accepted, and potentially, eventually available, what are some challenges that we might face that may be new for our society and healthcare landscape?

Sloshower: Thanks, Alana, that's a great question, there's going to be a lot of challenges to integrating psychedelics into the health care landscape, for a variety of reasons, especially because, again, the powerful nature of these compounds. And the model in which they're being administered as far as drug-assisted psychotherapy is requiring a shift in how we think about delivering care in mental health settings and figuring out how to administer these compounds effectively and safely in a variety of different settings for a diverse population or different populations. So it's going to be a lot of different challenges.

These compounds have been used in indigenous communities for centuries, and also in underground settings in the West since the 60s, but never really integrated into mainstream societal structures, like what's happening in Oregon or into the health care system. So in order to actually do that we need a lot of things. And this actually gets to the work that I'm involved with, with the American Psychedelic Practitioners Association, which is a practitioner body that's thinking deeply about what's needed to bring these therapies forward and are working on developing things like standards of care and ethical guidelines and standards of training. We're going to need accreditation bodies to certify those programs to say who's actually met standards for training, the practitioner certification boards will need mechanisms to deal with ethical issues that arise, and there certainly has been attention to the ethical issues with the administration of psychedelics in clinical settings recently. Again, because under the influence of these medications, our patients or clients are put in a very vulnerable state, and we need really good guardrails and processes and trainings to ensure their safety and that this all happens in a good way.

And then lastly, we need to think—not lastly—but another issue is to think a lot about accessibility, both in terms of cost and having insurance companies understand the model of drug-assisted psychotherapy and being willing to pay for that. And that will require cost-effectiveness research and convincing government and payers that this is a worthwhile treatment. And not only for those who are refractory to other treatments, but potentially as early or first line treatments, depending on the data. And beyond just the affordability of these treatments, we also need to ensure that they're culturally sensitive, culturally attuned to diverse populations that we have therapists in, and physicians and pharmacists, from diverse backgrounds who are trained to administer these to diverse populations, because certainly, in this area of research, there's been a lack of diversity amongst both practitioners, but also the patients who are taking part in clinical trials. And there's many reasons, historical and structural reasons, why that's the case. But that's also going to be a challenge for rolling this out and making sure that actually the treatments benefit everyone who can benefit.

Hippensteele: So, Jordan, what is your outlook on the psychedelic medicine space and its impact on health care in the near term and in the long term?

Sloshower: I think psychedelic medicine is just a fascinating and promising area. There's so many nuances and complexities both from scientific lenses, social science, humanities—we need so many different types of practitioners weighing in and providing their perspectives to both evaluate the utility of these as medications for different conditions and to deliver them safely and effectively and come up with the models and find out how to integrate them into health care. So much promise here potentially, and opportunities to learn, as well as perils if there's not sufficient guard rails, and we don't do this thoughtfully.

So, at its best, I think this could represent a new model for addressing mental disorders and potentially other physical and psychosomatic illnesses, which is an upcoming frontier. So I think there's a lot to dig in to and I just want to invite all of you to join our course if you're interested in digging into the nuances of this field and how this research is playing out.