Behind the Scenes on the First Study To Compare the Effects of LSD and Psilocybin – Technology Networks

A new study has compared the effects of varied doses ofpsilocybin and LSD for the first time. These two popular psychedelics have been of increasing interest in clinical research. The new paper, which detailed a double-blinded, randomized and placebo-controlled study of 28 healthy volunteers, compared the impact of placebo, LSD (100 and 200g) and psilocybin (15 and 30mg). The study was a collaboration between the Liechti Lab at Switzerlands University Hospital Basel and MindMed, an established player in the psychedelics drug development industry.

Technology Networks caught up with Rob Barrow, CEO of MindMed, to discuss the findings in more detail and explore pressing issues around blinding in psychedelic drug development.

Barrow spent 10 years as the chief operating officer of a clinical stage private pharma company before joining the psychedelic non-profit Usona Institute, followed by a move to MindMed in 2020. Barrow says that his vision for MindMed was of a psychedelics company that can operate at scale and juggle multiple assets. It's an ambitious goal. In this interview, he discusses how this aim has been realized in 2022.

Ruairi J Mackenzie (RM): How are doses in psychedelic drug studies decided upon and measured?

Rob Barrow (RB): As in most drug development programs, dosing is one of the key aspects you need to fully characterize throughout early development. When you go into your pivotal phase III studies, you need to have your dose nailed down. There are a number of elements that can factor into dosing on an individual basis, but you're arriving at a dose that you feel is reliably going to induce the pharmacology that you want, to lead to the clinical outcomes that you're seeking to provide to patients.

When we think about dosing with psychedelics, there has been, fortunately, decades of research to well characterize the pharmacokinetics and dynamics and we really have a good understanding of how those interactions play out.

To have a drug that you can bring out to market at scale, you typically end up at a fixed dose regimen unless there's a particular concern, often more of a concern for safety, which tends to not be the case with this drug class. Most of the studies look at metabolic phenotyping and genotyping and drug-drug interactions with LSD; all these things are important in terms of labeling. But often it's not the case that they're labeled for an efficacy or pharmacodynamic reason, they're labeled because of safety. When you think about psychedelics, at this point we feel like we're confident enough in the safety that we are aiming for a fixed dose regimen.

We have launched a phase IIb dose optimization study of LSD. That's really to explore which of those fixed doses reliably gives you the activity that you're seeking to generate both acutely, but also more importantly, in terms of clinical outcomes over the course of several weeks.

RM: You compared LSD and psilocybin doses in a new study. What were the key findings?

RB: The key finding is that LSD is much more potent than psilocybin (which we knew previously) but also that it does appear to induce the same acute psychoactivity and acute perceptual effects as psilocybin. What we don't know this is the key question that remains from this work what we aren't certain of is whether that acute activity directly modulates the clinical response. Whether the acute, perceptual effects are directly causative to antidepressant or anxiolytic effects of these molecules. Nonetheless, we certainly think that this study provides a solid evidence base to allow us to read across the assets.

As we look at data from psilocybin, it gives us increased confidence that we can learn from those results and that they would be applicable to LSD, for instance, which gives us an enormous additional opportunity to learn from research outside of our own programs. And it continues to de-risk our approach and give us more opportunities for expansion of our label and where we might go with marketing one day if we get these therapies approved.

RM: Were these results surprising to you?

RB: It wasnt terribly surprising, given the thousands of patients that have been administered LSD and psilocybin, and anecdotally, you can certainly look at the evidence and say, these are going to behave similarly. But it's important to definitively establish these things. Having scientific evidence to link the two is much more valuable than just anecdotal observation. At the end of the day, its not particularly surprising that there's quite similar activity.

One remaining question is, based on the differences between LSD and psilocybin, and based on the doses that we are exploring between the two molecules, does LSD more reliably induce a certain response at a certain dose? There's a lot more to be discovered about that translation in terms of clinical activity.

This was not done in a population with a diagnosis. We need to understand if there's a similar response in the clinic or how they differentiate. Some of the observational evidence we have from our colleagues who have been working with LSD for a long time is that it very well may be even better at treating the clinical outcomes. Now, we have to prove that.

RM: Theres been a lot of discussion in the field recently about the issue of blinding in clinical trials. In your new study, which was double-blinded, participants were able to guess whether they were taking a drug or a placebo96% of the time. What are the ways forward to try and minimize these issues with blinding?

RB: Its a fascinating topic, I've personally had a lot of interesting engagement, both with researchers and the FDA about this. The FDA and other researchers have preferences in terms of what we're using as control conditions; niacin has been offered up many times, some studies have used diphenhydramine. At the core, the reality is that it is going to be very difficult to fully blind LSD or psilocybin in a two-armed randomized controlled study. We're doing this study with four active doses of LSD plus a placebo. That probably gives you the best quality of the blind if you're looking at dose response, because it's going to be harder to differentiate 50 g from 100 g or 200 g, and 100 g from 200 g. That gives you some complexity that will aid in blinding, but in a two-arm study, it's going to be very difficult.

That said, it's also important for us to not forget that this is not a unique problem to psychedelics. If you look at think of any other CNS-active drug, very often, there is a clear perceptual effect that is going to make it more difficult to blind.

That may be more profound with psychedelics. But consider ketamine, which is a dissociative agent. If you look at the adverse event tables for esketamine versus placebo in the esketamine approval [esketamine is one of the two molecules that make up the racemic mixture of ketamine and was approved by the FDA for treatment resistant depression in 2019], the rate of dissociation in the esketamine arm was many-fold higher than in the placebo group.

RM: Two years is a long time in psychedelics research how do you feel MindMed has moved closer to your goals of making psychedelic research more high-throughput since you joined?

RB: Weve been building substantially over the last year. When I came into the organization, we had only about 10 employees and now we're at about six times that. We've been bringing in the talent and the people from pharma who know how to build big organizations and how to take on challenges in a scalable way and take on multiple programs at the same time. We have been absolutely delivering on that vision internally. In drug development, clinical trials do take a long time, this is just the reality of any development program is that a single trial can often take several years. Were still in a phase where we're continuing to build and have announced new programs over the last year. We also have a number of the studies with our collaborators in the Liechti lab at University Hospital Basel. There are a number of studies they have ongoing with LSD and other indications with other molecules. These give us good evidence to make decisions about how well continue to grow and how we think about potential label expansion and new programs. All of that has been progressing very well.

As we look out over the next year or two years, there are going to be many data sets coming out that are going to be quite informative to us and to the wider world about where the potential lies with LSD and where we think other molecules may fit into the pipeline.

We added a program in the second half of last year, which is the R-enantiomer of MDMA for treatment of autism spectrum disorder. We're making sure to remain laser focused on executing what is in front of us and what we've already taken on, but we are continuing to see an enormous opportunity and one that spans far beyond just a single asset and a single indication and we're continuing to make advancements across all our programs to achieve that goal.

Rob Barrow was speaking to Ruairi J Mackenzie, Senior Science Writer for Technology Networks

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Behind the Scenes on the First Study To Compare the Effects of LSD and Psilocybin - Technology Networks