3 big unanswered questions about psychedelics
With one approved drug (Johnson & Johnson’s Spavaro) already doing $468 million per quarter in sales, and with companies like AbbVie and Otsuka paying hundreds of millions in M&A, it’s safe to say that psychedelics haven’t been fringe science for a while. Yet, despite all the investment, attention, and research in the sector, there are still some important foundational questions lacking settled answers.
We spoke with several executives and researchers about this burgeoning space, what we still don’t know, and how companies are approaching the challenges created by these gaps in knowledge.
1.
What’s the relationship between the hallucinogenic “trip” and the therapeutic benefit?
Psychedelics have a long history of recreational use, and users in both scientific and recreational contexts report having meaningful experiences during a psychedelic “trip”. And an increasing body of scientific data shows these drugs can have powerful therapeutic effects in conditions like depression and PTSD.
But is the trip providing the therapeutic benefit? Or is the drug providing the benefit and causing hallucinations as a side effect?
“On the hallucinogenic thing, we don't know,” Tarak Rabah, president and CEO of Otsuka North America, told pharmaphorum during a JPM interview. “That's the question. Obviously, if you can reduce the time for the trip, then, that could be a little bit easier. But I think the jury is still out on whether this is necessary or this is a side effect or it's part of the treatment. I've been in extensive debriefs around the science behind it. There are still a lot of things that are actually unknown.”
It’s not an academic question, because the hallucinogenic experience creates infrastructure challenges around drug delivery that could be eliminated if the two elements could be separated out.
“There's some evidence to support this notion that the mystical experience that comes with large doses of psychedelics, that is what's driving the effect,” said Rotem Petranker, a psychedelics researcher with Rose Hill Life Sciences. “Because we have seen that people who have smaller or less or kind of deflated mystical experiences under their influence have less benefit some of the time. But there are so many methodological and statistical issues that are involved in these measurements that I think at least we should be cautious in our interpretation.”
Efforts to answer this question have yielded some creative approaches, such as a study where patients were given ketamine while sedated. Patients who received ketamine while unconscious reported a strong therapeutic effect. Unfortunately, so did the patients who didn’t. The conclusion of the study was that the ketamine had no improvement over placebo.
Petranker’s research focuses around microdosing, which he thinks might be one way to separate out the trip from the therapy.
“I agree that we should be solving this question and it should be fairly urgent,” he said. “But I think that this is coming along with the change of the old guard. I think the more young people are joining the academic study of psychedelics, the more we'll see kind of more creative approaches that don't just follow, you know, ‘You gotta trip, Bro.’”
2.
Is it possible (or necessary) to properly blind studies of psychedelics?
The “tripping” aspect of psychedelics treatment also creates problems around the scientific method: it’s extremely easy for most participants to know whether or not they’ve been given the drug, so it’s difficult to rule out the placebo effect.
“People correctly guess their condition something like 95%, 96% of the time,” Petranker said. “So, basically, blinding is a failure. People, you know, they're either tripping or they're not. And something that, actually, my colleague Balázs Szigeti, who has been doing very interesting […] statistical and methodological work for the last couple of years, has noticed [is] a lot of what happens in these large dose trials is that people in the placebo group, because they know they're in the placebo group, they don't improve. And, a lot of the time, they actually get worse a little bit because they're disappointed that they didn't get to try this life changing drug.”
Even more confusingly, as Jane Hu reports in an excellent piece for Slate, some patients on placebo actually experience hallucinogenic trips anyway, and many of them show improvement.
Steve Levine, chief patient officer at Compass Pathways, whose drug Comp360 is close to FDA approval, feels that the blinding concerns around psychedelics are a bit overblown.
“This issue, though, of functional and blinding is not unique to psychedelics,” he said. “There's been a lot of attention paid to it, but it's not unique because, whether it's an SSRI or an antipsychotic or a benzodiazepine, with any of these, if you are taking one of those or a true placebo, an inert placebo, you will be able to tell the difference. They're all unblinding. Again, there's special attention paid to psychedelics, but it's not the unique domain.”
Nonetheless, Compass Pathways has an approach to blinding that seems to work for them, and that the FDA has even included in its draft guidelines for psychedelics companies: rather than a true placebo group, different experimental groups are given different amounts of the drug. Efficacy is assessed based on the existence of a dosage effect: if patients given more of the drug did better than those given less, it shows the drug is working. Crucially, this works best if care is taken to screen out patients who have used psychedelics before and might have a better sense of how much they’ve taken based on experience.
“In a naive population who are being adequately prepared and given the instructions that [they] will receive some dose of psilocybin, we've seen by measuring the experience that they have, because there are scales that can measure that subjective psychedelic experience, that there's a lot of overlap amongst the different dosage arms, which shows that they are confused about what they got. We've seen a dose response, which is all suggestive, that we actually have found ways to effectively blind these trials.” Levine said.
Petranker believes that microdosing can be used to similar effect, especially in larger trials. But there are other options as well, such as placebos that mimic the noticeable effects of drugs.
“I have a colleague from Brazil, Draulio de Araujo, who told me years ago they were studying ayahuasca and they developed an ayahuasca placebo that was absolutely disgusting and caused people to vomit, and it was good enough to fool people much of the time,” he said. “So, maybe we need to create better placebos, too, because I think, so far, it's a silly game to play if you're only putting this life changing experience versus nothing at all.”
3.
How long do the therapeutic effects of psychedelics last?
Despite all the difficulties in studying psychedelics, researchers continue to advance the science because the potential to help patients is so great.
“We are studying a population that lived with treatment resistant depression, which is major depression for which people have been failed by at least two treatments in their current episode. We also have a programme in post-traumatic stress disorder,” Levine said. “In total, this represents millions and millions of people. About four million living with treatment resistant depression, 13 million with PTSD. In both cases, there are very few FDA approved options. In TRD, there's really only one pharmaceutical product that is indicated for treatment resistant depression that's actually marketed right now – that’s Spravato. In PTSD, there hasn't been an approval this century. The only two products that are approved are two old SSRIs that are modestly effective at best.”
Not only do psychedelics represent help for patients with highly limited options, they also have the potential to be longer lasting and more effective than the options that exist now.
“What is really attractive for me in psychedelics is the fact that we may be talking about the trip and how many hours, but what we're seeing is that it probably needs much less frequency in the treatment,” Otsuka’s Rabah said. “Instead of taking a drug every day or every week or every month, we're talking about a few times a year, and we don't know whether it's going to be longer or shorter. There's a lot of excitement, of course, but we still need to see the concrete science and data coming out of that.”
Petranker mentioned a recent study out of the Ohio State University (albeit, with a small sample size) that found remission of depression persisting five years after psilocybin-assisted therapy.
In addition to potentially long-lasting effect, psychedelics can also produce an unusually immediate effect.
“We've seen that participants, a subset of them, may have an almost immediate benefit, which is detectable at the first day, the first measured time point after administration, and that one or two administrations for them may be durable out to at least six months, which is the latest time point we've measured so far,” said Levine.
If psychedelics do prove to have a consistent, durable, long-term effect, it could mean the companies making these drugs will have to be creative about payment models, similar to the challenges that have faced curative cell and gene therapies. Levine says they’ll cross that bridge when they get to it.
“If people stay well for so long and there are so few treatments, I think of that as a good problem,” he said. “The reality is, sadly, that there are four million people with TRD. Only about 100,000 got Spravato last year. There is a huge unmet need. There are a lot of patients. So, if a patient can be treated quickly and then they have a durable response for a long time, that means there's more capacity for these centres to treat more patients.”
