Hardman: Right, so it’s just one example of creative thinking with regards to approval pathways for psychedelics. But the deeper point, presumably, is to poke at the standards required for approval of drugs in the U.S., no?
Zorn: Right, questions like: ‘Are we using the right standards of safety and efficacy?’ I think there’s a really good case that we shouldn’t be testing for efficacy, or that can be done post approval, or that there are ways to have medicines on the market in an off-label or no-label way while still testing for efficacy.
But then there’s also the notion that the more there’s a need in society, the more urgency there is, which calls for a different level of evidence and a different standard. (And there are statutes and laws that allow for accelerated approval or whatnot.)
So I think you can make a pretty good argument that requiring safety and efficacy for approval needs to include a third element or simply a balancing test that is more of a risk-benefit type approach. The benefit in an emergency is tremendous, and there’s an acknowledgement that if we have to wait ten years for a vaccine, the vaccine will simply have no purpose. In that case, the level of evidence we would require maybe on safety should be high, but on efficacy, probably not so much.
With the FDA giving a thumbs down on MDMA plus the election of Trump and RFK Jr., I think it creates somewhat of a chaotic moment where we can really ask these deeper questions about drug regulation, because at the end of the day, the reason we don’t have psychedelics as medicine is mostly an economic problem. A lot of people put the blame on the Controlled Substances Act, but at the end of the day, if it were more economical to bring these treatments to market, they would have been brought to market ten, twenty, thirty years ago.
Hardman: In terms of funding the necessary studies?
Zorn: Yeah. Efficacy is really hard to evaluate and it can be evaluated with double-blind placebo-controlled studies or it can be evaluated in the real world, but it can’t be evaluated in the real world when you’re making it a precondition for it to be used in the real world. So you’re kind of caught in this catch-22, where the only way to do it is with these expensive double-blind studies. And then that raises all sorts of issues about recouping costs on the backend and profitability.
Even assuming this is a successful treatment, it’s simply not economical to take the drug all the way through the process.
Hardman: So when you’re talking about FDA just taking more of a position on safety as opposed to also requiring efficacy as a precondition to getting approval, you presumably expect some effectiveness data to be collected in the post-marketing environment. Do you think the FDA should still be the one that oversees that side of things, or do you think it should be ‘the market’?
Zorn: Most people misunderstand the role of FDA, and today it’s called one of the leading public health agencies. But when it was created in 1906 and even in 1962 when the statute was amended to include evidence of efficacy, its primary mission was a consumer protection agency. We were talking about patent medicines, snake oil and whatnot, and so the purpose of these pre-marketing approval requirements was to protect against consumer deception, which is why when you look at the law, it’s about the labelling of drugs and the intended purpose.
One of the simplest reasons I believe we don’t need efficacy to be proven pre-approval today is that in 1962 you could not get on your computer and go to PubMed and get all the evidence, so you could make the case that there needed to be a centralised body to review this evidence and give a recommendation.
In the internet age, the need to have a centralised government body review all the evidence, and where AI would probably do as good of a job as FDA of reviewing these data, the case for this is severely diminished.
So I would argue that a sober rational assessment of this is that efficacy should not be required to introduce medicine to the market. I think the better argument is that there needs to be efficacy data if you’re going to put an indication on the label.
Almost certainly the insurance market is still going to want that evidence, so companies are still going to be incentivized to do it, but they could do it a lot cheaper because once the medicine’s on the market, you can start collecting real-world evidence, which I believe would be more useful in the case of mental health treatments in particular.
In this world, MDMA is already on the market.
Hardman: But aren’t many like drugs that are approved for certain indications not particularly safe in and of themselves? Obviously, everything has side effects, so they’re only deemed relatively safe in the context of the risk-benefit calculation. In your world, would the sponsor be looking to prove safety, or simply characterise the safety profile and then leave it up to prescribers, patients, payors, and other participants to decide what’s appropriate?
Zorn: Yeah, I think so. I think that if you were to require a lower standard for efficacy, that could also work too. At the end of the day, you’re kind of getting to this moral question: ‘Should the FDA be in charge of our medical system?’ And I think the answer to that question is ‘no.’ That’s not just based on morality, but also efficiency. I don’t think the top-down approach produces optimal outcomes.
Hardman: We could talk about this for days, but just so I understand your position correctly: Before FDA had these efficacy requirements in the ‘60s, people were getting hoodwinked by snake oil salesmen and so on. But you’re saying that’s less likely to happen now as there’s less information asymmetry, because people could read the studies online and so on. One concern, however, would be that the studies we read online are a very sanitised form of the data. But, in your world, other participants like payors would presumably be able to demand access to that data and do their own inspections?
Zorn: Payors, tort lawsuits… There are tons of other fields where there are products that are defective that get to market and they get sued. And I just want to be clear about the 1960s thing. I’m not saying that before 1962, it was all snake oil. In fact, the Golden Age of pharmaceuticals was from the ‘40s to the ‘60s.
Hardman: We are talking a lot about FDA approval, but many people are wondering right now whether an aligned government could just reschedule psychedelics and whether that would supersede all these issues.
Zorn: It would not. I know this with certainty because the Food, Drug and Cosmetic Act prevents any of these substances being used in the medical system absent FDA approval.
Certainly, if legislation was passed that legalised recreational cannabis then that would take precedence, but rescheduling alone does not change the Food, Drug, and Cosmetic Act. It doesn’t even make these things legal, unless you’re talking to descheduling, which is taking them entirely out of the Controlled Substances Act.
You could argue that the tax consequences would be different and I think that could make these state-level regimes financially solvent.
Hardman: On the topic of state-level psychedelics programmes, do you think that something like a Cole Memo, some kind of federal non-intervention statement regarding the systems in Oregon and Colorado, is likely to be more forthcoming with the new administration?
Zorn: A lot of folks are talking about, with RFK Jr., legalised psychedelics and cannabis, but he happens to be in the wrong agency for that one. That would be more on the attorney general side of things.
Hardman: Which is Pam Bondi, and she’s been somewhat anti-marijuana, right?
Zorn: It’s hard to tell. And I think there’s every indication that Trump’s not going to tolerate people deviating from his position, so it depends on what stance he takes.
Hardman: To what extent do you think psychedelics advocates should be watching marijuana rescheduling closely, and how much of an impact do you think it would have on psychedelic policy reforms?
Zorn: Extremely closely. If you are at all interested in rescheduling, this is the highest profile, most impactful rescheduling that has ever occurred.
Hardman: You’ve spoken in the past about how the opposition to these reforms, like Kevin Sabet’s Smart Approaches to Marijuana (which is also successfully opposing psychedelic policy reforms), is very successful with quite a modest budget and headcount. And I know you’ve also criticised the marijuana industry for not being more organised when it comes to pushing for regulatory changes. How much money do you think it would take and how organised would the psychedelics field would need to be to start thinking about and pushing for some of these more fundamental changes? What would you like to see happen?
Zorn: The folks against us, they have the high ground. They have the home-court advantage because they’re not trying to change anything.
First of all, they’re good. They know their stuff, they know the laws and they have these relationships and whatnot. In psychedelics, we are starting to do that, but it takes time to build those connections. So again, it’s easy to be critical of one side or the other, but I think it’s instructive to understand why it is they have very good success with potentially fewer resources and it’s not just because of the advantage or whatnot, I think they understand the laws, they understand the strictures, and they’re very strategic about what they’re doing. They’re obviously very good at piloting certain narratives, many of which I agree with.
I think with psychedelics it’s a little less strategic and a little more guided by emotions in terms of trying to come up with short-term solutions instead of attacking the deeper structural issues.
One of the areas that I’ve worked on is religious use, which is a place where that high ground is actually a pretty even playing field. It’s a good place to do battle.
And I support clinical trial reform wholeheartedly and other reforms, but if you are going to go the FDA path, when in Rome, do as the Romans do. I think that was the problem with the MDMA-assisted therapy. We can complain that the rules of this game are unfair, but if you’re going to play that game, you have to play by the rules. Or alternatively, change the rules.