Is Pharma Research Worse Than Chance?

[Epistemic status: very speculative]

The two most exciting developments in psychopharmacology in the 21st century so far have been ketamine for depression and MDMA for PTSD.

Unlike other antidepressants, which work intermittently over a space of weeks, ketamine can cause near-instant remission of depression with a single infusion – which lasts a week or two and can be repeated if needed. Ketamine use may be successful in 50-70% of patients who have failed treatment with conventional antidepressants. Ketamine treatment has some issues right now, but the race is on to create an oral non-hallucinogenic version which could be the next big blockbuster drug and revolutionize depression treatment.

MDMA (“Ecstasy”) is undergoing FDA Phase 3 clinical trials as a treatment for PTSD. Preliminary research has been small and underpowered, but suggests response rates up to 80% and effect sizes greater than 1 in this otherwise-hard-to-treat condition. None of this is on really firm footing – that’ll have to wait for the Phase 3. But signs are looking very good.

I say these are the two most exciting developments mostly because no other developments have been exciting. In terms of normal psychiatric drugs, the best that the 21st century has given us has probably been pimavanserin and aripiprazole, modest updates to the standard atypical antipsychotic model. These drugs are probably a bit better than existing ones for the people who need them (especially pimavenserin for psychosis in Parkinson’s) but they don’t revolutionize the treatment of any condition and nobody ever claimed that they did. And most drugs aren’t even at this level – they’re new members of well-worn classes with slightly different side effect profiles. The landscape was so quiet that ketamine came in like a bolt from the blue, and MDMA is set to do the same in a couple of years when the trial results come out.

(if I’m wrong, and history decides these two drugs weren’t the biggest developments, the most likely failure mode is that psilocybin turned out to be more important than MDMA)

There’s a morality tale to be told here about how the War on Drugs choked off vital research on some of the most powerful psychiatric compounds and cost us fifty years in exploring these effects and treating patients. I agree with this morality tale as far as it goes, but I also think there’s another, broader morality tale beneath it.

Suppose that neither ketamine nor MDMA were illegal drugs. Ketamine was just used as an anaesthetic. MDMA was just used as a chemical intermediate in producing haemostatic drugs, its original purpose. Now the story is that, fifty years later, we learn that this anaesthetic and this haemostatic turn out to have incredibly powerful psychiatric effects. What’s our narrative now?

For me it’s about the weird inability of intentional psychopharmaceutical research to discover anything as good as things random druggies use to get high.

For decades, pharmaceutical companies have been coming out with relatively lackluster mental health offerings – aripiprazole, pimavanserin, and all the rest. And when asked why, they answer that mental health is hard, the brain is the most complicated organ in the known universe, we shouldn’t expect there to be great cures with few side effects for psychiatric diseases, and if there were we certainly shouldn’t expect them to be easy to find.

And this would make sense except in the context of ketamine and MDMA. Here are some random chemicals that affect the brain in some random way, which people were using mostly because they felt good at raves, and huh, they seem to treat psychiatric diseases much better than anything produced by some of the smartest people in the world working for decades on ways to treat psychiatric diseases. Why should that be?

One could argue it’s all about numbers vs. base rates. There are way more chemicals synthesized each year by people who aren’t looking for psychiatric drugs than by people who are. Even if the people who are looking for drugs are a thousand times more likely to find them, the people-who-aren’t-looking can still overwhelm them with sheer numerical advantage. And maybe when a psychiatric drug is discovered by people who weren’t looking for it, what this looks like is a few random people trying it, noticing it feels good, and turning it into a drug of abuse.

And I’m sure this is part of the story. But that just passes the buck to the next question. Abusers take the vast flood of possible chemicals and select the ones they think will feel good at raves. Psychopharmacologists take the vast flood of possible chemicals and select the ones they think will treat mental illnesses. How come the abusers’ selection process is better at picking out promising mental health treatments?

Here’s one hypothesis: at the highest level, the brain doesn’t have that many variables to affect, or all the variables are connected. If you smack the brain really really hard in some direction or other, you will probably treat some psychiatric disease. Drugs of abuse are ones that smack the brain really hard in some direction or other. They do something. So find the psychiatric illness that’s treated by smacking the brain in that direction, and you’re good.

(in fact, the most effective existing treatment for depression is electroconvulsive therapy – ie giving the brain a big electric shock. This is maybe the crudest, most literally “smack the brain really hard” treatment out there, but it sure does work)

Actual carefully-researched psychiatric drugs are exquisitely selected for having few side effects. The goal is something like an SSRI – mild stomach discomfort, some problems having sex, but overall you can be on them forever and barely notice their existence. In the grand scheme of things their side effects are tiny – in most placebo-controlled studies, people have a really hard time telling whether they’re in the experimental or the placebo group.

Nobody has a hard time telling whether they’re in the experimental or placebo group of a trial of high-dose MDMA. I think this might be the difference. If you go for large effects – even if you don’t really care what direction the effect is in – you’ll get them. And if you go for small, barely perceptible effects, then you’ll get those too. The dream of the magic bullet – the drug that treats exactly what it’s supposed to treat but otherwise has no effect at all on you – is just a dream. The closest you can come is something with miniscule side effects but a barely-less-miniscule treatment effect.

But given that we’re all very excited to learn about ketamine and MDMA, and given that if their original promise survives further testing we will consider them great discoveries (and given that ECT was also a great and productive discovery) it suggests we chose the wrong part of the tradeoff curve. Or at least it suggests a different way of framing that tradeoff curve. A drug that makes you feel extreme side effects for a few hours – but also has very strong and lasting treatment effects – is better than a drug with few side effects and weaker treatment effects. That suggests a new direction pharmaceutical companies might take: look for the chemicals that have the strongest and wackiest effects on the human mind. Then see if any of them also treat some disease.

I think this is impossible with current incentives. There’s too little risk-tolerance at every stage in the system. But if everyone rallied around the idea, it might be that trying the top hundred craziest things Alexander Shulgin dreamed up on whatever your rat model is would be orders of magnitude more productive than whatever people are doing now.

Or it might not be. I can also think of a counterargument to the theory above, which is that our current best model of ketamine suggests it’s a non-psychoactive metabolite that has most of the useful antidepressant effect. In fact, a lot of people think that one form of ketamine is hallucinogenic (and extremely effective against chronic pain) and another form (or its metabolite) is the antidepressant. I’m a little suspicious trying to calculate the odds of a single chemical having two forms, one of which is a really exciting analgesic, and the other of which is a really exciting antidepressant, by two different mechanisms. It sounds too much like finding some new chemical compound whose solid form is a room-temperature superconductor, and whose liquid form catalyzes cold fusion, by two totally different mechanisms. It seems a little too lucky (see here for some ketamine skepticism, and here for my response). But if it were true, it means that ketamine’s psychoactive effects were a red herring in helping us discover it as an antidepressant, even though they were a very effective red herring.