Pop science likes to dub dopamine “the reward chemical” and serotonin “the happiness chemical”. God only knows what norepinephrine is, but I’m sure it’s cutesy.

In real life, all of this is much more complicated. Dopamine might be “the surprisal in a hierarchical predictive model chemical”, but even that can’t be more than a gross oversimplification. As for serotonin, people have studied it for seventy years and the best they can come up with is “uh, something to do with stress”.

Serotonin and brain function: a tale of two receptors by Robin Carhart-Harris and David Nutt tries to cut through the mystery. Both authors are suitably important to attempt such an undertaking. Carhart-Harris is a neuropsychopharmacologist and one of the top psychedelic researchers in the world. Nutt was previously the British drug czar but missed the memo saying drug czars were actually supposed to be against drugs; after using his position to tell everyone drugs were pretty great, he was summarily fired. Now he’s another neuropsychopharmacology professor, though with cool side projects like inventing magical side-effect-free alcohol. These are good people.

And they have a good theory. One stumbling block in past attempts to understand serotonin was the brain’s dozen or so different types serotonin receptors, all of which seem to do kind of different things. Carhart-Harris and Nutt (subsequently: CH&N) focus on two of these which show up again and again in psychiatry: 5-HT1A and 5-HT2A. Past studies had always shown these two receptors having kind of opposite effects, which confused things pretty thoroughly: why would you want a chemical that does two opposite things?

5-HT1A is the most common serotonin receptor in the brain. When SSRI antidepressants like Prozac, Zoloft and Celexa increase serotonin, this is the receptor most of that serotonin goes to. Some other antidepressants and antianxiety medications like BuSpar, Viibryd and Trintellix just stimulate this receptor directly. So it looks like this receptor does something like “reduce depression and anxiety”. But this falls afoul of a version of Algernon’s Law: there shouldn’t be any switch in the brain which is 100% good or 100% bad. Why have a receptor for treating depression and anxiety, rather than just always keep the receptor at maximum so you’re never depressed or anxious?

5-HT2A is another pretty common receptor. Most new antipsychotics like Seroquel and Abilify block this receptor. And most psychedelic drugs like LSD and magic mushrooms stimulate it really hard. Since psychedelics make you kind of crazy, and antipsychotics make you stop being crazy, 5-HT2A must have something to do with psychosis. Of course, this is another Algernon’s Law violation: why is there a receptor just to make you psychotic?

1A and 2A seem to “fight” each other. The more you activate 1A, the quieter 2A becomes – this is why people on SSRIs get less effect from psychedelics. And all the drugs that block 2A are also decent antidepressants – this is why people recommend Seroquel for depression even though it’s an antipsychotic – and this seems to work because blocking 2A increases 1A.

On the other hand, there also seems to be some deeper unity. 1A makes you less depressed. 2A – well, we keep hearing all these studies, some of them from Dr. Carhart-Harris himself, showing that magic mushrooms treat depression really well. Not just as a once daily medication, but in the sense that one trip on mushrooms can make you long-term – maybe permanently – less depressed. This is pretty weird. Blocking 2A makes you less depressed? But stimulating 2A also makes you less depressed, in a different and more permanent way? What’s going on?

CH&N argue: both 1A and 2A promote coping with stress. 1A promotes “passive coping”. 2A promotes “active coping”.

Passive coping is basically being stoic, having a stiff upper lip, and waiting it out. Imagine you’re at some kind of terrible job and your boss is bullying you all the time and you can’t stand it and you get depressed and anxious. Your psychiatrist gives you an SSRI (or BuSpar, or Viibryd, or some other 1A stimulator) and now, you can stand it. Your boss is still just as mean. Your life is still just as bad. But you sort of shrug, think “what can I do?” and get back to work. This isn’t the most inspiring story, but it’s better than alternatives like “being a wreck” or “snapping and attacking your boss”. Did I mention that 1A is known to decrease impulsivity and aggression? Makes sense.

Active coping is…uh…sort of unclear from the paper. It sounds like it should mean working to solve the problem – quitting your job, finding a way to stand up for yourself. Heck, even snapping and attacking your boss would tie in with the psychosis angle. This is…not exactly where CH&N go, as far as I can tell. Active coping is like…an LSD trip? It’s some kind of grabbing the brain and shaking it, in the hopes that maybe when it settles it will be in a state that’s better able to deal with whatever’s going on. This sort of makes sense, insofar as big steps like quitting your job might require a lot of mental shake-up to consider. It seems to have something to do with a process of increased plasticity, becoming bolder to avoid getting trapped at local minima, and increasing the information-theoretic entropy of brain states. This definitely sounds like the sort of thing that can cause psychosis, and maybe it sounds like the sort of thing that might help?

MDMA, a strong 2A agonist, is currently in Phase III trials as a treatment for post-traumatic stress disorder. It looks really promising. Under CH&N’s theory, this makes a lot of sense. If you have trauma, your thoughts get stuck in some pattern which is useful for dealing with or avoiding the traumatic situation – for example, an abused child learns to be suspicious and afraid of everybody. People do therapy for years trying to cast off these thought patterns; they know they’re no longer adaptive, but they just can’t get rid of them. On MDMA – and especially in MDMA-assisted therapy – people find it easy; the usual metaphor is calcified thought patterns suddenly become fluid and re-writable. Is this the sort of “increased plasticity” that CH&N describe?

This theory gives an explanation of how 1A and 2A can have such a complex – and sometimes antagonistic – relationship. When a person undergoes adversity, their brain releases serotonin, which starts by hitting the 1A receptors. They bear it stoically and hopefully soldier through. But if the adversity gets really bad and the serotonin release passes some threshold, it starts hitting the 2A receptors instead. Now their brain realizes things are pretty bad, it’s got to try high-variance strategies, and so it increases its randomness in the hope of stumbling across a way-out-there solution to the problem.

(not super-clear what problem John Lilly thought he was solving by accusing space aliens of orchestrating a massive conspiracy to manipuate the world’s coincidences, but it’s a pretty safe bet the 2A receptor was involved somehow.)

I find the whole thing pretty plausible. But as written, it doesn’t entirely answer the Algernon’s Law questions. Why doesn’t everyone just have 1A and 2A functions set to max all the time? What’s the tradeoff?

There are some obvious possibilities. Too much 2A stimulation makes you psychotic. This puts the efficacy of atypical antipsychotics like Seroquel in a new light: they’re saying something like “keep your thoughts very careful and low-risk, this isn’t a good time to be deviating from normal patterns”. And so maybe someone who otherwise would have believed the space aliens were putting a transmitter in his teeth will decide not to think that. Is there a shade of Bayesian brain theory here? Is the phrase we’re looking for “strength of priors”? I don’t know.

Likewise obvious: if 1A promotes stoic coping, then too much of it prevents you from actively making your life better. One can imagine how this would be more relevant in the environment of evolutionary adaptedness than today. Back then stressors could have been some specific person whose skull you could bash in with a rock. Nowadays they tend to be things like corporations, national governments, and groups of people with terrible politics on Twitter; attempted skull-bashing, as satisfying as it might feel, is highly disrecommended.

I don’t know if these stories are true. They don’t really explain why 1A and 2A function seem inversely related. Is this just a wiring issue? Or is there some fundamental reason why ability to passively cope can’t coexist with creative outside-the-box problem-solving? Maybe the coping involves some sort of mental resolution not to let all the stress change the brain at all, and the problem-solving involves the brain becoming superplastic and really easily influenced by external events. But it’s not really clear why either of those things should be necessary.

Also, we should remember that although CH&N’s theory explains a lot, we’re reading the case they’re presenting, and there’s a lot they leave out. Some might complain that calling 2A the “active coping receptor” is as reductionistic as the whole “dopamine is the reward chemical” thing – 2A is also involved in obesity, sexual dysfunction, some forms of insomnia, possibly chronic fatigue syndrome, platelet clumping, et cetera. All of these psychedelics do opposite things acutely and chronically – something CH&N acknowledge – so you have to be really careful with time course in order to figure out whether your acid trip is treating depression due to acutely increased 2A stimulation or chronically decreased number of 2A receptors. Both Carhart-Harris and Nutt have spent big parts of their careers advocating more use of psychedelics, so them coming up with a theory of why psychedelics are really good is both reasonable and suspicious.

Still, this is as good a theory of serotonin function as anything else I’ve seen, and it will be exciting to see if it suggests any avenues for experimental research to confirm or refute it.