My good friend Tommy Blanchard wrote a great article the other week, on the question “Are humans (and biological organisms) simply wetware machines?”

He gave a really good look at it with illustrations and everything, highly recommend reading it here:

I just wanted to add some more interesting - for me - context to this point. In fact, I kind of want to do a loosey-goosey, unscientific look at what I’ve learned about the utter chaos of how the brain is put together by evolution. I think it really illustrates just how incredible these systems are, but also how mind-bogglingly complex and seemingly illogical, and how it might compare to a brain if we designed it like we might a computer.

Prepare thyself.

So the boss comes in to the office one morning. He rushes over to your desk.

“Nicholas!” he says, breathlessly. “I’ve had a revelation!”

Uh oh. It’s never good when the boss has had a revelation.

“Since the brain is just too complicated to figure out, we should design a new one from the ground-up. It will be modular, maintainable, and debuggable!”

You convey your misgivings for such a project, but their mind is made up. You’re now project lead for Brain 2.0

What now?

Well you might start by analysing the existing behaviour of the current brain. In software engineering, when needing to do this, we often study the behaviour of the “legacy” version to identify each discrete “capability”, “feature” or “flow”, and map it to its own objective. Brain 2.0 should at the very least match the existing “legacy” behaviour.

To know if it’s working, we have to formulate test criteria which the legacy brain should pass consistently to guide our work. The end goal should be for Brain 2.0 to also pass all those tests consistently.

An example set of functions and features for a brain might consist of:

* Sensory input processing

* Language processing

* Autonomic systems

* Threat detection

* Motivation state management

* Bodily resource management

* Memory

* Motor function

…and so on.

Under each of these “feature buckets” we’d have to break it down into constituent parts based on what we understand of each set of behaviours or needs. For instance, “sensory input processing” is a very broad set of things. It includes vision, olfactory, tactile, proprioceptive and auditory inputs. We’d have to break each of these down into discrete modules.

I’m already looking at it like:

“Create a base schemata for modelling input data from a sensory organ, each sensory organ then extends that base with its own variations and needs.”

This way, we have a basis for shaping the data for all sensory organs, and we can even add entirely new ones arbitrarily. Each sensory organ could have its information passed through a single module which would route the information to the correct destination for processing.

So let’s say we get all this working, and now sensory inputs are coming in to the brain and informing it about the environment in which it finds itself. Furthermore, we have magically made motor control work, so our Brain 2.0 can respond to its environment via control of a physical body.

But we’re running into problems.

Something we need to consider is how to turn this discrete sensory information into a unified world model, but before we even get to that, we’re faced with a more serious challenge: compiling a world model directly from sensor data is slow. It takes time for signals to travel up nerve fibres, and yet more time to get filtered and processed, making it too slow to be viable when rapid near-reflex responses are sometimes required to avoid danger.

To solve for this, we can borrow an idea from the legacy brain: its predictive model.

The real human brain doesn’t feed sensory information directly into consciousness. Instead, it runs a continuous on-going prediction of the world, and uses sensory data only as a comparison to measure how accurate the prediction was, and to make corrections when necessary. The prediction is able to run ahead of the sensory input processing, making it ideal for rapid responses to potentially volatile environments since it doesn’t have to wait around for the data.

So that’s what we’ll do with Brain 2.0! We’ll include a module for that as well!

Notice what we’re doing here?

We’re designing architectures, circuits, modules, patterns, and structures. We’re grouping things into neat, discrete boxes. We’re wiring things up cleanly and logically.

The real human brain is nothing at all like this.

Despite the way we often talk about it as though it were a modular architecture, it’s not really. It is a chaotic mess, worse than some ancient decades-old banking code base which has never been refactored. Change one thing, and you get unexpected side-effects all over the place, in ways that make no sense at all.

Some people call evolution “The Blind Watchmaker”; quite frankly I think that’s an insult to blind people and watchmakers.

It’s more like the proverbial infinite monkeys on typewriters, except also they’re blind and mildly deranged, have a total of 3 fingers, and for some unknown reason become obsessed with pressing only 4 keys on the typewriter: A, C, G, and T (or sometimes U instead of T, but no one knows why)

Said monkeys never get even close to Shakespeare.

Now, the universe didn’t really know what to make of this when it saw the crap these monkeys were coming up with. So in some strange act of madness, it invented a mechanism to interpret these long streams of 4-letter nonsense, and associated each letter with a nucleotide molecule: Adenosine, Cytosine, Guanine, and Thymine (or Urasil, depending on the monkeys particular whim)

It is truly a remarkable achievement, then, that from such building blocks came all we see before us.

Indeed, the legacy brain is a billions-of-years-old project. Every time evolution has demanded a new feature, or even a bug fix, our infinite blind and semi-deranged monkeys almost never clean up the old mess. Instead, they simply patch over the top of it. Everything becomes a patch on top of another patch. They live and die by one golden principle: if it increases survival and/or reproduction, ship it immediately and patch it over and over and over again.

In digital computers, we would have electrical signals crossing wires and circuit pathways, transmitting digital information: a stream of 1s and 0s. By interpreting the specific sequences of 1s and 0s in a known way, we can derive its true meaning. Each processor that receives data knows how to interpret these signals in that way.

In the wetware brain, things began much more simply.

The earliest neural networks are thought to have been made out of highly multifunctional generalist cells, which combined sensory functions, inter-cellular communication and muscle contraction all into one, similar to the epithelial muscle cells still found in the modern cnidarian. Communication between these cells was necessary for rapid adaptive injury and stress responses. When damaged, a cell would release a flood of cheap, abundant signalling molecules into its surroundings to trigger coordinated, defensive/repair responses in neighbouring tissue.

It was a rather crude but effective method of volume-transmission, and a bit like a mesh-network of light switches; damaged cell releases a messenger chemical, chemical binds to receptor on a neighbouring cell, cell activates a prepared response, and in turn releases its own chemical messenger molecules to recruit other neighbouring cells, and so on.

This rapid cell recruitment and activation strategy proved highly successful, and the blind monkey that happened to stumble upon this particular configuration with its 4-letter alphabet was made to breed a whole new lineage of infinite blind monkeys.

Then the scope creep began.

These ancient multifunctional cells began specialising, separating the responsibilities of sensory receptor and muscle contraction into their own distinct cell types. Because these newly specialised sister cells became physically separated, and the traditional chemical messenger approach used before was too slow for communicating over larger cellular distances, a new type of cell which would bridge the gap between sensor and muscle contractor was needed: thus, the electrically-active neuron was born.

Complex functionality first evolved within localised systems. Instead of a central brain suddenly appearing, small groups of these proto-neurons would connect up together in various parts of the body to control specific local reflexes.

The Carribean Box Jellyfish, for example, has no central processing for sensory inputs, despite having 24 eyes. Instead, it has 4 separate “sensory ganglia” dangling off its body, each one processing input from 2 high-fidelity camera-like eyes, and 4 simpler ambient-light-sensors.

These ganglia don’t communicate with each other, and have no world model. They continuously fire a regular pacemaker signal which controls the contractions of surrounding musculature for swimming. When one ganglia recognises an obstacle in the visual data from its 6 connected eyes, it changes the rate of the pacemaker signal, causing it to steer away.

Over time, these networks grew to span even longer distances, and as organisms became more complex and evolved more sophisticated limbs and musculature, there was an evolutionary need for coordination and synchronisation.

The Starfish’s approach to this problem was very simple. Each arm kept its localised network of nerve cells with all their localised sensory processing, but added peer-to-peer networking via a broadcast ring.

When one of the arms detects food, a signal gets sent out to the other arms and degrades over distance. So the nearest neighbour arms will get a strong impulse, while the arms further away will get a weaker or no signal. The starfish will then crawl towards the food.

The successes kept coming, so evolution went and scaled this up to an absurd level. Enter: the Octopus.

Octopi have around 500 million neurons (a small fraction of a humans 86 billion), yet are highly intelligent. Their central brain consists of only about 10% of all its neurons, while the optic lobes have around 30%. The rest is distributed across its many infinitely-flexible arms. In fact, the central brain doesn’t control the limbs at all. Not directly. Instead, it might make strategic decisions and set objectives - “lets hunt”, “run away”, or something more specific like “grab that target” - while the local nervous system in each arm determines exactly how the kinematics for moving that arm will work to achieve the objective.

The brain doesn’t coordinate movements either; each limb talks directly with other limbs to coordinate movements, something called “self-organised embodiment”. The signals from sensors on each arm are also processed locally, deciding whether something is food, a rock, or dangerous, before sending that information to the central brain for a strategic decision.

This decentralised architecture is especially advantageous in the Octopus, as each arm has infinite degrees of freedom, and the processing required to compute all the kinematics for all the arms in one place would be overwhelming. Thanks to this decentralisation, in theory an octopus could have any number of additional arms added to it, without needing to change anything about the central brain.

Interestingly, in software engineering, decentralisation has always been held up as a pillar of “good architecture.” We like the idea of being able to swap out components at will, and allow the system to reorganise itself according to certain rules. Change to something at a lower level of abstraction should not require major changes to things at higher levels of abstraction, and vice versa.

In fact, it seems that invertebrates in general tend to follow this more decentralised architecture in their neural networks, while vertebrates opted for heavily centralised architectures where everything is hard-wired into the central brain, which micro-manages all downstream activity.

You might, like me, wonder why. Wouldn’t this be more brittle?

It is.

We know this because of conditions like phantom limb syndrome.

The human brain has a rigid map of the body hard-wired into itself, which cannot handle changes in configuration. This map is called the “cortical homunculus”. If a limb or other body part is removed or is disconnected from the brain or body, the neurons representing that body part in the homunculus can end up searching for other nearby neurons to connect to instead.

Due to this rewiring, some amputees can feel sensations in their phantom limb when touching an area of the body adjacent to the phantom on the cortical homunculus; for example, due to their proximity, some people with foot or leg amputations can feel sensations in their phantom when their genitals are touched.

(Neurologist V.S Ramachandran speculated this proximity might explain foot fetishes)

Octopi have no such hard-wired body map.

There are, however, some advantages to having such a rigidly centralised brain, which have served us well. The big headline one is imitation learning and mimicry.

Humans are really good at “monkey see, monkey do.” Since the central brain has that unified knowledge of where each part of our body is located in physical space, our visual system can be presented with a shape and map it onto the cortical homunculus. So when we see someone else move in a certain way, we can mimic them pretty much immediately, something an Octopus simply cannot do as effectively.

Over time, certain branches of the evolutionary tree really pushed hard on the brain centralisation track, and new features began to proliferate. If you look closely, you can see an interesting pattern forming: there seems to be inhibitory systems everywhere, apparently bolted on as an after-thought.

For example, signals between two neurons can only flow in a single direction for a given synapse; there is almost always a strict division of labour between who the sender is and who the receiver is. However, at some point, evolution seemed to discover a need for the receiving neuron to have some control over how much signal it is being sent, so although it can’t send signals back in the other direction, it can do something called “retrograde inhibition”, telling the sender neuron to essentially “shut the fuck up” by throwing endocannabinoid molecules at it.

In fact, this inhibitory bolting-on seems to happen at every level of abstraction.

Lets take a look at something called the “direct pathway”, a bunch of ancient structures located deep in the brain which are heavily involved in voluntary motor movements. Even when we’re at rest, the motor cortex is continuously trying to get us to move, firing off signals non-stop for every possible movement we could make.

The reason we’re not in constant motion at all times is thanks to a structure in the basal ganglia acting as a gate; by default, it fires a constant inhibitory signal to block motor movements. When we decide to move an arm to reach for a coffee cup, the cortex talks to the striatum, and the striatum sends a selective inhibitory signal to the gate, causing it to stop inhibiting those necessary motor signals.

It inhibits the inhibitor.

Then there’s the “indirect pathway”, which adds an extra inhibitor that inhibits the inhibitor of the inhibitor!

It’s inhibitors all the way down!!

It’s like if you were writing to a friend to tell them what colour the sky was, and so you write:

“The sky where I am is not not blue, what colour is it where you are?”

and your friend replies:

“The sky here is not not not green.”

In fact, our entire prefrontal cortex, one of evolutions most recent additions to the brain, is basically a giant slab of inhibitory neurons, helping to moderate and modulate our base impulses of fear, aggression, and drive for instant gratification. Without it, we would do the very first thing that popped into our heads moment to moment.

Now, I’m not one of those militant atheists determined to argue the point, but I will say that perhaps those folks posting youtube videos about how a flagellum is evidence of intelligent design should take a closer look at the brain.

The last point I’m going to make shows how truly incredible all of this is, because despite the sheer chaos and utter lack of any design whatsoever, the efficiency and power of biological neural networks are truly astounding.

One of the most challenging things when it comes to actually simulating the biological brain on a computer is how much raw computational power it seems to require.

Let’s compare, say, simulations for a fruit fly vs a mouse brain.

So the fruit fly is only around 150,000 neurons and 50 million synapses, and if you run it as a simple stripped-down leaky integrate-and-fire network - like a typical AI model - you could run it comfortably on a laptop. However, to run a full simulation of the brain’s biology at real time speed would require about 100 Teraflops of computing power from a cluster of modern GPUs all running in parallel.

You could technically do it with a home rig, if you had a motherboard with enough ports and data transfer bandwidth. It would require a ton of electricity, as well as making a lot of noise and heat, since the sheer communication overhead of tracking 50 million synapses forces us to throw massive amounts of hardware at the problem just to prevent the memory bottlenecks from slowing the simulation down.

A mouse brain is around 71 million neurons, and 100 billion synapses; the neuron count is nearly 500 times larger, with 2,000 times more synapses.

You couldn’t simply add more GPUs to your home cluster, because the bottleneck is in transferring the neuron data in these enormous matrices between all the separate compute devices, and then having the new data be re-integrated again at each step. The extra communication overhead for this would utterly overwhelm any cloud data centre.

So first, you would need to obtain an enormous empty warehouse, like an aircraft hangar. Then you’d need to fill it with the very latest, most specialised, most powerful unified hardware. If we take for example the NVIDIA GB200 NVL72, which is essentially a rack-mounted 72-core GPU supercomputer on a chip, we get about 2.88 petaflops per unit. It has fully integrated memory, so inter-chip communication won’t become bottlenecked as easily.

We’d likely need a full 200+ petaflops - with a P - to make this work.

That means we’d need at least 70 racks of these.

Each NVL72 draws 120kW of power. Running 70 of them at once would require 8.4 megawatts of electricity, continuously. But hey, at least you’d have one of the most powerful supercomputers that exists on this planet today.

Which is kind of crazy, considering the biological mouse brain uses only about 8 milliwatts of power. The computational simulation of it requires over 1 billion times more energy to achieve.

How in Darwin’s name did these infinite, blind, semi-deranged monkeys pull off such absurd levels of energy efficiency?

Each neuron is like a single processor core operating in parallel. The fruit fly brain has 150,000 of these. That’s likely more parallel processing power than every single electronic device within a 1km radius of your house combined. The flip side is that neurons are not capable of everything that a single electronic CPU can do (which is a lot), however they don’t need to be.

A lot of computational math is also obtained for free just by the nature of the organic chemistry happening at the cellular and synaptic layers.

Digital hardware burns massive amounts of power to do large scale mathematics using rigid, binary logic gates. Evolutionary biology does it using fluid dynamics.

The sprawling branches of a neuron act like microscopic, saltwater-filled cables with little holes that can open and close. When a synapse fires, it opens a hole at one end, letting a wave of voltage carried by ions rush in. The membrane is slightly leaky, so this wave naturally decays as it travels, giving the brain spatial filtering for free. If multiple waves fire in quick succession, they physically stack on top of each other in the fluid volume before leaking out, which gives the brain temporal integration.

They leverage the natural electrical resistance of the cell membrane and the passive diffusion of ions, with positive and negative voltage ripples crashing into each other at the junctions of these branches, physically adding and cancelling each other out in real time.

It gets complex calculus practically for free just by letting physics sort it out.

Lastly, no central integration is required for biological neurons. They get their inputs, produce their outputs, and it just gets sent to the next set of connections. Each neuron can add or reconfigure or remove synaptic connections they have with other neurons in response to this, so this serves as fully integrated weighted memory. A computer, however, needs to keep shuttling the outputs from processors over to memory storage and back again to use as inputs just to simulate synaptic input/output.

It’s a lot.

All this is to say that while we can technically simulate biological brains on computers, it’s the many differences between logical design and evolutionary free-for-all which make it challenging.

While we can use analogies to computers or modular architectures and the like to help us learn about the brain, we should do so with eyes wide open to the fact that it obscures just as much as it reveals.

That’s all for today, thank you so much for reading all the way to the end. I hope I’ve been able to inspire you in some way with new thoughts, ideas and possibilities. If so, please consider upgrading to a paid subscription if you haven’t already, or drop me a donation over at ko-fi:

I’ve been working hard on content for a complementary Youtube channel where I hope to deliver more digestible video versions of this stuff, as soon as the first set of episodes are ready, you’ll all be the first to know.

Many thanks to everyone who has a subscription or made a donation at any point, you literally keep this show on the road.

Until next time!

TLDR: Serotonin has no association with depression whatsoever. Instead, some cases are thought to be caused by reduced neuroplasticity during chronic periods of stress (mediated by the HPA axis and cortisol), resulting in a reduction in BDNF (brain-derived neurotrophic factor). SSRIs might work not due to serotonin, but due to significantly increasing BDNF expression, which is likely why psychedelics can also help in some cases.

Few molecules in the history of biology have travelled as strange a road as serotonin.

It was discovered twice, on two continents, by researchers chasing two completely different problems; one studying why blood serum constricts vessels, the other studying a substance in the gut that makes smooth muscle contract.

Within a decade of its chemical identification it leapt from a curiosity of vascular physiology into the centre of psychiatry, becoming the basis of a “chemical imbalance” myth that has shaped how hundreds of millions of people think about depression.

Today, that simple story has collapsed under the weight of evidence, even as serotonin has turned out to be far more biologically important - and far more widely distributed through the body - than its early champions ever imagined.

In this episode, we trace the rise and fall of the “serotonin hypothesis” of depression, dig in to its surprisingly broad function that modern research has revealed, and take a peek at the current leading theories for what makes clinical depression happen (oh, and why SSRIs work at all!)

Get in on these insights early! Hit the button:

In the late 1930s, the Italian pharmacologist Vittorio Erspamer, working in Pavia, was studying a substance concentrated in the enterochromaffin cells of the gastrointestinal mucosa which caused smooth muscle to contract.

He named it enteramine.

Over years of painstaking work he and his colleagues characterised its biological actions, and Erspamer correctly suspected it was an “indole”-derivative (an unpleasantly-oderous organic compound found in coal tar and poo.)

Interestingly, the Italians also played a major role in the West’s discovery of Dopamine, but that’s a whole other story.

Independently, at the Cleveland Clinic in the United States, a team interested in the vasoconstrictor activity of blood serum was trying to isolate the agent responsible for raising vascular tone.

Some 10 years later, in 1948, Maurice Rapport, Arda Green, and Irvine Page succeeded in isolating and crystallising the target agent from beef serum. Because it came from serom and affected vascular tone, they coined the name serotonin.

Rapport then went on to determine its chemical structure, publishing the proposed vasoconstrictor principle the following year. Shortly afterward, serotonin was chemically synthesised, and it became clear that Erspamer’s enteramine and Rapport’s serotonin were the very same molecule: 5-hydroxytryptamine.

This double discovery is why the molecule carries two naming traditions to this day: pharmacologists and neuroscientists usually write 5-HT, while the popular and clinical name remains serotonin.

Then, in 1953, serotonin suddenly became a rather important subject of study to those who investigated diseases of the brain when Betty Twarog and Irvine Page demonstrated that serotonin was present in mammalian brain tissue.

This was the moment serotonin became a candidate neurotransmitter, and the timing couldn’t have been more extraordinary.

It coincided almost exactly with the discovery that the powerful hallucinogen lysergic acid diethylamide (LSD) was structurally related to serotonin, and could even antagonise (promote) its actions on smooth muscle (as serotonin does.)

The inference - that a serotonin-like compound could so profoundly alter perception and mood, and make you hallucinate like the devil - electrified the young field of biological psychiatry and planted the seed of an idea that serotonin governed states of mind.

Even before receptors could be cloned, classical pharmacology hinted at serotonin’s complexity.

In 1957, Gaddum and Picarelli, studying guinea-pig ileum, proposed that serotonin acted on at least two distinct receptor types, which they called the “M” (morphine-blocked) and “D” (dibenzyline-blocked) receptors.

This early two-receptor scheme was the ancestor of what is now recognised as one of the most complicated receptor families in all of pharmacology, encompassing at least 14 distinct receptor subtypes today.

The serotonin theory of depression did not emerge from a direct observation that depressed people lacked serotonin. It emerged, somewhat backwards, from pharmacology.

In the 1950s and 1960s, clinicians noticed that certain drugs altered mood, and researchers reasoned backward from the drugs’ known effects on brain chemistry to a presumed cause of the illness.

Two foundational papers framed the debate:

Joseph Schildkraut proposed the catecholamine hypothesis of affective disorders in 1965, arguing that depression might be associated with a deficiency of noradrenailne at functionally important brain sites.

Two years later, in 1967, the British psychiatrist Alec Coppen advanced the case that 5-HT, rather than (or in addition to) the catecholamines, was central to the biochemistry of affective disorders.

Together these papers crystallised what became the monoamine hypothesis of depression; the idea that mood disorders stem from a deficit of monoamine neurotransmitters in the brain, such as dopamine, noradrenaline, and serotonin.

The hypothesis gained enormous traction because drugs that increase synaptic serotonin can apparently relieve depressive symptoms.

The decisive commercial and cultural moment came with fluoxetine (Prozac), developed at Eli Lilly and described by David Wong and colleagues as the first selective serotonin reuptake inhibitor (SSRI) to reach the market. Wong’s retrospective review traces the deliberate, two-decade evolutionary process by which fluoxetine was engineered specifically to block serotonin reuptake while sparing other systems.

SSRIs supposedly work by inhibiting the serotonin transporter (SERT), thereby raising the concentration of serotonin in the synaptic cleft.

The marketing logic was seductive and simple: if a drug that raises serotonin treats depression, then depression must be caused by too little serotonin - a “chemical imbalance” that the medication corrects.

This framing was widely communicated to the public through advertising and clinical encounters, and it became one of the most successful pieces of medical folk-knowledge of the late twentieth century.

And, as Psychopharmacologist Stephen M. Stahl noted in his 1998 paper, Prozac and similar agents are “among the most frequently prescribed therapeutic agents in all of medicine.”

It turns out, however, this simple pharmacokinetic story was built on far shakier foundations than anyone believed at the time.

Crucially, the inference is a logical error of the form of “the drug raises X, therefore the disease is a deficiency of X.”

Aspirin relieves headaches, but headaches are not caused by an aspirin deficiency.

Even at the time, serious problems were visible, such as the therapeutic delay, and a heterogenous pharmacology of anti-depressants.

SSRIs raise synaptic serotonin within hours, yet clinical antidepressant effects typically take weeks to appear. This temporal mismatch suggested that the relevant therapeutic mechanism is not the acute rise in serotonin itself, but slower, downstream adaptations.

For example, one such adaptation is the desensitisation of somatodendritic 5-HT1A autoreceptors (these are receptors that detect the molecule in the “extra-cellular space”, i.e outside or overflowing the synaptic cleft) in the raphe nuclei.

Meanwhile, drugs with very different effects on serotonin can all have antidepressant activity, which is hard to reconcile with a single, simple serotonin-deficiency model.

Something was clearly not right with any of this. The drugs definitely work; we just couldn’t quite figure out how.

The empirical case against the simple serotonin-deficiency model was assembled most comprehensively in a 2022 systematic umbrella review led by Joanna Moncrieff and colleagues, published in Molecular Psychiatry.

Together, they synthesised the principal bodies of evidence:

* serotonin and 5-HIAA (its main metabolite) concentrations in bodily fluids;

* 5-HT1A receptor binding;

* serotonin transporter (SERT) levels by imaging and post-mortem;

* tryptophan-depletion experiments;

* and SERT gene associations and gene–environment interactions.

Their conclusions were revealing.

First, meta-analysis of the serotonin metabolite - 5-HIAA - showed no association with depression.

A meta-analysis of serotonin in blood plasma showed no relationship with depression, either.

Shockingly, it actually found that lowered serotonin was associated with the use of antidepressants - suggesting these medications might be doing the exact opposite of what we all believed.

Then, further analysis of the largest and highest-quality genetic observations of Serotonin Reuptake Transporter - SERT - showed no relationship whatsoever with depression, and no gene-by-stress interaction.

Not only had we been wrong about how these medications worked, we had been ass-backwards wrong.

Upside-down looney-tunes wrong.

We had been living in opposite land.

The bottom line was that the main areas of serotonin research provide no consistent evidence that depression is caused by lowered serotonin activity or concentration.

The authors wrote that the areas surveyed “provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations”; more provocatively still, “some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.” (emphasis mine)

The paper - as you might expect - generated intense debate; the journal published numerous commentaries both supporting and criticising its framing and methods, but it crystallised a scientific consensus that had in fact been building for years:

The simple “low-serotonin-causes-depression” story is not supported by the evidence.

It is important to be precise about what collapsed.

The umbrella review undermined the claim that depression is caused by a serotonin deficiency. It does not prove that SSRIs are ineffective, nor that serotonin is irrelevant to mood.

The efficacy of antidepressants is a separate empirical question, addressed by large network meta-analyses such as Cipriani and colleagues’ 2018 study of 21 antidepressants, which found that all examined antidepressants were more effective than placebo for acute major depression, albeit with modest effect sizes and varying acceptability.

The most defensible modern position is that SSRIs can be clinically useful, but that their benefit does not validate a serotonin-deficiency theory of causation.

Stahl puts it bluntly: “the immediate actions of SSRIs are mostly side effects,” and locates the cure elsewhere: “The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations,” of which “a leading hypothesis… is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe.”

If the psychiatric story narrowed and then partially collapsed, the broader biology of serotonin expanded enormously.

The single most important re-framing of the past two decades is captured in the title of a landmark 2009 review by Berger, Gray, and Roth: “The expanded biology of serotonin”.

What we did in fact discover is that most serotonin is not located in the brain.

Although serotonin is famous as a brain neurotransmitter, the overwhelming majority of the body’s serotonin is found outside the central nervous system, predominantly in the gastrointestinal tract, where it is produced by enterochromaffin cells and stored in circulating platelets.

Within the brain, serotonin’s character is one of a neuromodulator via volume transmission, a characteristic it shares mainly with various kinds of peptide: it does not so much carry discrete point-to-point messages as set the gain and tone of large brain networks.

Its functions are remarkably broad; it is involved in the regulation of mood, sleep, appetite, food intake, aggression, impulsivity, and many other processes, and it is the precursor for melatonin synthesis in the pineal gland.

The diversity of serotonin receptor subtypes - each with its own distribution and signalling - is what allows a single molecule to influence so many distinct functions, and it explains both the therapeutic breadth and the side-effect profile of serotonergic drugs.

So, if not serotonin deficiency, then what is depression?

There’s a word - “stress” - that often comes up in the literature these days. I’ve often found myself wondering what exactly kind of “stress” is being referred to here. When we talk about stress, we’re often talking about psychological and psychosocial challenges, such as losing a job, concern over finances, marital instability, and so on.

However, stress in biology is usually something different; infection, illness, disease, anything that results in systemic inflammation, in which large quantities of leukocytes (white blood cells) and cytokines flood the body, with wide-ranging biochemical impacts across all systems.

Something that has emerged recently is an understanding that psychological stress doesn't stay psychological. It is converted into biological signals by the hypothalamic–pituitary–adrenal (HPA) axis, which releases cortisol.

Sustained high cortisol is itself neurotoxic to the relevant circuits; it is one of the proximate drivers of synaptic atrophy, and a reduction in signalling of the brain’s growth hormone, “brain-derived neurotrophic factor” (BDNF.)

It effectively slows your brain’s ability to adapt, significantly reducing its neuroplasticity, as well as weakening existing connections.

Presently, this is hypothesised to be one of the leading causes of clinical depression: the inability for the brain to adapt away from negative thought patterns, due to the massive reduction in neuroplasticity caused by chronically high cortisol.

Interestingly, this also seems to be where SSRIs have their anti-depressant effects; one idea posited that the chain of events that causes the desensitisation of serotonin autoreceptors in the brain may also result in the increase of BDNF expression, restoring levels of neuroplasticity that resemble the “critical period” of brain development.

A related and increasingly influential idea is that serotonergic drugs (and psychedelics) may enhance a window of plasticity that allows the brain to “relearn” healthier patterns, with environment and psychotherapy determining the outcome. In this model, the SSRI unlocks the gate, allowing the patient to pass through.

This would explain why combined SSRI and psychotherapy treatment regimens are typically much more successful than either one on its own: SSRIs seem to give the brain the opportunity to break out of negative thought pathways.

These mechanisms are areas of intense ongoing investigation and are not yet settled.

Although the leading hypothesis of depression has crumbled beneath our feet, the effect on research has been to blast wide-open many new and exciting areas that were once thought to be settled.

The failure to find a robust SERT-gene association with depression is but one, showing depression is almost certainly not one disease but a heterogeneous collection of conditions with overlapping symptoms and many contributing causes, including genetic, developmental, inflammatory, social, and environmental.

Identifying biologically meaningful subtypes, matching them to mechanisms (serotonergic or otherwise), and translating that into clinical treatments, is among the very frontiers of biological psychiatry today.

There’s also more being found on the psychological front, such as how antidepressant treatments “decrease the negative bias in the processing of emotionally salient information early in the course of antidepressant treatment, which leads to the clinically significant mood improvement later in treatment”, as described by Godlewska and Harmer.

This model reflects “a change in the view of psychological and biological processes, from seeing them as separate to complementing one another.”

What we are still discovering may be the most exciting part: how antidepressants and psychedelics actually reshape the brain, how the gut and its microbes talk to the mind, and how a single small indole built from a dietary amino acid came to touch so many corners of human physiology.

Serotonin’s story is not finished.

If anything, after seventy-five years, it is becoming more important than ever.

References

* The discovery of serotonin and its role in neuroscienceWhitaker-Azmitia PM | Neuropsychopharmacology | 1999

* The serotonin theory of depression: a systematic umbrella review of the evidenceMoncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA | Molecular Psychiatry | 2023

* Serum vasoconstrictor (serotonin): the presence of creatinine in the complex; a proposed structure of the vasoconstrictor principleRapport MM | Journal of Biological Chemistry | 1949

* Two kinds of tryptamine receptorGaddum JH, Picarelli ZP | British Journal of Pharmacology and Chemotherapy | 1957

* International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-Hydroxytryptamine; Pharmacology and FunctionBarnes NM, Ahern GP, Becamel C, Bockaert J, et al. | Pharmacological Reviews | 2021

* The catecholamine hypothesis of affective disorders: a review of supporting evidenceSchildkraut JJ | American Journal of Psychiatry | 1965

* The biochemistry of affective disordersCoppen A | British Journal of Psychiatry | 1967

* Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publicationWong DT, Bymaster FP, Engleman EA | Life Sciences | 1995

* Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effectsStahl SM | Journal of Affective Disorders | 1998

* Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysisCipriani A, Furukawa TA, Salanti G, et al. | Lancet | 2018

* The expanded biology of serotoninBerger M, Gray JA, Roth BL | Annual Review of Medicine | 2009

* A unique central tryptophan hydroxylase isoformWalther DJ, Bader M | Biochemical Pharmacology | 2003

* Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotoninFrost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M | Journal of Bone and Mineral Research | 2010

* Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesisYano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY | Cell | 2015

* The role of glutamate underlying treatment-resistant depressionKim J, Kim TE, Lee SH, Koo JW | Clinical Psychopharmacology and Neuroscience | 2023

* Psychedelic Psychiatry’s Brave New WorldNutt D, Erritzoe D, Carhart-Harris R | Cell | 2020

* Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatmentBR Godlewska, CJ Harmer | Psychopharmacology | 2020

I know you’ve heard of it.

“Dopamine.”

It’s supposedly a chemical in the brain that causes pleasure, right?

I mean, everyone says so. Even Harvard says so, and surely we can trust Harvard, right?

No, sadly, this most perpetuated of common wisdom is perhaps the most common medical myth of our time. If you thought dopamine had anything to do with feelings of pleasure, it’s time to set the record straight.

To do that, we need to start at the beginning of the story; the story of how dopamine became so misunderstood.

While you’re here, check these out:

In a sterile room of a McGill University laboratory in 1954, a surgical mistake birthed a fascinating discovery.

James Olds and Peter Milner were attempting to study the neural mechanisms of learning in rats, using a microelectrode embedded into the midbrain reticular formation.

When it came time to test “rat number 34”, the electrode slipped, misaligning by a fraction of a millimetre, and embedding itself into the septal area.

Like the others, this rat was placed into their operant conditioning box and given a lever which, when pressed, delivered a fraction of a volt through the electrode into the brain. Unlike all the others, however, this particular animal became utterly transfixed by this device. It pressed the lever again, and again, and again. Soon, it was pressing it thousands of times an hour.

The rat ignored food, it ignored water, and it ignored females in heat.

It would actively stimulate its own brain until it collapsed from exhaustion, and starved to death.

Olds and Milner concluded they had stumbled upon the mammalian brain’s “pleasure centres.” The pathways radiating from these regions were rich in a specific neurotransmitter: Dopamine.

Thus began one of the most persistent biological myths, one that has survived for over 70 years despite rigorous scientific falsification, embedding itself in the popular consciousness, and even today being repeated in academic research as an axiom that “everyone knows” without any citation or reference.

Look again at that article from Harvard; do you see any citations?

This idea - that dopamine was “the brain’s pleasure chemical” - was further crystallised in 1978, when researcher Roy Wise formulated the “Anhedonia Hypothesis” after observing that administering the dopamine receptor antagonist (blocker) pimozide to rats caused them to stop working for food.

To the naked eye, the rats behaved exactly as if the food had been removed entirely.

Wise argued that blocking dopamine systematically eroded the “hedonic impact” of the reward itself. In this paradigm, dopamine was pleasure incarnate; chemically turning off dopamine meant chemically disabling the capacity for enjoyment.

It was a neat, beautifully simple and consumable theory that resonated deeply in the minds of scientists and laypeople alike, and helped to invent many of the most ridiculous pop-psychology fads we see today.

That anhedonia hypothesis held for a decade, until neuroscientists Kent C. Berridge and Terry Robinson fundamentally broke everything about the model in 1989.

Berridge reasoned that if dopamine was the quintessential chemical of pleasure, a rat stripped of all dopamine should exhibit a total absence of hedonic response. The question was: how do we really test “hedonic response” with confidence?

Using the neurotoxin 6-hydroxydopamine (6-OHDA, or “oxidopamine”), Berridge selectively destroyed 99 percent of the dopamine neurons in the rat striatum. Predictably, the rodents became entirely aphagic (refusal or inability to swallow). They refused to seek out food and would rapidly starve unless they were artificially fed via gastric tubes.

However, Berridge also introduced a novel metric originally designed by Grill and Norgren in 1978: the “taste reactivity paradigm.”

It turns out, rats give off a remarkably consistent signal of receptivity to taste through their facial expressions. It’s so consistent, in fact, it can be used as an empirical measurement.

Given something sweet and delicious, rats exhibit rhythmic tongue protrusions and relaxed facial muscles: the “positive” response.

When given something bitter and yucky, they gape with mouth open wide, jaw dropped, and corners of the mouth retracted, followed by a sequence of physical aversive reactions: the “negative” response.

When given something entirely tasteless, such as room-temperature water, only rhythmic mouth movements occur, without either the tongue protrusions of sweetness or gaping from bitterness: the “neutral” response.

If dopamine really was the chemical responsible for pleasurable sensations, blocking or destroying dopaminergic neurons should result in the total elimination of the “positive” response to sweet or delicious-tasting substances. In fact, that’s exactly what Berridge had been expecting to find: that all taste reactivity would become either “neutral” or “negative,” regardless of what was given to the rats.

So when Berridge manually pipetted a sweet sucrose solution directly into the mouths of these dopamine-depleted rats and recorded their facial micro-expressions in slow motion, the results were… confusing.

The rats still exhibited the same rhythmic tongue protrusions and relaxed facial muscles as would be found in the unmodified control rats; the positive pleasure response.

So then what, exactly, was dopamine-depletion doing to them? If they still experienced pleasure, why were they so... depressed?

Berridge and Robinson spent the subsequent decade proving an idea: that dopamine does not mediate “liking” (hedonic impact, pleasure).

Instead, it mediates “wanting”.

They believed dopamine in the mesolimbic pathway supports an unconscious tagging system that makes reward cues fundamentally attractive, propelling the organism’s behaviour toward an objective.

They called this “incentive salience.”

The dopamine-depleted rats still liked and enjoyed sugar; they merely stopped caring for it one way or another. They stopped pursuing it. They no longer particularly wanted it.

It turns out there is a distinct difference in the brain between liking something and wanting something.

True pleasure, or “liking,” is actually fragile and remarkably localised in the brain. It is mediated by isolated “hedonic hotspots” predominantly driven by opioid and endocannabinoid signalling in the nucleus accumbens shell and ventral pallidum. By contrast, the dopamine-driven “wanting” system is massive, robust, and highly susceptible to sensitisation.

This neurological divergence explains the bleak reality of severe addiction. As Berridge noted, the dissociation of wanting and liking means a drug addict can reach a neurobiological state where their mesolimbic system, driven by dopamine, is so heavily sensitised to a particular sensory cue - in this case, a drug - that they possess a desperate, overwhelming want for it, even if subjective tolerance is so high that they no longer like the experience of taking it.

Furthermore, in 2025, Berridge was able to demonstrate conclusively that it is possible for an organism to want something that they severely dislike by directly manipulating the mesolimbic pathway with electrical stimulation: using this mechanism they were able to cause rats to feel an overwhelming motivation to bite on an electrified rod, causing them pain and discomfort.

Clearly, we can like things we don’t want, and want things we don’t like.

It has been scientifically proven that you both want and like articles just like this one; subscribe!

Here’s another fact about dopamine you probably didn’t know: your eyes use dopamine to signal the brightness of light entering the retina.

Your brains motor cortex uses dopamine to gate movement signals for fine motor control.

In fact, dopamine is used in lots of completely different ways throughout the brain and body; it makes no sense whatsoever to pin any one function on it.

Suggesting dopamine is the brain’s pleasure chemical is not only specifically wrong, it’s also wrong in general.

It would be like suggesting radio waves are how software engineers communicate cat videos with each other. Sure, if you follow enough reductionist reasoning, you can reach a level where cat videos are indeed carried across the internet which sometimes includes radio waves, but would anyone describe “the internet” explicitly as a “system for transmitting images and videos of cats?”

Don’t answer that.

(On that subject, this is one of my earliest youtube videos:)

Anyway, you get my point. Sometimes people watch other sorts of videos on the internet, too.

Not me, though I’ve heard rumours of it happening.

So, if dopamine really isn’t relevant to the phenomenon of pleasure, why has the myth been so persistent?

My only guess is that it lets us quickly and easily explain away things like addiction, ADHD, depression, “youths” (get off my lawn.)

It makes it easy to say that drug addicts are just out to get “high”, that it is a choice they make  - choosing to seek pleasure even to the detriment of all else  -  which they could change if they really wanted to, if they simply “took responsibility for themselves.”

It allows us to pretend ADHD isn’t real, that such people need to “be responsible”, as if it’s all just a choice they make to pursue only “enjoyable things”, or that it’s only a childhood phase one grows out of: because, you know, being a “grown up” means you start making “good choices” and “doing the hard things” which is the antithesis of ADHD, right?

It makes it easy to wave away depression as merely an absence of joy, to say “come on, it’s not that bad”, as though the cure were merely to realise that butterflies and rainbows exist, and allow all the joy to flow back into the brain just like that.

These simplistic explanations may allow us to forget about the complexities of the world around us, and especially our own brains. We don’t like things being too complicated; part of being human is trying to simplify and explain things, even things we don’t understand.

We also don’t like to believe anything which suggests a lack of human control, especially over our choices. To believe it’s all just some chemical reaction makes it seem like it’s not really a conscious choice, doesn’t it? (It isn’t)

The illusion of the ethereal conscious self as being in absolute control over our physical bodies, like an external puppet-master, is indeed a very powerful and very useful one to our sense of a unified identity, despite the fact that our bodies are an amalgamation of uncountable numbers of other micro-organisms.

What’s more, it’s no doubt comforting to believe our choices are made by some fully integrated and consciously aware entity, as though we design the choices we make with intent.

We don’t.

It’s all just chemistry.

Don’t forget to check Part II:

References:

Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. | J. Olds and P. Milner | 1954 | Journal of Comparative and Physiological Psychology, 47(6), pp. 419-427.

“the electrical stimulus in the septal area has a positive reinforcing effect of a very high order”

Neuroleptic-induced “anhedonia” in rats: pimozide blocks reward quality of food. | R.A. Wise, J. Spindler, H. deWit and G.J. Gerberg | 1978 | Science, 201(4352), pp. 262-264.

“Pimozide appears to selectively blunt the rewarding impact of food and other hedonic stimuli.”

Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function. | K.C. Berridge, I.L. Venier and T.E. Robinson | 1989 | Behavioral Neuroscience, 103(1), pp. 36-45.

“The persistence of normal taste reactivity argues against... an anhedonia... hypothesis”

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? | K.C. Berridge and T.E. Robinson | 1998 | Brain Research Reviews, 28(3), pp. 309-369.

The incentive sensitization theory of addiction: some current issues. | T.E. Robinson and K.C. Berridge | 2008 | Philosophical Transactions of the Royal Society B, 363(1507), pp. 3137-3146.

Wanting what hurts: D1 dopamine neuronal stimulation in CeA is sufficient to induce maladaptive attraction | Nguyen and Berridge | 2025 | Nature

Note: I am not a doctor (I didn’t even finish High School) and none of this should be taken seriously let alone be considered medical advice, or in any way accurate, rational, logical, grammatically correct, or even comprehensible, and should probably be ignored by all of humanity. Anyone taking this too seriously might want to get checked out for Autism ahem I mean ENT J/P.

I’m not usually interesting or popular enough to be written about, but on occasion it happens. This time, it was due to a post I made about being accepted into a “secret society of neurodivergents” at my new workplace:

(If you can’t see the light-hearted, tongue-in-cheek nature of this post, you should perhaps consider therapy)

I got into an interesting discussion in the comments, challenged on whether ADHD is just a personality profile, and what exactly makes it pathological. I think we had a good discussion about it.

Turns out, however, the same individual went to the trouble of interpreting this as me being self-diagnosed, and decided to turn me into the poster boy for everything that is wrong with the kids these days and all their social-media-driven self-labelling rainbow-67-skibidi-toilet nonsense.

Apparently I’m not who I think I am?

Take this fellow, Nicholas Kircher, who posted about being added to a ‘secret’ AuDHD group. Now, those not up with the lingo, this Frankenstein word is a fusion of Autism and ADHD, two of the most conflated and error-prone ‘diagnoses’ of the last 15 years.

The authors take issue with the whole neuro-divergence thing, and seek to un-diagnose me. They paint me as having succumbed to some tiktok fad, joined a bandwagon, been “influenced” into self-diagnosis.

Nicholas and the rest of the Neurodivergent bandwagon

Which, lets be honest, is pretty funny considering my history (and I don’t even use tiktok.)

The whole thing is horrifically over-cooked, and although probably not meant to be mean-spirited, it definitely smells like self-righteous silliness. This might be a valuable teaching opportunity. Then again, it might not. Time will tell.

So I am posting today to send the whole thing even more over-the-top than is necessary, or responsible, or even legal. For one time only. After this, I’m not spending any more time on the subject, as we all have better things to do.

Example of a better thing to do: subscribe!

First, some history about me and my situation, because nobody asked (and perhaps if anyone had asked, the original article could have been significantly improved, and maybe a lot shorter):

I was diagnosed with ADHD and Autism Spectrum in the year 1999 - the same year The Matrix came out - when “Social Media” didn’t even exist yet, and MySpace was still a good 4 years away. Back then, my diagnoses were known as ADD-Inattentive and Aspergers Syndrome.

Why was I diagnosed?

I was nearing the end of primary school. I’d already repeated one grade, and was failing another. I’d had no success in making any in-school friends or proper connections with others, and I fidgeted incessantly at all times. Some developmental goals I was reaching, but many I was hopelessly behind in.

I was not absorbing anything being taught, I was constantly getting lost in time and in space, and for nearly every activity in class, I would somehow draw a blank when instructions were given, having no idea what was happening or what we were doing. I almost never remembered to do homework, or quite frankly anything else unless it was squarely within my “special interest” bubble, and when I did remember or was reminded, I could rarely get it started, and even then I didn’t last more than 5 minutes before I’d crash and burn, hard.

I didn’t even complete the IQ test I was given by a psychologist, and never got a score. (I like to joke that I got a zero)

I came home every day to my mum - who was suffering in the throes of a chronic illness - sobbing intensely, because I could not understand why I could not do what all the other kids were doing with apparent ease.

Every unqualified person and their dog seemed to have an opinion on why this was. The greatest hits:

* he’s lazy,

* he’s faking (for attention, apparently)

* he has a bad/lazy mother,

* he needs to take more responsibility for himself,

* he’s not being punished enough (bring out the lash),

* he just needs to apply himself,

* he just needs to pay more attention (duh),

* he’s a designer moron

Wait, a “designer moron?” Yes, friends, that was the term used for me by some of my extended family after I received my formal diagnosis. They, too, thought all this fancy label stuff was just to hide the simple fact that I was an idiot.

Growing up with a single mum, she worked hard to find a way to help me. She was the only person in my life for a long time that gave a s**t, and she refused to give up on me. I saw several different specialists as we searched for some explanation that actually made sense. Most of the opinions we got in those early days were nonsense - like mum being told she needs to take “parenting classes” - while some of them were outright scams. However, two interesting leads came along.

The first: perhaps I was having “absent seizures”, a kind of epilepsy that causes a blanking of conscious awareness, without the typical shaking/motor movement symptoms commonly associated with epileptic seizures. Thankfully that one can be pretty definitively tested, and it came back negative.

The second: maybe I have some combination of attention deficit, and/or Asperger’s. This one was - and still is - far from having a definitive test, and very few specialists in Australia at that time were well equipped to diagnose either of them. We got a lucky break however, and managed to get in to see perhaps the leading specialist in these two psychiatric conditions in the country.

My mum remembers the moment he came to a conclusion about my case:

“Mrs Kircher, I see a lot of kids brought in who are suspected of having one of these conditions, and the fact is, most don’t have it. In the case of your son, there is absolutely no doubt in my mind that this diagnosis fits.”

Since that day, it has been re-evaluated at least 4 separate times by independent specialists for various reasons, each time being re-confirmed.

So let’s just get one thing absolutely clear before we do anything else:

I am not one of your guinnea pigs for hypotheses about self-diagnosis.

And back to the beginning, when we mix personality types of both individual and cultural, where the US is an amalgamation of dozens of cultures, what is neurotypical? Ironically, for Nicholas and the rest of the Neurodivergent bandwagon… They are.

Currently, 20% of the US population and a whopping 53% of Gen Z self-identify as neurodivergent.

53% self-identify. Read that again: self-identify. One person’s self-identity is not the same as my psychiatric diagnosis.

I’m not self-diagnosed, I’m not Gen Z, and I’m not American.

Could have spent 5 seconds to find all that out, but instead of “doing the hard things,” why not just make assumptions and roll with them?

And that is also a very typical human behavior because doing hard things is… hard.

I bet.

What’s more, I’ve lived my whole life with people casting all kinds of aspersions about whether I’m “really” this or that or the other thing, or whether I’m just bereft of moral fibre and/or character, based on some 5-second observation they’ve made of me.

This is not the first time - not by a long shot - and won’t be the last.

As the New Zealand pathologist Dr Temple-Camp said: “That’s the thing about opinions and arseholes, isn’t it, gentlemen; everyone’s got one.”

So I asked Nicholas how he defined typical, but in answering my question, he skirted with vague statements about holding a standard job, maintaining social connections, and navigating daily life without significant distress. Which I’d like to find a single human who does this with frictionless ease.

I didn’t realise I was expected to provide some sort of DSM-version of the definition of a word that arose originally as a joke.

The term “neurotypical” was actually coined in the late 1990s by the autistic community, specifically by the autism rights group Autism Network International (ANI). It was created as a satirical counterpart to the idea that people with Autism were “neuro-defective.”

They wanted a neutral word to describe non-autistic people (whom they playfully referred to as having “Neurotypical Syndrome”) to shift the framing away from autism being a “disease” and neurotypicals being the “healthy default.”

The author’s actual question was this:

What, specifically, is Neurotypical because neither Level 1 Autism, nor ADHD are divergent, given the quantities they exist and they can be easily explained by Personality proclivities, not pathologies.

The reason I ask is people keep trying to tell me I’m both Autistic (I’m not, I’m analytical, disagreeable, and not nuerotic) and ADHD (I’m not, I’m Intuitive, fast thinking, and middling contientiousness.) What I’m saying I’m an ENT J/P… which is one of sixteen personality categories, totally neurotypical…

Here’s the actual part of my much longer response to their overall comment that partially dealt with the author’s specific question, framed within the context of how neurological conditions and personality constructs relate and differ:

So if you’re able to hold a standard job, maintain social connections, and navigate daily life without significant distress or the need for specific accommodations, you may still exhibit traits common to people with Autism or ADHD without being impacted by the symptoms which make it pathological. A diagnosis is only necessary when the underlying neurological factors create barriers to typical functioning.

I wasn’t even trying to explicitly define anything, merely explain how one might differentiate between a trait or variation and a functional disorder.

ADHD, Autism Spectrum Disorder, OCD, are psychiatric conditions defined in medical literature. The reason why the medical and psychiatric fields don’t explicitly define “neurotypical” or “neurodivergent” is because they’re overly-broad generalisations that don’t take into account the particular neuropathology involved. “Neurotypical” being a state of “the absence of a neuropathology” is obviously unsatisfactory as a medical term.

It’s like the word “healthy” - what is “healthy?” Is it just the absence of disease? How can you even be sure they truly are absent of disease?

Having dispensed with the assumption that I am a product of some modern social-contagion, this article can essentially be broken down into 2 arguments:

* People self-diagnosing (”collecting”) psychiatric conditions are really just seeking belonging and validation

* But also, ADHD and Autism Spectrum Disorder aren’t reeeeeally real anyway, it’s just an excuse to be an entitled self-absorbed little brat

The first argument is, in fact, an important topic of debate and discussion, and has been for many years now. The highly successful campaigns for awareness of these conditions could very well have resulted in over-saturation, with terms like “OCD”, “Autistic” and “Dopamine” being used as verbs in day-to-day language and completely outside their proper medico-psychiatric context (e.g “I’m so OCD about keeping the house tidy”, or “I need more dopamine, I’m really low today”).

However, stepping back to the world of 1999, most people simply defaulted to moral judgements: “he’s just lazy.” They weren’t adequately aware of other possible neurological explanations. They might have heard the term “ADD”, but until they had an adequate comprehension of what it meant in terms of the impact on behaviour, perception etc, they would quickly dismiss it as “some made-up medical jargon.”

The authors argue that we are wrongfully pathologising healthy human behaviour; that framing my traits as ADHD or Autism is simply medicalising the “perceiving” side of a normal personality matrix. I am just disorganised and analytically minded, they argue, and trapping myself in clinical language strips me of my agency to just “do hard things” and mature.

This might be true for some people who are self-diagnosing after watching a few youtube shorts about being “neurospicy.” Hell, sometimes even formal medical diagnoses are wrong. That happens in all fields of medicine, not just psychiatry. Sometimes, medication is given to the “worried well” in order to make them go away. That’s a legit thing we can be concerned about as a society.

It has absolutely nothing to do with me and my situation, nor that of many others who have spent their lives in constant and often fruitless struggle against disorders of this kind.

Then, there’s the sheer irony of trying to use a scientifically meaningless corporate sorting-hat like Myers-Briggs to debunk heavily researched neuro-developmental disorders; it’s quite something to behold.

The fundamental clinical description of ADHD was established in 1902 in a series of famous lectures by the father of British paediatrics, Sir George Still.

The first pen-and-pencil version of the MBTI (Myers-Briggs Type Indicator) was established 42 years later by two amateur mystery writers with zero clinical, psychological or medical training.

It’s like using Astrology to debunk General Relativity.

Let’s see what a tiny portion of the research says:

In 2017, the journal Lancet Psychiatry published the largest-ever global MRI study of ADHD brain structure, evaluating scans from over 3,200 individuals. The researchers concluded decisively that “Attention-deficit hyperactivity disorder (ADHD) is associated with the delayed development of five brain regions and should be considered a brain disorder.”

The data reveals robust, quantifiable reductions in the volume of the amygdala, accumbens, and hippocampus in individuals with ADHD compared to controls. These regions form the core of the brain’s reward, emotion-regulation, associative learning and impulse control circuitry. A reduction in their volume is a strong indicator of an innate, physiological deficit in how dopamine is transported and utilised.

Claiming this is just a behavioural choice or a natural inclination toward untidiness is equivalent to claiming clinical myopia - short-sightedness - is simply a preference for looking at objects closely.

Then, there’s the environmental argument, one which I’m fairly sympathetic towards, but it’s also a sociological trope: the idea that our educational systems and modern work environments “were designed for factory workers to perform a specific function,” and therefore, my brain is simply reacting normally to an abnormal environment. Put an ADHD brain in a hunter-gatherer society, the logic goes, and it is perfectly adapted.

I think there is some truth to this, but it’s far from clean-cut.

Dr. Russell Barkley, one of the world’s pre-eminent clinical authorities on the subject, characterises ADHD as a profound impairment of executive function, which is seated squarely in the under-stimulated prefrontal cortex. Executive function is what allows a human being to pause, evaluate the consequences of an action, recall past mistakes, and carefully decide what should happen next. It also plays a major role in inhibiting immediate emotion-driven responses.

Executive dysfunction does not just make sitting at a desk for eight hours difficult. A person lacking behavioural inhibition can frequently act on impulse, chronically misplace essential tools, forget crucial steps in multistep processes, and struggle to regulate their emotions and temper.

Even in a theoretical nomadic tribe free from the tyranny of the eight-hour workday, an inability to accurately track time or evaluate risk can be a significant disadvantage. Despite the fact that there do exist some benefits to particular traits which ADHD brings about in other environments, that doesn’t nullify all other deficits. Sometimes, it can even magnify them.

Without a doubt, environment can play a role in improving overall outcomes or degrading them; yet it does not necessarily follow that the environment makes the disorder.

This brings us to the most dangerous aspect of redefining these conditions as healthy variations.

The critics state that adopting these labels leads to a closed feedback loop where “entropy rules” and “that means no growth.” If you just chose to lean into the hard tasks and matured, they argue, you wouldn’t need accommodations or medication.

The epidemiological data tells a much darker story, as your typical personality quirks aren’t likely to carry a body count.

In 2019, Barkley and his colleagues published a ground-breaking longitudinal study evaluating the life expectancy of children with ADHD tracked into adulthood. The data was pretty stark.

Barkley noted that childhood ADHD “may more drastically shorten a patient’s life expectancy than any other single health threat including high cholesterol, obesity, and alcohol or tobacco use,” determining that the associated risk factors may decrease longevity by up to 13 years.

Notoriously elevated rates of substance abuse, severe traffic accidents, impulsive violence, and significantly higher rates of suicide mean ADHD all too often translates to an early grave.

The critics argue that clinical diagnoses and pharmaceutical interventions strip a person of their agency. In reality, the exact opposite usually occurs. The entire point of a diagnosis is understanding and treatment. The whole point is to find ways to thrive in spite of challenges which we are unable to overcome by other “common-sense” means.

That’s why we have the freakin labels!

When a person with a broken leg gets around using a crutch, we don’t accuse them of denying their personal accountability or demanding special treatment. We understand that the crutch provides the mechanical support required for them to actually participate in society.

We don’t wax philosophical about how a broken leg is really just a broken environment, how such people could just roll down a slope and they’d get around fine, so they just need to live on a hill-side and how hill-based societies had benefits for people with broken legs, yaadaa yaadaa.

“Isn’t it just a healthy variation in leg bone structure?”

It’s true that medication is often given to the “worried well”, yet that has no bearing on whether ADHD, or Autism Spectrum Disorder, or any other conditions are real or not.

What’s more, stimulant medication and clinical accommodations do not create an excuse for laziness. By medically counteracting the excessive reuptake of dopamine in the ADHD brain, we make it possible to actually exercise better discipline, build effective habits, and take genuine accountability for one’s life.

The diagnosis and treatment make this possible when all other options have failed.

We do need to have a serious conversation about the sociological impact of internet self-diagnosis. The proliferation of influencers turning serious clinical disorders into quirky aesthetic identities is doing immense damage to public understanding.

However, the solution to that entirely valid problem is not to swing the pendulum back into the dark ages and pretend that structural neuro-developmental disorders are just an amalgamation of normal personality traits, which essentially translates into “it’s just a will-power issue.”

One can argue about whether one person or other could be reasonably diagnosed. We can argue about whether Autism is a spectrum disorder. The fact is, everything in the DSM, and pretty much everything else in science, is simply an approximation, and is up for discussion and refinement.

We use language - “fancy labels” - for categorising and finding treatments for challenges which take shape in the extremely complex biology and neurophysiology of human bodies. It’s an attempt to take something mind-bogglingly complex and bring it down to a level of human comprehension.

If you want to talk about normal, language is normal.

Words, like “ADHD” and “Autism”, are just language, and using language to communicate with others is normal.

The disorder itself is not.

If you recognise yourself in my self-description, or are facing similar challenges, and need medical advice: you should speak to a qualified medical professional. I am not one, and most people on the internet are wrong, including me.

Don’t just self-diagnose: trust the professionals.

Footnotes:

Addiction Resources: https://chemicalmind.substack.com/p/addiction-support-resources

Ko-Fi Link: https://ko-fi.com/dopamine

Note: This is a true story, taken from one of the many fascinating case reports of medical literature. This is a fairly famous example in the annals of addiction neuroscience, and it reveals in stark colours the counter-intuitive nature of addiction.

She couldn’t stop herself. She had to push the button.

She kept it on all day, dialling the power knob between 75% and 100% in rapid bursts.

All she could do was blast the electrodes buried deep in her brain, triggering an experience she called “pleasant discomfort,” a kind of “erotic sensation” as though her genitals were sending signals to her brain at kilowatts of intensity.

By all objective measures, though, she was disintegrating completely.

She would exhibit the physical symptoms of stroke. She would become extremely thirsty. Her verbal IQ would drop by a whopping 25 points. She even developed an ulcer on her index finger, the one she used to tune the power dial rapidly. This was not a particularly pleasant experience. Indeed, it was painful.

And yet, she stopped going outside.

She stopped talking to other people.

She even stopped bathing, and eventually, eating.

She could not pull herself away from the button.

There were times when she’d beg for her family to take it away, and they would; only for them to give in when she went through inevitable withdrawal symptoms, and demanded its return.

It was an addiction like any other; except this was not chemical. It was electrical.

In 1954, James Olds and Peter Milner released a remarkable study that would go on to shape our understanding of addiction. They implanted electrodes at various locations into the brains of rats, and gave them a series of levers they could press to stimulate the different electrodes.

The behaviour of the rats demonstrated the existence of specific locations in the brain which, when stimulated, could produce profound addiction: the rats would go to stimulate them again and again and again, until collapsing from exhaustion.

Such experiments would have been completely unethical if done in humans, and would never be approved by a review board. So, how had this woman, in the 1980s, ended up in the position of one of Olds’ and Milner’s rats?

Years earlier, the 48-year-old New Yorker had suffered a herniated disc right at the base of her spine, between L5 and S1; an excruciating experience, leaving her with severe sciatica. Pain would surge through her legs like a bolt of lightning. Her lower back was in constant agony. The pain and suffering was constant and intractable.

Eventually it became too much; she obsessed about finding a way to halt the pain.

Although of limited effect, so far, opiates - specifically, methadone - was the only thing keeping her functional at a basic level. That wasn’t ideal. She had a history of alcohol abuse, and knew the dangers of addiction all too well.

So she had turned her body into a veritable pin-cushion, subjecting herself to any and all ideas, in search of an alternative.

She had seen so many specialists. They tried pharmacological treatments of all kinds, including antidepressants, atypical analgesics, and more.

Every drug wore off quickly.

Massages and exercises had no effect. Acupuncture was useless. Cognitive Behavioural Therapies made no difference.

The TENS units - skin-conductance electrical stimulators of nerves - achieved nothing.

They tried surgically removing the back plates of 4 of her vertebrae to relieve pressure on her spinal cord. They denervated the area at the base of her spine, and even severed specific nerve fibres in her spinal cord they believed were transmitting pain signals to the brain.

All of it failed.

All this medical science, all these doctors and specialists, all this money, and they were at a loss. Here they were - in the 1980s - and they had no idea what was wrong or how to fix it.

One well-meaning specialist had an idea: if we can’t seem to solve it from the nerve side, perhaps we can find another way through the brain itself.

Pressing the button below will instantly cure all ailments, guaranteed! (note: not actually guaranteed, but it might work?)

Electricity for pain management is, remarkably, far from a new idea. There really is nothing new under the sun.

The first written description we have found of using electricity to manage pain was by the ancient Greeks, where both Plato and Aristotle described the use of the “Torpedo Fish” - a kind of electric ray, after which the submarine weapon is named - as an aid in curing ailments; but it was the Romans who wrote specifically about its use in treating headaches and gout.

Some 2000 years later, in the 1950s, we began to seriously experiment with delivering electricity directly to the brain. The implanting of electrodes directly into neural structures could bypass faulty central nervous system wiring, not to mention all the chemical filtering which made pharmacokinetics such a challenge.

Early experiments with this method as a treatment for chronic pain seemed to yield some positive results.

Deep Brain Stimulation (DBS) was, indeed, originally meant to treat pain. Later, people like José Delgado would begin experimenting with the technique to treat movement disorders, epilepsy, and paralysis.

DBS has a storied and controversial history. José Delgado, among others, would become the targets of crazy conspiracy theorists like Peter Breggin, who for their own political purposes ran a campaign of lies designed to paint Delgado in particular as an evil mind-control villain, eventually chasing him out of the United States.

Despite this, by the 1970s, DBS for pain was quickly gaining traction, with companies like Medtronic setting up its neurological division for manufacturing devices to control electrode stimulation. Case reports started to come out showing positive results for pain with electrodes implanted into the thalamus.

So, although still quite a new treatment, it wasn’t as hare-brained an idea as it might seem to us today, though it still sounds utterly counter-intuitive: stimulating a brain region that is signalling pain in order to suppress that pain. However, it was based on a historical precedent, or perhaps, neurological dogma: that stimulation mimics ablation (destruction).

The thinking was that with electrical stimulation, based on this precedent, they could use it as a reversible alternative to destroying those neurons entirely. If it worked, we might never need to surgically damage or destroy anything in the brain, whether in cases of severe intractable epilepsy or chronic pain. It could eliminate the use of lobotomies, which were still popular in the United States at the time.

So in ~1979, specialists handling the case of this woman’s intractable pain decided to give it a try.

They made 2 attempts.

First, they implanted an electrode in the right Posterior Medial Thalamus, the region of the brain mostly concerned with your emotional response to a sensory input, e.g being startled by sudden sharp pain. When they turned on the electric current, she felt a warm flush spread across the left side of her body, and the pain dissipated.

For 6 months, this seemed to work remarkably well.

However, like everything else, it was only temporary, and soon the device gave her no relief from pain at all. They left the electrode in place, dormant, and continued to pursue other treatment options.

Four years later, they made another attempt.

The target this time was the left Ventral Posteriolateral Nucleus, the region which helps to determine what a sensation is (touch, pressure, temperature, pain) and where it’s coming from; it then relays the information to other regions of the brain relevant to that specific sensation.

Again, it seemed to have a reasonable impact on the pain. She initially reported a tingling “paraesthesia” down her left side, but that was it. For a few months, the pain became manageable again.

Then, there was something else.

She had begun to experiment with the settings on the stimulator. She found that by manipulating the controls in a certain way, she could induce these peculiar “erotic sensations,” and reported this to the clinicians shortly following the procedure.

Unfortunately, this did not ring any alarm bells.

When the pain inevitably returned a few months later, her need for stimulation didn’t end. Indeed, it was only beginning.

She found herself continuing to need more and more stimulation. She would keep the device on, set to 75% power, and every few minutes rapidly turn the dial between 75% and 100% power. It brought her to the edge of climax, but never over the precipice. She was always just out of reach of satisfaction.

During these intense stimulations, her body would writhe in severe discomfort. The left side of her face would droop as though she were in the throes of a massive stroke. She would experience paroxysmal atrial tachycardia, and the most extreme thirst leading to psychogenic polydipsia (compulsive water drinking to the point of toxicity.)

There’s simply no way this could have been pleasure she was experiencing, and even if there was, it would have paled in comparison to the devastation and pain being inflicted upon her body and brain.

Somehow, she managed to continue like this for 2 years. Her addiction was so total, she spent most of that time in complete inactivity, save for occasions when her obsession with stimulation drove her to tamper with the device in an effort to further increase its amplitude.

IQ tests she performed shortly before and shortly after implantation of the electrode, and again by the authors of the case study 3 years later, reveal the utter devastation wrought on her brain.

Initially scoring 99 both before and after implantation on full-scale IQ - a reasonable score - by the time of the case study, she had lost a whopping 11 points.

Her memory quotient - initially around 96-97 - had plummeted to 64 (though interestingly, when stimulating, it rose slightly to 73).

They had her do a PET scan before and during stimulation to see how much energy her brain was using (by measuring glucose) and the results were striking.

When the device was off, the scan showed a startling lack of activity. Specifically, the researchers found right-sided hypometabolism and significant asymmetries between the two hemispheres. In this state, her metabolic rates were so low they were comparable to patients with advanced dementia.

With the device on, this reversed completely, with both hemispheres lighting up with thalamic noise, essentially jamming much of the cross-region communication required for normal brain function.

She had become completely enslaved to the button, and it was eating her alive.

My friend Prof Kent C. Berridge - inventor of Incentive Salience theory of motivation, along with the Incentive Sensitisation theory of addiction - knows this study well, so I emailed him to get his thoughts on the idea of someone being trapped so tightly inside a “wanting” loop that even aversive stimuli, such as pain and discomfort, are not enough to break the cycle. He replied:

“No one would sign up for such an electrode if advertised by her description, so there’s a massive explanatory gap between the not-very-pleasant experience and the intense desire to repeat and continue it.”

Rather propitiously, just last year he and a colleague David Nguyen published a paper in Nature’s Communications on Biology about “Wanting What Hurts” (the title I also borrowed for this article, because it’s too good.)

Imagine you are a rat. You’re in a little box with soft tray bedding at your feet. You look around and find a shiny rod-like object that you’ve never seen before.

You wander over and give it a poke with your nose, and a sudden, painful electric jolt hits you!

What do you do?

Well, typically, rats will do something called “defensive burying”, where they will kick bedding litter over the top of some object that they see as harmful. They will bury it, to get it out of their environment.

That’s what a rat would normally do to such an electrified rod.

However, using specially optogenetically-modified rats hooked up to a device which stimulates the anticipatory reward centres of the brain using a light beam whenever the rat comes within 2cm of the rod, following their first shock, they seem to do something unusual.

They give it another poke.

Obviously, another shock ensures, making them flinch back, but this does not deter them.

They give it yet another poke.

Despite the total absence of pleasant sensation - indeed, in spite of the particularly unpleasant and painful sensation from electric shock - they develop an overwhelming addiction to poking the electrified rod with their nose. Some of them would even nibble and chew it with their mouths, all while receiving continuous electrical shock.

The rats were even given the option to self-stimulate their own brain using a lever, which delivered no harmful or aversive stimuli; yet they would ignore the lever and consistently favour a zap from the rod. Something about the salience of that shock was like an answer to the question posed by the anticipatory reward circuits: “I predict this is going to be good for us, now let’s see…”

Zap.

As soon as the artificial stimulation of the brain ceases, the “addiction” disappears entirely, and the rats proceed to bury the rod. However, the point is still proved: the ability for an organism to become addicted to something can be independent of whether the experience is pleasant or unpleasant.

Since her case report in 1986, there has been no further information on the New York woman. Her story remains a singular, frozen snapshot in the annals of neuroscience. We don’t know whether she managed to recover from the addiction, nor even do we know whether the electrodes were removed, though we should probably assume they were at least deactivated.

Her case stands as a remarkable demonstration of the physical anatomy of what we might call “the will,” encoded within our biochemistry.

Although we like to believe our choices are guided by a pursuit of happiness, as both the New York patient and Berridge’s rats prove, something like addiction isn’t just some base hedonist’s failure of self-control.

It’s a physiological malfunction, and one we are all susceptible to at some level.

If you are suffering with addiction, beating yourself up over your inability to break free, remember this:

It is not a character flaw. It is not a weakness of will. It is not a free choice.

No amount of character or willpower alone can beat an addiction whose claws are embedded deeply enough. That doesn’t mean that nothing can be done, just that we need to look at the problem through a different lens, and approach it collaboratively, leaning on others for help.

I know that getting away from the feelings of shame and guilt is easier said than done, but I hope that understanding the physiological factors that cause it helps.

If you or someone you care about is struggling, please make contact with addiction support services in your region. For help figuring out where to start, I’ve put together this list: https://chemicalmind.substack.com/p/addiction-support-resources

Thank you for joining me on this episode of A Chemical Mind. A big welcome to all the new paid subscribers, and those that have been added from the Ko-Fi list. I’m still figuring out the plan for paid content, but I will get to it, I promise. Please let me know your thoughts for what you want to see!

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“The common conception that the brain is primarily for thinking, or other cognitive processes, is potentially misleading... neuroscience may benefit from a theoretical structure that centers on basic questions of how the brain coordinates and efficiently regulates the body.”

What if our entire understanding of the purpose of the brain is wrong?

By default, we have come to believe the main task of a brain is to think, to wield intelligence, to learn and remember and feel. Is this not what our own brains do the most?

It turns out it’s not nearly so simple, and by focussing on just our own perceptions - our conscious mind - we have completely ignored perhaps its most fundamental role: regulation of bodily systems to keep us alive.

I’m talking about the system of allostasis, or predictive regulation.

Unlike homoeostasis, where the body reacts to problems when they arise, allostasis is all about predicting the bodies needs ahead of time and adequately preparing for them, regulating internal systems to manage energy and resource-use. It’s tasked with efficient logistics planning, ensuring the supply is available at times when demand is predicted to rise.

This makes for a very obvious evolutionary purpose to the brain: it likely evolved as a means of managing the complex biochemistry of large multi-cellular organisms, and consciousness arose from the eventual complexity of its allostatic functions.

Although not a new idea, allostasis seems to be going through a bit of a revival.

According to an article recently published in Neuron Volume 113 (Issue 24), Jordan Theriault et al. argue that thought and consciousness might be a case of exaptation, a kind of happy accident of evolution which turned out to be useful in its own right.

If we adopt this "allostasis-first" lens, the very things we traditionally call "the mind" - our emotions, awareness, even sensations - appear to be low-resolution readouts of our metabolic state. Your mood, for instance, may function as a low-dimensional "allostatic barometer," a summary of how efficiently your brain is managing your body’s internal energy budget.

Even "stress" loses its purely psychological weight. In this biological framework, stress is simply the brain predictively issuing commands to deliver glucose and oxygen to your tissues in anticipation of a metabolic outlay. It is a value-neutral preparation for action should action be necessary.

This is not to suggest that these barometers and predictions are always correct. Like any sensor, they can be fed faulty data or be improperly calibrated. Like some safety systems installed on aircraft, a bad sensor can kick off a distinctly inappropriate response (see: Boeing 737 Max)

Still, this regulatory priority is etched into the very architecture of the human cortex. The brain is organised along a structural gradient that stretches from a "limbic core" to our primary senses. At this limbic core, signals are abstract and low-dimensional compressed summaries of the body’s collective needs. As these signals flow outward toward the motor and sensory systems, they "decompress" into the specific particulars required to move a muscle or adjust a heart rate.

Simultaneously, the firehose of raw sensory data coming from the world is compressed as it travels inward. It is stripped of its noise and categorised into meanings, with the most salience being placed on its allostatic value, i.e “what does this sight or sound mean for my survival?”

Ultimately, this shift in perspective dissolves the artificial wall we have built between the mental and the physical: we are not merely a mind inhabiting a body. The mind and body are a unified system.

What happens if we look at cognitive decline using this allostatic lens? Take Alzheimer’s, one of the main examples cited in the paper: the perspective shifts from a system breaking down, to a series of desperate, yet calculated, sacrifices.

Higher-order cognition uses up a fair bit of energy, but is non-essential for staying alive. It also produces a lot of waste products, due to the rather-inefficient method of anaerobic metabolism of glucose products into ATP (up to 15 times more inefficient than the aerobic alternative.). These waste products need to be removed regularly, mostly via the bloodstream, otherwise they can build up and cause havoc.

However, as we age, our vascular health naturally declines and becomes less efficient at this waste-removal task.

So when a system is faced with a situation where the waste produced by this high-energy, higher-order cognition begins to out-pace the brains ability to remove that waste, the authors suggest we might be forced into an “allostatic trade-off”, with the allostasis mechanism automatically rationing the amount of glucose supplied to the brain to reduce the overall demand on the vascular system.

If brain waste clearance is compromised, then it may be allostatically beneficial for the brain to downregulate glucose metabolism by restricting the transport of glucose into neurons and across the blood-brain barrier. Consistent with this, in older adults, glucose uptake and glucose transporter density (GLUT1 and GLUT3) decline following amyloid accumulation but before the appearance of cognitive decline.

That trade-off might allow the body to physically live longer than it otherwise would, but at what cost?

Put your email in this box. Just trust me.

Alzheimer’s results in the gradual destruction of the inner self; cognitive ability, memories, beliefs, even volition, eventually slip away.

However, the allostasis model does suggest that approaching Alzheimer’s as an energy-management syndrome centred around glucose and the function of the vascular system in general might lead to better treatments. Perhaps, if we work on improving vascular system health, as well as finding ways to clear up debris as we presently do, this combined, systems-driven approach might give us a fighting chance.

Everything psychological that a brain accomplishes—sensing, perceiving, thinking, feeling, deciding, acting—can be considered a means to the end of its core ongoing task: coordinating and regulating internal bodily systems, as an organism navigates a constantly changing but only partly predictable world.

The mind is a prediction machine. That’s its purpose: to predict what happens next, what’s coming down the pipeline, where and when we need energy levels to be at their highest readiness and when we will need to rest. The mind is all about forward-projection, and from birth it is continuously training against the incoming data to identify sequences and patterns in time.

As a fellow Substacker mentioned recently, it’s possible that consciousness arises only when the subconscious mind is inadequate to the task of managing one particular system in a particular context.

Take breathing.

You breathe autonomically, and are entirely unconscious of it most of the time. However, now that I’ve mentioned it and brought it to your attention, it will have entered your conscious awareness. You’re now aware of the action of your diaphragm, as it works to expand and contract the lungs. You can now choose to alter its action, slow it down, speed it up, or hold your breath for a period of time.

This also happens at times of physical exertion, or when your head is underwater, or your conscious mind perceives the air around you to be unsafe to breathe: your conscious mind takes over to analyse the situation and decide when and how to take your next breath.

Soon, likely in the next few minutes, it will return to subconscious autonomic action, and your conscious mind will focus on other things.

If allostasis is the brain’s primary job, then it must prioritise the body’s internal state over external data. This leads to a phenomenon called sensory gating.

Emerging evidence suggests that our distance senses - vision, hearing, and touch - are synchronised to our internal rhythms.

We’re not perceiving the world at a constant, steady rate; the brain “samples” the environment in time with the cardiac cycle. In fact, so much about our perception is aligned with such cycles.

For instance, during systole (when the heart contracts and pumps blood), we are statistically slower and less accurate at detecting visual or auditory stimuli. The brain actually suppresses external input during these moments of high internal pressure, effectively “blinking” our sensory awareness. We saccade - rapidly move our eyes - more frequently during systole, but we fixate and actually process the world during diastole, when the heart is at rest.

Breathing acts in a similar way, functioning as a global “oscillatory pacemaker”. It synchronises neural signalling across the brain, impacting everything from memory consolidation in the hippocampus to how we process emotion and make decisions.

Self-regulation isn’t a silo, either. Humans are social animals, we have evolved to “outsource“ some of our allostatic regulation to others.

This is known as Social Allostasis, and resembles the concept of co-regulation.

When we are in close, trusting relationships, our companions help regulate our heart rates, breathing, and even our core temperature, effectively reducing the metabolic “tax” on our own systems. The sense of safety these relationships provide allows us to operate at a reduced level of vigilance.

This explains why loneliness is so physically toxic; without a social network to help distribute the load, our brains can remain stuck in a highly costly state of vigilance, which eventually wears down the system. In the context of Alzheimer’s, it’s one way to explain why strong social support shows a slower rate of cognitive decline; the social environment can help regulate a struggling internal energy budget.

In short: we see and hear with our hearts, think with our lungs, and heal with our friends.

Thank you for joining me on today’s short dive into some new research that I’ve been looking into. What do you think about the Allostasis model? I’d love to get your insights, let me know in the comments!

This is also the first post of 2026! If you’ve been here a while, please consider a paid subscription; it comes with some perks, and will give me the ability to deliver so much more value to all of you chemically minded folks out there.

Thank you so much to everyone that has donated, subscribed, liked, shared, restacked, and commented. Please share this around with your friends as well! The more the merrier.

Take care, until next time!

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Note from Author: Yes, the title is slightly click-bait; but only slightly. Welcome to another deep dive.

Morality (from Latin moralitas ‘manner, character, proper behavior‘) is the categorization of intentions, decisions and actions into those that are proper, or right, and those that are improper, or wrong.

Let me ask you a simple question: would you ever commit murder?

We need to dig deeper. Let’s clarify a bit: would you ever commit murder if you knew there would be no negative consequences?

What if the proposed victim had brutally abused and murdered your children, and would not face justice in any other way?

If you answered either “Yes” or “No” to any or all of these, you’d actually be wrong. The only possible answer to these is “maybe”. There is no way to know what you will or will not do in any future situation.

However, if I were to ask: “is it ever morally acceptable to commit murder?” the answer is quite simple: No.

Morally, it is never OK to commit murder, despite some backward parts of the world remaining committed to capital punishment (which is, indeed, a type of murder.)

The distance between what we know as being morally right or wrong and our commitment to that moral judgement in our actions can be vast and incredibly dynamic. One easy example is this: is it ever morally OK to lie? Technically, the answer here is more of a “maybe,” but even so, you negatively judge those that you believe to have lied for personal gain, while simultaneously fudging the information on your résumé.

Don’chya?

The presence of a moral sense is consistent with a focus of human evolution on mechanisms of individual behavior that maximize survival in social groups. Evolution has promoted social cooperation through emotions against harming others, a need for fairness and the enforcement of moral rules.

Mario F. Mendez, The Neurobiology of Moral Behavior: Review and Neuropsychiatric Implications (2009)

Our moral values feel universal and immutable. We struggle to talk about them or think about them in any other way. We disdain others who don’t share our moral values, and often dehumanise them entirely.

The Imperial Japanese in WWII believed dying for the emperor was the single highest moral good a human being could achieve on earth.

Compared to the Yankee boys in the Pacific who, although ready and willing to fight and avenge the attack on Pearl Harbour, would have preferred to be home and warm and safe and at peace.

They could not comprehend each other at all, and saw each other as less than fully human.

When starting and waging war it is not right that matters, but victory. Close your hearts to pity. Act brutally. Eighty million people must obtain what is their right. Their existence must be made secure. The stronger man is right. The greatest harshness.

A troglodyte with a toothbrush moustache.

Interestingly, that brutality Hitler spoke of to his Generals shortly before the war, was never intended for to the soldiers of the nations at war with him (except for the Russians, of course.)

No, that brutality he spoke of was meant only for a specific subset of people: those considered “racially impure” or “defective”, such as Jews, Gypsies, Slavs, the disabled, and many more men, women and children. The Germans would go on to murder millions of them with industrial efficiency.

Considering the fairly frequent self-justifications made by officials, they knew it was wrong. Hitler knew they would know, and demanded they operate with black hearts regardless.

Despite having some of the most potent chemical weapons ever made (even to this day) and having mass stockpiles of them ready to be used, Hitler refused to deploy them on the battlefield, not out of fear of retaliation, but as a moral judgement.

Imagine that.

The Japanese saw it as quite acceptable to decapitate captive enemy soldiers with a samurai sword, and did so frequently. They saw this as building up their own “Sei-shin”, or “Fighting Spirit”.

The Allies saw this as barbaric; they preferred to do their slaughter from a great distance and with superior technology, such as the fire-bombing attacks on Japanese cities which burned alive around half a million men, women and children.

Indeed, it was perhaps this idea that the Japanese had deliberately crossed some kind of universal red line into immorality in their waging of war which may have helped to loosen the Allies own inhibitions on morality, allowing them to adopt one of the most barbaric war-fighting tactics: terror-bombing.

More recently, there have been debates about how pharmacology may one day provide “moral enhancement”, in which certain drugs could re-enforce a specific set of moral ideals and behaviours. The problem is: whose moral ideals and behaviours, exactly?

It’s hard for many people to imagine that simply changing the balance of certain chemicals in the brain and body could change how we make moral decisions, but in fact, they already do.

Research in 2014 found that we already have such drugs, and they’re already impacting our morality so much more than we could imagine; beta-blockers for example were found to significantly reduce racial bias in tests with only a single dose.

So, if certain drugs can strengthen our moral inhibitions, there must be others which can weaken them, right?

Press this button to get your fix!

Weakening the Will

In the late-2000s, a teacher from the UK was caught downloading sexually explicit images of minors. During the investigation and trial, it was found that the medications he was on - to treat his worsening Parkinson’s Disease - had been a direct cause of this paraphilia which had not been present before treatment.

The medications in question - primarily dopamine agonist levodopa, but also the many others which contribute to overall dopamine agonist effect - have long been linked to the development of various psycho-social/sexual disorders, but this was a fairly landmark case which essentially found that a psychoactive medication was the causative agent of a persons offending.

This leads one to wonder: how exactly does this occur, and in what circumstances?

As far as I am aware (IANAL), individuals that go on drug-fuelled binges and commit crimes are considered responsible for their actions under the law. The reason is fairly straight forward: despite the mass of information put out about the impact on decision making by various drugs - alcohol, cocaine, methamphetamine, PCP, and more - choosing to take them anyway means you assume full moral and legal responsibility for your actions while under their influence.

However, in a case like this, the substance was medically necessary (quite literally life-saving), properly prescribed, and the potential influence on decision-making was not widely known.

All medications which have an effect can influence us in one way or another; even placebos which have no biological or chemical effect can change our perceptions and decision-making. Paracetamol reducing pain can result in a better mood, with decision making patterns that would be different to those made while in pain. Beta-blockers like Propanolol inhibit instant amygdala-driven fear responses, significantly reducing things like racial bias.

Then, there’s dopamine.

I’ve long been fascinated with the Nucleus Accumbens (NAcc). It’s a tiny little blob of brain cells (two of them actually, on both sides of the brain). It’s essentially the seat of motivation and goal-directed valuation.

My friend Kent C Berridge developed the Incentive Salience theory of motivation, in which the NAcc plays its part by calculating how much value something has. This calculation is done using dopaminergic neural circuits running along the mesolimbic pathway.

When we think of an action that might have some value - regardless of morality, consequences, effort, or any other cost - a signal is sent out along that pathway. The stronger the signal, the greater the potential value.

Inhibition then acts to counter that signal. It is essentially subtractive, performing the other part of the Volition Equation, which is to subtract cost - in effort, risk, social standing - from the original value, thus weakening the signal.

In order for an action to be taken, this signal must run the gauntlet of our inhibitions, and remain strong enough to clear a minimum threshold. Anything below that threshold is dropped.

Morality can play a part on both sides of the Volition Equation; either adding or subtracting, so on the one hand, doing the “morally right thing” can boost the motivating signal. On the other, it can slam the brakes on behaviours and actions which might be detrimental to those social measures.

Morality evolved to help us maintain conformity with a group, and as a core part of our own sense of self. So, while moral behaviour is an obvious benefit when in a group context, we still often exhibit moral behaviour when alone.

Sometimes, this need for conformity can work against us, and lead to horrible and dramatic consequences.

Drugs of Brute Force

A teenager is hanging out with his friends one day, when one of them - a leader in the group - brings out a crack pipe. The teenager has never seen one before, but he’s able to make an inference on what it’s likely to be. He’s been told, by his parents, teachers, the government, and others, never to try it, because one hit is all it takes to cement a permanent addiction and lead him into a life of ruin, destitution, and early death.

His friends, however, are all jovial about it.

“Nah that’s all b******t, I can stop whenever I want to. I just like having fun, it feels f*****g awesome. C’mon don’t be a pussy.”

The attitude of his in-group - the group with whom he identifies - significantly reduces the inhibitory effect of anxiety about the potential dangers, and his need to prove himself a bona-fide member of his in-group - a core part of moral decision making - proves stronger than the inhibitions of broader social norms regarding drug use.

So he takes the hit, and the addiction is indeed cemented permanently. It is a grievous mistake, the consequences of which will last his entire lifetime. Severe neurochemical changes have already taken place in his brain, not just to cement the addiction, but also to break many more of his existing inhibitions.

This straw-man example demonstrates the result of an explosion of dopamine in the NAcc occurring nearly immediately following the act of consuming the drug. Normal incentive-based re-enforcement learning in the human brain is hijacked, and the drug causes a reward signal so large that nothing else in normal life can ever compare.

Even if all µ-opioid signals - the neurotransmitters that cause pleasurable sensations, including endorphins - in the brain are blocked entirely, resulting in no pleasurable sensations whatsoever, the addiction would still be just as strong, because pleasure - or a “high” - isn’t what’s driving this; it’s pure chemical computation.

What happens when you take any action in which there is potential for reward - so basically any and all actions - is two-fold: first, a prediction signal is fired, indicating the expected reward for the course of action being contemplated. When the action is a novel one, the expected reward is a guess, synthesised from past experiences which might be similar, and from any observations of others taking the same action in the past. If - after various inhibitory processes have subtracted from the signal - it remains above the activation threshold, then you will take the action.

Second, upon completing the action, the brain awaits a signal to indicate the actual reward obtained. When this signal is received, the predicted signal is subtracted from the actual signal, and you get something called a Reward Prediction Error (RPE).

If the RPE is positive, then the actual reward was more than what was predicted, and structural changes occur in the brain, making you more likely to pursue the same reward in the future. If the RPE is negative, this has the opposite effect. The difference between positive and negative values is indicated by a phase change. This is part of Associative Learning. The greater the value - in either positive or negative directions - the more significant the structural changes.

What a drug of addiction does, however, is amplify the actual reward signal so much, that the most extraordinary changes in the brain occur. Typically, these are supposed to be small, and developed through repetition. Instead, a drug of addiction can, from a single solitary action, re-wire the brain to a similar degree as a concert pianist from decades of daily and intensive practice.

To be clear, this method is simple brute force: the moral compass is not necessarily re-oriented. Instead, it’s simply rendered ineffective at inhibition. It can’t subtract enough from the action signal to play any meaningful role, so long as cues related to the drug are triggered.

Drugs are not the only way to achieve this. For a small subset of the human population, there is a built-in dysfunction to their dopaminergic circuitry, one they were likely born with.

Parkinson’s Paradox

Brain damage or dysfunction induced by neurological diseases can profoundly alter different higher-order human functions including moral, religious, and criminal behavior.

Ponsi et al. Human moral decision-making through the lens of Parkinson’s disease (2021)

I’ve tried gambling on a few occasions; playing roulette a few times at a casino, playing around on the stock market a little. Each time, the novelty for me is very brief, and as soon as I start losing money - an inevitability - I lose interest.

I’m not particularly motivated by money in general anyway.

For some folks, though, even the smallest chance for a big win is enough to power them on like a perpetual motion machine. Every throw of the dice - or in most cases, press of the button, such as in those awful pokies machines - is like a novel experience. Even when they know that the odds of winning are so small to be practically insignificant, it doesn’t faze them.

In patients suffering from Parkinson’s Disease, the vast majority exhibit “hyper-honest” behaviours and are extremely risk-avoidant compared to the general population. In fact, it’s such a common observation that it is sometimes referred to as a “Parkinson’s trait”. They are significantly more inhibited and reward-desensitised in general, meaning any given stimuli to the brain is less likely to reach the threshold needed for activating “motivational salience” (the property that drives us to take action in pursuit of something.)

In a study of moral decision-making among Parkinson’s patients, a small subset was found to exhibit the exact opposite behaviour. This subset is called the “hypo-honest” group; people who become much more prone to immoral tactics for personal gain as the disease takes hold. The factor most common among them is a history of gambling addiction.

This doesn’t make sense. How can people suffering from the same disease exhibit two completely opposite behaviours?

Their early symptoms before diagnosis don’t seem to differ much from the norm. Only once treatment begins do these new “hypo-honest” behaviours emerge.

In Parkinson’s disease, not all dopaminergic neurons in the brain are destroyed; the damage occurs primarily to those which help to control motor movement. Other pathways, such as the motivating Mesolimbic pathway, are much less affected.

So it turns out, the answer lies not in the disease, but in its treatment.

Pathways

There are several locations in the brain that produce dopamine, but the majority originates from just two areas. First is the Ventral Tegmental Area (VTA), which fuels the “Value/Motivation Pathway” (the Mesocortical and Mesolimbic routes). Second is the Substantia Nigra, the engine of the “Motor Pathway.” Nestled within the Basal Ganglia, the Substantia Nigra exerts a “right of veto” over the motor cortex, and modulates movement like a sculptor shaping clay.

Parkinson’s disease strikes the Motor Pathway with surgical precision by destroying its main dopamine supplier: the Substantia Nigra. However, the characteristic motor symptoms only become recognisable after a staggering 70–80% of these neurons are gone. By the time of diagnosis, the Motor Pathway is already operating on a nearly-empty tank.

While medications like levodopa are life-changing - a miracle on par with penicillin - they suffer from a fundamental lack of selectivity. Chemistry is a blunt instrument, while biology is a masterpiece of organic “urban sprawl” without a tidy master plan. There is currently no practical way to ensure a drug reaches the Motor Pathway alone.

Instead, we are forced to flood the entire brain with newly minted dopamine. This excess is up-cycled by transporters across all circuits, including the Value/Motivation Pathway. This “brute-force” method is the central difficulty of all pharmacotherapy (Lauren Cortis back me up here)

Adjusting neurochemistry isn’t as simple as adding fibre to your diet. Because the disease is progressive, symptoms begin while some natural production remains, yet we have no way to measure that remaining capacity in a living patient. Short of a post-mortem slicing of the Substantia Nigra into a kind of usu-zukuri sashimi to examine under a microscope, we are flying blind.

Consequently, treatment is a game of trial and error. We start with small doses and gradually increase them, trying to strike a balance before the “overflow” of dopamine into healthy systems triggers debilitating side effects, ranging from physical nausea to complex cognitive shifts.

We remain limited by this lack of targeting.

For now.

What comes next?

Research continues into delivery systems which might have improved tropism (selectivity). Since we know that compounds like MPTP and Manganese can selectively target and destroy the Substantia Nigra, there is hope; if those compounds can be so selective, there might be a way to achieve something similar and deliver dopamine to that area.

Levodopa alone can’t do this. Although it can cross the Blood-Brain Barrier (BBB), finding its way to the right places would require something more.

During the last 2 years, research has been focussed on 2 main approaches to this problem:

* Gene Therapy: The use of viral vectors (Adenovirus and Lentivirus) to biologically implant dopamine synthesis enzymes directly into the putamen, effectively turning other neurons in the Basal Ganglia into dopamine factories;

* Nanotechnology and Molecular Transport: Utilising specially-engineered liposomes, exosomes and polymers which can cross the BBB, decorated with special homing beacon chemical compounds which can locate damaged areas to deliver their cargo of dopamine;

Although much of this research relates specifically to treating Parkinson’s, the mechanisms could pave the way for developing highly selective treatments for a whole range of neurological diseases and disorders.

ADHD patients, for example, often suffer from side-effects such as dyskinesia, dry mouth, elevated heart-rate and anxiety when taking their medications. If we could target just the areas of dysfunction mainly related to the motivation pathway, we could avoid many of those side-effects.

The better we get at highly selective treatment of the brain, the better are patient outcomes. This would also unlock doors to much more interesting experiments which could identify how specific parts of the brain respond to specific compounds.

However one thing is already quite clear: we are what our neurochemistry makes us.

Where’s your free will now?

Thank you so much for joining me on the last edition of A Chemical Mind for 2025. I’ve been running this little series for over 3 years now! How time flies. If I ever reach 1,000 subscribers, we’ll have to do a special edition.

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Thanks for reading. Until next year!

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WARNING: The following contains MANY spoilers for the show Pantheon (2022) from AMC. You probably haven’t seen it yet, but reading this article will make you want to see it, so I highly suggest you watch it first if you care about spoilers. If not, let us proceed.

On the 30th of November 2022, the technological landscape tilted on its axis. OpenAI released ChatGPT, and suddenly Generative AI was the only thing anyone could talk about. We became obsessed with Large Language Models, transformers, and the eerie ability of a machine to predict the next token in a sentence.

Just two months earlier, in September 2022, a show called Pantheon aired on AMC. While the rest of the world was about to lose its mind over a chat bot, Pantheon was quietly laying out a roadmap for something far more profound: Computer-Simulated Human Consciousness, or “Uploaded Intelligence” (UI).

It contained some of the most realistic depictions of mind uploads, and the potential effects on society, that I have ever seen. It grapples with the hardest philosophical questions head-on, such as the true meaning of consciousness, personality cults, the consequences of immortality and digital death, self-copying, and the universe-as-simulation theory.

I don’t think many people saw it when it came out. (I didn’t)

Yet there are so many fantastic, mind-bending, life-changing things about AMC’s Pantheon not just in its philosophy, but also the way it depicts cyber-security, software engineering and big data concepts; not to mention the cut-throat world of big tech both within and beyond Silicon Valley. It’s not perfect, but it’s easily the most accurate I’ve ever seen from a show of this kind.

Watching it today makes it feel somewhat prophetic, but likely was the result of extremely good footwork by the producers and their team, getting the most up-to-date picture of the inner world of big tech at the time, between 2021 and 2022. Facebook became Meta at the end of 2021 as a result of Zuckerberg’s Metaverse strategy, and you see a lot of those ideas were depicted in Pantheon.

We also see clear depictions of things Generative AI are doing today: chat interfaces with digital intelligence, for instance.

The digital intelligences in Pantheon weren’t artificial neural networks, but fully scanned and emulated human brains. They call these “Uploaded Intelligence”, or UI (which is confusing in tech, since UI stands for User Interface, but we’ll roll with it.)

In the show, a UI is created by laser-scanning a biological brain, layer by layer, down to the stem. The brain is destroyed in the process - vaporised - but stored apparently in its entirety in digital form. This is a human mind, stripped of its biological substratum which is replaced by silicon.

The entire connectome is then reconstructed digitally, presumably with simulated sensory receptors; the rest of the central nervous system is not included in the actual scan.

Somewhere in between all that, there is some magic fairy dust that allows the full emulation to happen, but since that is still one of the great millennium-type problems of our time, I don’t expect them to have that bit of detail.

At one point in the show, a UI produces an 80-page patent in seconds. Although GenAI today would likely screw that up with hallucinations, you can see the resemblance. It feels eerily prescient.

However, we’re not here to talk about GenAI, and neither does the show: the real focus is on the Uploaded Intelligence and the ability to fully simulate a human being computationally. This requires a few major assumptions:

* The brain - that is, the cortex and brain stem - constitutes the entirety of who we are as individuated conscious beings

* An individual’s behaviours, emotions, and cognition, can be simulated in their entirety from a scan of the cortical network using classical and quantum computing platforms

Before we can even begin to tackle these assumptions, we need to understand what it is to compute, to be intelligent, and to be conscious.

I Am, Therefore I Compute

When we perform a mental task, sometimes we are conscious of the effort expended to perform it. Other times, we are unconscious of that effort, and an input gets processed and turned into an output which is re-integrated with our conscious awareness sometime later.

To us, these results arrive as flashes of inspiration or insight; that is the moment of reintegration. In truth, the brain was likely working on that problem for a period of time without you consciously being aware of it.

These unconscious computations are presently done in our biological circuitry. Technically, the physical medium of computation doesn’t matter, and could be electronic. However, there is an inherent problem in viewing the brain as equivalent to electronic circuits.

Classical computing and electronics are based on gates. Gates allow you to perform simple, but exact, operations on incoming electrical signals. For example, an OR gate takes 2 inputs, and so long as at least one of those inputs is receiving a signal, the OR gate outputs a signal. A simple way to model this would be like:

0 OR 0 = 0

1 OR 0 = 1

0 OR 1 = 1

1 OR 1 = 1

The number 1 denotes an electrical signal, while 0 is no signal.

Meanwhile, an AND gate takes 2 inputs, and only outputs a signal if both inputs have a signal:

0 AND 0 = 0

1 AND 0 = 0

0 AND 1 = 0

1 AND 1 = 1

Gates like these feel intuitive to us. They follow a simple logic. They’re also exact and about as deterministic as it gets. They have no hidden influences outside the two expected inputs which can affect the result; so 0 AND 1 should never result in 1, just as 2 + 2 should never equal 5.

Brains, and biology in general, are nothing like that.

The thing about biological computation is that it is fuzzy. For most of us, doing novel arithmetic in our head is a combination of heuristics learned from repetition in similar tasks, which we use to get a sense of approximating a value; then more heuristics refine it down until we have a value in mind that we feel confident enough about.

Let’s do a quick experiment. Solve the following 2 problems:

* What is half of 10,000,000?

* What is half of 8,626,400?

Which one required more time/mental energy, the bigger number or the smaller one?

If we followed a purely computational way of thinking about things, our expectation should be that the bigger number would be more computationally expensive to calculate than the smaller one. However for the human brain, it’s not dependent on the size of the numbers we’re working with, but on their composition.

In the first problem, although the number was larger, its composition was vastly simpler, made almost entirely of zeroes. To solve it, we could reduce it by 6 decimal places, and then the problem becomes “What is half of 10?”

The second smaller number had many more non-zero digits, meaning we could not reduce it in the same way. Instead, our natural inclination is to solve for each non-zero digit separately: “What is half of 8? What is half of 6? What is half of 2?” and so on.

1 problem instantly turns into 5.

“Therefore, our brains are not computers, therefore, our brains cannot be simulated by computers.”

Woah hold up there cowboy, not so fast. Plenty of things which are not computers are simulated on computers literally all the time in every field ever; we just haven’t simulated literally everything in the universe that exists.

This argument, that the brain is not a computer and therefore could never be modelled by one, always drives me a little insane: just because it doesn’t follow gate-based logic does not mean it is not performing computation, and does not mean that it cannot be simulated computationally. It is, and it can. The problem here is one of dimensionality.

To simulate the human brain, you need way more than merely its connectome. We know this from simulations of C. Elegans, the Nematode Worm whose species all have exactly the same number of neurons: 302, no more, no less. We have been working to simulate its entire set of known behaviours for decades computationally, and we have made progress; but consider how incredibly simple C. Elegans is, and yet we still haven’t figured it out? How complicated can a near-microscopic worm possibly be?

Some have reached the conclusion that the complexity is not in simulating the worm, but rather, simulating chemistry itself.

Chemistry is, in my opinion, the most sophisticated and most powerful phenomenon in the physical universe. Chemistry is like the operating system, the essential firmware, upon which the software of human minds can run. Even firmware requires something firmer: hardware. That’s quantum mechanics. That’s effectively the architecture upon which the Firmware must execute.

Indeed, if the answer is that we need to simulate chemistry itself, then think of our predicament this way:

Imagine you were trying to simulate a classical gate-based Turing machine on some highly exotic computer, and you only managed to implement AND and OR gates; then you proceed to try running DOOM on it (as is tradition.)

You wouldn’t get very far, would you?

Technically, we can build a complete computing machine using any combination of “NOT” operator with “AND” or “OR” gates, but we don’t even know the NOT operator exists, let alone what a universal Turing machine even is.

That’s more or less where we are in the grand scheme of things when it comes to simulating all of chemistry.

I Am, Therefore I Intellect

Another very common assumption made by just about everyone is that the ability to think implies intelligence. It’s also extremely common to conflate intelligence with emotion, with motivation, with the survival instinct. This is part of the problem which has often taken debates on simulated cognition in circles: we assume a full suite of human cognitive abilities as the baseline for any model of cognition.

Although you likely cannot have intelligence without the ability to think in some sense, it is not necessarily a given that thought brings with it intelligence. It is also essential to be aware of the fact that emotion is not included by default; in fact, emotion is a wholly separate concept. A machine that can think is not, by default, emotional. To be emotional, it would need to be given emotions explicitly; emotions evolved much earlier than intelligent cognition, and were a useful tool for boosting our instinctual motivations which promoted survival.

We tend to assume that a super-intelligence will naturally develop super-ambition, or super-benevolence, or super-hatred. But this is a fallacy.

This is best explained by the Orthogonality Thesis, proposed by philosopher Nick Bostrom. It states, effectively, that intelligence and final goals are independent variables. You can have a clumsy intelligence that wants to conquer the world, and you can have a god-like super-intelligence whose only motivation is to count every paperclip in the universe.

In a “pure” AI, there is no inherent reason for it to care about its own survival unless we program it to. It has no fear of death, no pride, no resentment.

This is where Pantheon (and the concept of Uploaded Intelligence) gets interesting. The UIs in the show are not “Pure AI” sitting on an abstract graph. They are brute-force scans of biological architecture. They inherit the “spaghetti code” of human evolution. They maintain their human wants and human needs. They carry the baggage of the limbic system simulated alongside the cortex.

If we are to achieve full emulation of a human mind, we must be prepared to emulate biological drives, emotions, hormones, the lot.

A Means Without An End

Everyone always asks “What Is Consciousness”But no one ever asks “How Is Consciousness”

Finally, we arrive at the most challenging hurdle of all. Let’s assume we solve the chemistry problem. Let’s assume we achieve full emulation. We boot up the simulation. The digital eyes open.

The entity speaks.

It says, “I am.”

How do we know it is really aware?

This is part of the Hard Problem of Consciousness. If we wanted to simulate a human mind, we must assume consciousness is part of the success criteria. Whatever else it might be, it must be conscious.

Yet here we are, at the end of 2025, and guess what? We still have no idea how to tell for sure. We can’t even be sure that a rock is not conscious. I’m serious.

Think of it like this; what, exactly, is conscious, when it comes to a human being? Is it the brain alone? Or the body? Do the proteins that make up the neuron cell count as being conscious? Is it the whole system?

In our daily lives, we assume other humans are conscious because they act like us and are made of the same wet biological stuff as us. We assume a rock is not conscious because… it just sits there.

This is an assumption based purely on external observation. We have no “consciousness detector”, yet. We cannot measure the internal subjective experience (qualia) of another being.

Philosophers talk about the P-Zombie (Philosophical Zombie); a being that is physically identical to a human, acts exactly like a human, screams when you pinch it, and laughs when you tell a joke, but has absolutely zero inner experience. The lights are on, but supposedly, nobody is home.

If we simulate a mind on a silicon chip (or a quantum substrate), and it screams in pain, is it actually feeling pain? Or is it just executing a code function, equivalent to:

if (pain_intensity > 3) play_audio(”ouch.mp3”)

I don’t personally believe P-Zombies can exist. If I simulate the universe, and within that simulated universe I also simulate a human being, and the simulation behaves exactly the way a human would in every case, to the degree that they are entirely indistinguishable from any “real” human being when observed from the outside, on what grounds can one deny its consciousness?

If we can’t even prove a rock isn’t silently judging us, we certainly won’t be able to prove a digital mind isn’t experiencing qualia.

The Integrated Future

Simulating the human mind in its entirety, including chemistry, is something which we will not see happen for a very long time; some have estimated a timeline of 100 years from where we are now.

However, I believe there is a kind of part-way point which we are fast approaching, and when it hits, could herald another exponential growth curve in technology.

For at least the past 10 years, I have thought about a future where the integration between the biological and digital is real and deep.

It’s something I call “Neuro-Integration.”

It’s the idea that we can extend on the human brain’s existing biological modules of cognition, adding digital ones. Not only could we add additional sensors - infra-red video, say - we could add vastly more powerful computational abilities, such as floating-point arithmetic, physics simulations, statistics, and more, all accessible directly to the conscious mind at a thought.

Simply being able to control your laptop’s cursor with your mind isn’t what I’m talking about; we already can do some of this sort of stuff, but it’s fairly pedestrian. I’m talking about an input-output loop, two-way communication between mind and digital computers, via Brain Control Interfaces (BCI) and Transcranial Direct Current Stimulation (tDCS) devices, without invasive techniques such as surgical implants.

The technologies as they exist today are far from perfect; challenges remain to be solved around the level of accurate targeting, focal area, inter-individual variability and sensitivities, information encoding, and much more. Regardless, I truly believe these are solvable challenges.

It could reduce to zero the friction and effort required to make use of terrifically accurate and high-speed computation. Similar to how LLMs can access tools, these tools could one day be accessible directly from the human mind, and the result could arrive the same way as a flash of insight or inspiration does now.

If we combine this with various multi-modal ML technologies, and solve the problem of encoding various information modes so the brain can understand it, we could expand upon our own ability to visualise in our minds eye. We would never have to search our memory for the meaning of an uncommon word again; it could invoke an instant dictionary look-up. Semantic memory could be extended in ways which we can’t imagine, becoming a near-instant vector graph query for extended contextual information.

Hell, just imagine if you could add to your mental workspace with custom scripts, like you can with a shell environment.

What’s more, there are still questions of basic user experience, privacy and security to be answered before we can turn it into a platform for extending cognition: how does the human mind send input to the device, and in what manner does it perceive output? How do we minimise the risk of malicious passive scanning of brain activity? How do we address the risks of misuse and data security? How do we avoid amplifying inequality?

Perhaps the biggest challenge to the general availability of this technology - for very good reason - is the slow pace of regulatory approval.

Regardless, there is no doubt in my mind that this technology is coming, and probably faster than we think. The real question is: will we allow a small gaggle of tech bros to dominate the space like they have in Generative AI and Cloud Computing? Or will we take our destiny into our own hands for once?

I am, as you would know, not a fan of “big tech”; we can already see the insanity going on with the narcissists at the top of most of these companies, whose greed is now amplified to 11, desperate to replace human workforces with anything they can.

I am also much more cynical about the recent GenAI boom than most. However, I also know that some of that cynicism is a pure emotional response to the fact that this amazing technology humanity has developed has made that small gaggle of greedy narcissists at the top of Big Tech so much richer and more powerful than anyone ever thought possible, and it disgusts me.

The technology itself, however, when stripped of all the amphetamine-like hype and euphoria - though knowing CEOs as I do, it’s not amphetamine, it’s cocaine - is really quite remarkable.

The track we are currently on is one where corporations are desperately trying to scrape away the human “chattel”, whom they have long relied upon for their intellectual capabilities, in a race to replace almost all of their operations with machines, keeping on a skeleton crew of human meat sacks to monitor them, upgrade their hardware, keep the AC running; until they eventually get replaced by robotics. Meanwhile, the CEOs, board members and shareholders continue to rake in money until the mathematically inevitable collapse of aggregate demand.

I believe there is a future where human intelligence and machine intelligence are not in conflict. That may not be the future we are currently hurtling towards at trillion-dollar speeds; but it is reachable from where we are.

All that is required is for people who believe in the future of human kind and our continued relevance, who believe in fundamental ethics and open technology, to come together and start a conversation about how we can really create a future for all humanity, together.

Not for profit, not for domination, not for any one nation; for everyone.

Where we go from here should be up to us all.

If you enjoyed this post, please consider a paid subscription. I’m trying to keep all my posts free, but it’s a challenge. Please help out if you can.

Thank you for tuning in to today’s episode of A Chemical Mind; what do you think of the possibilities of neuro-integration technology? What did you think of Pantheon? Would you ever upload yourself to the cloud? Please let me know in the comments on the Substack article!

If you’re interested in further discussion on neuro-integration from all aspects and angles, I’ve set up a discord server here. Come join the fun!

Thanks for listening, and I’ll see you next time.

“So far, there is no convincing evidence for Abdominal Migraines. Migraines just don’t work like that.”

These were the words spoken to me by a Head of Neurology; a very accomplished man at the top of his career, running one of the most prestigious Neurology centres in the country.

He was smiling paternally at me from across the desk, his arms leaning against it and his hands interlocked in front of him, his suit and tie practically glistening with the importance and prestige that oozed from every fibre of his being.

I, the distinctly unimportant, uneducated, scruffy-haired kid in torn jeans and t-shirt that I was, glistened mostly with nervous sweat as I shifted uneasily in my seat, adjusting my direction of lean from left to right.

I never sit straight up in any chair ever; I’m always tilted somehow. Just more comfortable that way.

“Ok, well, what do you think it could be?” I asked. I knew he would have no good answer. Nothing I hadn’t already tried.

I was right.

“Sounds like an allergy, you should see a dietician.”

It’s hard to tell someone whose expertise rightfully deserves respect that they are wrong, especially when you don’t have the benefit of all those many years of medical school, real-world experience and countless citations, awards, and grants to your name. I can’t help but cringe to the depths of my soul when I read stories of folks who are into homoeopathy proudly proclaiming victory over medical science, because “it worked for me!” and so I have developed a habit of deferring to the experts, even when I doubt them. However, not all experts are made equal, and not all illness is necessarily found in a diagnostic manual either.

The reason I was even here, in this room, speaking to this highly accomplished medical professional, had nothing to do with abdominal migraines, or migraines at all for that matter.

Several months earlier, I’d had a tonic-clonic (grand mal) seizure. They were trying to find out if I had epilepsy (thankfully it was my first and so far only seizure, and no epilepsy was found). While I was there, I decided to ask them about something my doctor had mentioned to me. These were experts in the field of brain-things, surely they’d know something about migraines.

Right?

The fact is, I had gastrointestinal problems literally my entire life, and they go through periods of variation, kind of like “phases”. Y’know, like one day you discover them dressed up all in black, smelling of cigarette smoke and listening to My Chemical Romance. “It’s just a phase.”

Sometimes, a phase would manifest as episodes of excruciating abdominal pain. Sometimes, it would be bloating and general discomfort. Most of the time, it included nausea. Nausea was the worst, particularly because I had a fear of vomiting (something called “emetophobia”). It would often send me into a spiralling panic attack, forcing me to pace the floor, back and forth sometimes for hours, controlling my breathing and repeating little “safety” behaviours to myself.

Though certainly unwelcome, it was never a huge concern. That is, until I began working full time. There were days when I would be scared to get on the train in the morning when nauseous. A couple of times, I had to get off at a stop part-way to work and call someone to pick me up and take me home again.

Fear and tunnel-focus can make us do weird stuff. Since I was young, it had been drilled in to me that if I ever felt like I was in trouble or having a crisis at a train station or some other public place, that I should just ask for help. I don’t know if you have ever tried asking for help when your stomach is turning itself in knots and you are in a full-blown panic, possibly on the verge of ejecting its contents: I did, at a central train station, and I got nothing but confused, bemused and mildly annoyed apathy. In all fairness, what are they supposed to do?

Then again, what was I supposed to do??

My mind returned to the Neurologist’s office, and his suggestion of a dietician.

“I already tried that.”

A single eyebrow on the Neurologist’s face migrated north, followed eventually by the other eyebrow, before the whole face gave in to that expression people use when they no longer want to bother. That, or he didn’t believe me. I mean, I was so skinny and pale and young, I bet he thought I just needed some protein, grit, and a tan.

“Well, if it’s not dietary, then it’s almost certainly psychological. There is, medically speaking, nothing wrong with you.”

I realised this conversation wasn’t getting anywhere, and ultimately it didn’t really matter. I had suffered this for so long, I had come to assume it was going to be my life now. I was just being naive, thinking that there might be hope for me. That maybe there might be a legitimate explanation for my infuriatingly inexplicable malady.

My relationship with food had never been what one might call “normal”. I’d always been skinny, mostly because I was incredibly active and athletic, but also because I just wasn’t interested in food as a thing. I ate because I was hungry, and only to satiate that hunger.

For the past few years leading up to this conversation, my stomach issues had escalated significantly; that nausea which used to stop by just to visit before leaving again, turned into something called cyclic vomiting, with cold sweats and excruciating abdominal pain. It would turn up seemingly out of nowhere, though it was more likely during some anxiety-inducing event; it wasn’t consistent in that regard.

I went to hospital one time, thinking I was dying. I will never forget the looks of complete disdain from the hospital staff on that particular day. I was in total crisis, and I was made to feel like a fool for seeking medical attention. Thankfully that was the only time I had such an experience with a hospital (though perhaps that’s due to my avoiding them.)

Much of my medical history was psychiatric: ADHD, ASD, Panic Disorder and general Anxiety. Autism Spectrum Disorder has a lot of overlap with gastric discomfort and upsets, so for a while we thought maybe it was just more of that manifesting. My father had died of Crohns disease when I was 20, so we were also on the look-out for any signs that I might also develop the disease, but no sign of that was present.

Doctors had looked everywhere, poked and prodded, taken nearly my body weight in blood to be run through every test, had scopes of my gastrointestinal tract both up and down.

They looked for cancer, diabetes, thyroid issues, drugs, various types of flu, they even wondered whether I still had dormant malaria from the times I had contracted P. Falciparum during my time in the Solomon Islands. They looked for Hepatitis, Gastroenteritis, Meningitis, Strep, they even checked me for ticks. I was checked for Toxoplasmosis, considering my lifelong history with cats. They looked for gastric ulcers, appendicitis, liver function, kidneys. They did an MRI on me. Actually, they did 3 of them.

Nothing.

Not. One. Thing. Was. Found.

And yet, I was still losing weight, despite already being the skinniest guy I knew. It horrified me. I was struggling to keep food down. I was gaunt, pale, a bag of bones.

I chanced to bump into someone I hadn’t seen for a very long time in the street one day, and they were shocked when they recognised me. “Are you ok?” I remember them asking. “Are you... like, sick?”

I looked like a cancer patient.

I didn’t know how to explain. I couldn’t really say “Ok, sit down, this is gonna take a while”. So I shrugged. “It’s fine.”

The evening before my neurology appointment was when I had seen my GP. I had turned up to the clinic covered in sweat, trembling like mad, gaunt, and emaciated. It felt like an attack of the flu, but there was no virus. I was nearing a point of no return. If I couldn’t escape this cycle, I was seriously considering ending it all.

After listening to my entire medical history, I remember him sitting back in his chair, hands folded across his chest, staring at the wall. The look on his face was utterly perplexed. It was a look I hadn’t actually seen before in any medical professional. It was strangely reassuring. Perplexity meant consideration. It meant he was seriously thinking about my situation. He was running it through in his mind, peering into his experience and education, searching for a glimmer of light somewhere in the darkness.

He was taking me seriously.

“Hmm...”, he broke the silence after a minute or two.

“It’s a long shot, but from what you’ve told me, there’s only one thing you might not have tried yet.”

My ears perked up. “Have you heard of abdominal migraines?”

I hadn’t.

“This is unlikely to work, but I think we should try you on a simple beta blocker. The good thing is that it has almost no side-effects, and we can stop it any time without harm. But there is a tiny chance that it might help, we can just see. How does that sound?”

I jumped at it. A tiny chance that I hadn’t yet taken was a chance worth taking. I was booked in to see him again the next week.

When I came back to see him, I nearly cried. It was the first time in years that I had gone a whole week without nausea. No nausea whatsoever. No vomiting. I could keep food down. I hadn’t had a crisis on a train while commuting. No crises while at the office. I could even eat yoghurt and I felt absolutely bloody fine.

“You really don’t know what you’ve done for me”, I told him.

My voice was breaking. I didn’t want to come across as melodramatic, but it was difficult to avoid: this man had saved my life. Somehow, a simple idea, and a simple remedy, had cured me from an illness that had been utterly intractable, an illness which had eluded so many more highly-paid and highly-respected experts, many of whom preferred to think I must be making it all up rather than admitting to their failure.

It’s been over 10 years since then. I got back to a healthy weight (maybe a tiny bit over-healthy), I re-discovered food (it helps that my wife was once a chef), and after a few years, I didn’t even need the beta-blockers anymore. The migraines are gone, and they’ve never returned.

Research on abdominal migraines is still severely lacking.

Most cases are found in children and adolescents, and mainly in women and girls. It’s startlingly rare, but that’s more likely a factor of its vague diagnostic criteria. It’s one of these “functional gastrointestinal disorders” which can only be diagnosed by eliminating literally everything else which could conceivably cause that particular set of symptoms.

Wanna know what else causes these sorts of symptoms?

Frikkin everything, ever.

So that doesn’t help. I don’t envy those tasked with diagnosing people like myself, let alone curing. It’s not easy. Regardless, there are several clear hints about where to look for the problem.

It seems there are two possible biological mechanisms:

* Arbitrary electrical discharge from the hypothalamus into the cortex, brain stem, and out through the spinal cord

* Variable blood flow through the cerebral artery

It’s highly likely that they’re not mutually exclusive mechanisms, and could explain some variability in the effectiveness of simple treatment with beta-blockers. However, the study numbers are so small, there simply is not enough evidence to clearly show efficacy of any treatment.

People aren’t known to die of this condition.

It’s not heart disease, cancer, or stroke. It’s not a deadly parasite. It’s not flesh-eating. Not only that, but it’s so damn vague, and super rare in adults.

So who cares?

I care.

Those suffering it care.

Sometimes, you just happen to get something that isn’t in the textbook. In that case, f**k the textbook.

Find a way anyway.

Note: I’m neither an economist nor a demographist, I’m just some guy with an opinion about everything, and by default, you should assume that everything I’ve written here is wrong.

Most of you know me by now, I think. I’m a socialist, with radical leftist pacifist leanings. I have all the leftist badges, although I don’t wear them on my sleeve. I won’t bore you with them here.

I also frikkin love babies.

Noisy? Yes.

Smelly? Yes.

Utterly incoherent?? Yes.

Cute as hell? So much yes.

Despite this, something has always made me feel uncomfortable about identifying myself with “pro-natalism”. The reason is fairly simple: it tends to be conflated with the pro-life, anti-contraception crowd, not to mention the “your body, my choice” types who like to troll Xitter.

Quite frankly, contraception is one of the greatest public health boons in human history, and has saved an incalculable number of lives and livelihoods. Yet somehow, there have always been those among the super-religious of many kinds (and commonly right-wing though not exclusively) who have a thing for banning contraceptives; today you’ll typically find them wrapping it in the guise of “trying to stop a population crash”.

So I started to ask myself: is it possible to be pro-natalist and pro-contraceptive/pro-choice? Is it possible to have a pro-natalist policy which doesn’t infringe on the rights of women?

I think the answer is “Yes”.

But then I realised I hadn’t even asked myself the very first and most obvious question:

Question #1: What Is The Problem To Be Solved?

Already, I’m struggling. I’m not entirely sure there is a real problem (yet).

For many decades particularly following the baby-boom, there was widespread worry and panic about the possibility of over-population. For most of that time, there was good reason to be worried: it did look like we were in for unchecked exponential growth. In fact, we were in exponential growth for a while following World War 2.

See the following charts, from Our World In Data:

Y’know the term “baby boomer”? Yeah, that’s the sharp mountain bit. That was a thing that happened, and it was indeed exponential.

In close-up, it looks like the population boom only started to emerge around 1925 at the earliest. There was, without doubt, an absolute explosion in population growth from 1945, peaking in 1963 and has been falling ever since. However, if we zoom waaaaaay the f**k out:

Population growth has had a foot on the accelerator since the 1700s, and once we discovered how to treat disease - and, more importantly, avoid much of it - population hopped on a rocket sled and rode that sucker until the fuel ran out.

Right now, and since about 1974, we’re in linear growth with roughly 1 billion people added to the pile every 12-14 years. Based on projections by the UN, world population is expected to peak in 2068 at 10.43 billion, and dip slightly.

It seems to me that we might now be extrapolating that little dip the same way that people extrapolated the exponential growth phase - by simply assuming the immediate trendline to continue indefinitely - thus beginning a new panic about the coming “end of humanity.”

Whereas to me, what seems more likely is a kind of population plateau, rather than a crash (let alone one so apocalyptic).

As Hans Rosling once illustrated in a lecture on the subject (he did it with physical blocks, so I made a digital version):

Even without a crash, we are presented with several economic problems. The first is that any country which is losing population is going to have a hell of a time. The East Germans built the Berlin Wall not to keep out spies or prevent sabotage: they simply could not afford the loss of population to the west, and their primary financial backer - the Soviet Union - would not pay the bill indefinitely.

It’s often said that economics is not a zero-sum thing, but at a population plateau, it would certainly resemble one in important ways. There would only be a certain number of possible consumers world-wide, and population shift through migration is far less likely to be offset in any meaningful way by birth rates. That means there will most definitely be some losers.

So, is there a problem?

Well, maybe. It’s all very speculative at this point. If we remain at a plateau as I expect we probably will, things will be interesting for a little while, but very manageable.

It only becomes a real problem in the event of an actual crash, and in the interests of hedging ones bets, it’s probably a good idea to at least start working on the problem now, so that we’re not caught out if such a time ever comes.

So really, you could say pro-natalism is a bit of a “break glass” stance for me. If the future of the human population is ever at stake due to a crashing birth rate, then consider me a pro-natalist. Until then, babies are cute, and sex is awesome.

As I see it, there are two main directions pro-natalist policy can take:

* Subtractive policy: subtract the right to control how many children you have by making it difficult to have sex for fun or terminate a pregnancy (whether simply accidental, or due to a sex crime)

* Additive policy: add support and assistance to people who want to have kids (or more kids) to ease the burden on the family

Some people even suggest - as in one of the many really dumb-ass viral Xitter posts from a few months ago - that we should literally stop educating women, which is yet another wonderful example of subtractive policy.

All these policies cost money, but only one has a hope in hell of actually working and not leading to a mass proletarian revolt. Can you guess which one it is? Hint: it’s the one that isn’t a buzz-kill.

No, I’m not getting into an abortion debate in the comments. Don’t do it.

Yeah but what if?

Ok ok, lets talk about Japan. I know you really wanted to. Let’s do it.

Japan is a fascinating case study for all sorts of things, but population dynamics has been a big concern for them since the “lost decade” of the 1990s. From October 2021 to October 2022, Japan’s population shrank by more than half a million people. According to the Financial Times, they lose 100 people every single hour.

You might be surprised to know, however, that Japan isn’t actually the most relevant example for our purposes here. By far, that honour belongs to South Korea.

South Korea has, for many years, had the worst birth rate in the entire world, and it gets worse year after year. In fact, it’s so bad right now, that within 50 years, their work-age population will have fallen by half.

HALF.

That’s mind-boggling. In fact, I dare say that’s catastrophic.

This is all despite the vast amounts of money they have been throwing at the problem for the last 20 years, and despite politicians having declared it a legitimate national emergency. Honestly, for once, I don’t think that’s hyperbolic in any way shape or form.

At the same time, South Korean women are saying that government simply is not listening to them.

Whaaaaat?!

How can this be? Surely, incentives would be the most preferred way of going about finding a solution to the problem?

Clearly, spending to incentivise having children has not worked, neither for South Korea, nor Japan which has been taking many of the same approaches to a problem that has haunted them since the 90s.

Actually, no, that’s not really true. We can’t just say that it “has not worked”, we need to be more specific: it has not worked in the very unique cultural, social and political circumstances of these two Asian economies.

Much of Asia is a world that places incredible pressure on young people to have an all-consuming career, and where their malignant corporate culture and rampant sexism means that maternity leave is out of the question if you have any hope of remaining in work for the future.

South Korea has the highest rates of women’s education in the world, but much of this push for education is in service of their economy’s insane demands on workers. First you slave away at that degree, with your parents demanding that you be top of the class; then you slave away at a job run by (mostly) men that demand all your time and energy be committed to work, and the moment you’re burned out, you’re discarded like empty packaging.

This is when the great dragon that is Asia’s unique circumstances rears its head and stares us in the face: for the average South Korean woman, the near-impossibility of having both a work-life and home-life, let alone a balance between the two, is the determinant factor which drives them away from the prospect of raising a family. When actually asked, women will repeat this point consistently, though it seems their politicians prioritise the appearance of working the problem more than the substance.

[One South-Korean woman] also shares the same fear of every woman I spoke to - that if she were to take time off to have a child, she might not be able to return to work.

"There is an implicit pressure from companies that when we have children, we must leave our jobs," she says. She has watched it happen to her sister and her two favourite news presenters.

One 28-year-old woman, who worked in HR, said she'd seen people who were forced to leave their jobs or who were passed over for promotions after taking maternity leave, which had been enough to convince her never to have a baby.

Jean Mackenzie, BBC

Japan and South Korea are both in dire straits here. The only hope they have left is to radically overturn their entire social and corporate culture, one that is perhaps rooted in centuries of national development, and replace it with something that grants more individual liberty from their relentless “culture to succeed”, and at the same time, to punish businesses that directly or indirectly violate a persons right to return to work following maternity leave.

Or, to phrase it in the language of additive and subtractive policy: they must subtract power from corporations to add sanity and a minimal “work-life balance” for individuals.

Should they fail, they will become entirely dependent on immigration to cushion the fall. That’s going to be a very bitter pill to swallow for countries that are already fairly xenophobic at baseline. Given their socio-political and cultural problems, they’re unlikely to improve rates of migration without a systemic overhaul, either.

So what about The West? If we were one day faced with a calamity like that of South Korea, could we spend our way out of it? The answer is probably yes.

Firstly, we actually have a sane idea of work-life balance, when compared with our Asian counterparts. I’m not entirely sure why, but it’s true. We also place way less pressure on young people, prioritising holistic well-being and personal fulfilment more than corporate hustle.

Second, we also have some more progressive views on what constitutes a “family unit”:

Same-sex marriage is illegal in South Korea, and unmarried women are not generally permitted to use sperm donors to conceive.

"I'd love to have children. I'd have 10 if I could," [says Minsung, a 27-year-old Korean bi-sexual woman.]

"Hopefully one day this will change, and I'll be able to marry and have children with the person I love," she says.

The friends point out the irony, given Korea's precarious demographic situation, that some women who want to be mothers are not allowed to be.

Minsung’s idea of a family is considered perfectly reasonable in most Western countries, and as far as I know, there’d be little stopping her and her partner having as many babies as they like.

Right now, people like Minsung are a shining beacon, screaming “WE CAN SOLVE THIS! LET US HELP!”

Yet, South Korea’s political class refuse to acknowledge them, and then lament in front of the cameras: “We’ve tried nothing, and we’re all out of ideas!”

Here’s an idea which we could all use: try listening to women for once. After all, women are the solution.

The moral of this story? Leftist ideals can fit just fine into pro-natalism, and although I’m not ready to panic over world population levels yet, I’m not ready to write it off either. We can hedge our bets without picking a side.

With the world turning more and more to solar power and other renewables, we’re finally starting to see some light at the end of the tunnel on climate change (we’re not out of danger by any means yet).

It kinda says something about the human condition that we’re already looking around for a new existential crisis.