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