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Hackernoon logoWhy Depression Is A Chemical Imbalance. But Not The Way You Think. by@thingsvarious

Why Depression Is A Chemical Imbalance. But Not The Way You Think.

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Medical student. Biohacker. Addicted to learning about various things. Started writing instead of just consuming.

Background: I started to replace all of my hormones starting at the age of 23. Since then I have learned quite a lot about how changes in biochemical parameters affect your wellbeing and life. If you change biochemical parameters, over time, your life and happiness will evolve in a way to reflect these changes. You can read more about how hormones destroyed and saved my life here.

The mind is what the brain does.

In my very early days of hormone replacement, I was on the fence. I needed time to think. Time to ponder whether I wanted to keep doing this for the rest of my life. Time to reflect on why my life was breaking apart.

To do this, I had locked myself up in a monastery for some time. After some sleepless nights, I figured I just couldn´t see myself doing this for the rest of my life.

At the time I was replacing my thyroid hormones with triiodothyronine (T3) instead of thyroxine (T4). 

(Note: T3 is the active thyroid hormone and has a half-life of less than one day, compared to over a week for T4.)

Invigorated by the stimulating effects of T3 I had started only a few weeks or so ago, I decided to quit cold turkey. Bad idea as it turned out.

“Do I want to replace my hormones for life?… Will I even be able to? What if an apocalypse happens and I lose access to all the stuff I need?…What if I have severe side effects down the road? Will I destroy myself?… Am I fake? What will my wife say one day? My kids? Will I even be fertile? Will I even find a wife?… Am I even lovable?.”.

Panic attack.

There is nothing I could do, no way it will get better. Words are useless to describe the kind and intensity of anxiety I was feeling at that moment.

In these times all rationality is gone. I was completely carried away by the crescendo of thoughts and emotions both amplifying each other.

The window was open. In these moments of hopelessness and helplessness, people do stupid shit. A priest came to my rescue.

What I didn’t know at that time, was this. After (stupidly) stopping T3 cold turkey, my body temperature had dropped to below 35C within only a few days. To maintain core temperature, over the short term our bodies use the sympathetic nervous system.

This means my body and brain were quite suddenly chock-full with adrenaline.

I was led to believe that the shaking, the rapid heartbeat, the palpitations, the feeling of being choked during a panic attack are conjured up by my thoughts. But this was not the case. It was the other way around. 

(Note: The sudden T3 withdrawal was to blame. Monoamines (noradrenaline, serotonin, dopamine) rise and fall with T3. As these change, so does your mood/calmness (serotonin), your motivation/drive (dopamine), your alertness/energy (noradrenaline).)

In fact, all these destructive self-doubts and dark outlooks on life were a reflection of my biochemistry. A consequence and not a cause. With such a level of adrenaline cruising around your bloodstream for “seemingly” no reason, you can not not get anxious.

Let´s go back to a few weeks before this only day in my life I contemplated suicide. Back then, I was excited about life. Full of energy and optimism. I felt a little “superhuman” because of how much I can control.

Back then I was bordering on hypomania, now though it was the opposite. Anxiety and depression, even thoughts about suicide for a brief moment (unfortunately, one brief moment is all you need…).

Now, let´s go back a few months before all this. Then, my life was dull and grey.

From just trying to get by (months) to thoughts of grandeur (weeks) to extreme self-doubt (now). Funny, because the factual/objective content of my life hasn´t changed much over this time. Certainly not enough to warrant such a wild swing in mind states.

But one thing had changed. A lot. My neurobiochemistry. In each of these three periods, my thoughts and outlooks on life were puppets of it, swinging from barren wastelands, to heaven, to hell.

I reintroduced T3 again. Slowly.

As my neurobiochemistry reversed again, so did my thoughts, outlooks and thinking patterns. For a brief time, I was felt without a doubt a little “too well” again (which isn’t good either).

I was in awe like a child, grateful to be alive. “What the hell had I been anxious about?!”

Even though now I knew exactly what was happening neurobiologically, in this raw and visceral experience I was simply carried away by my emotions. It was impossible to use any “thoughts as an antidote” to talk down the euphoria. Telling myself “this is biology” was useless.

Sometimes it doesn´t matter what we know. What we feel takes over.

From this unfortunate experience, I learned three lessons.

First, hormones (or drugs that screw with your neurobiochemistry) are nothing to be messed around with, especially if you don’t know what you are doing. While you certainly can have a valuable learning experience, you could also do something really stupid. Something irreversible which will leave a lasting impact on your life and the life of others.

Second, it is impossible to imagine what it is like to suffer from a mental illness without having briefly touched the limits of the fragile condition we call sanity. If nothing else came from all this, as a prospective physician, at least now I truly understand what it means for people to have an anxiety disorder. Now I have deep compassion for people with bipolar disorder, perpetually and naturally cycling between these two states and often in rapid succession (and minor versions of this cycling are experienced by the fertile half of the planet, every single month).

Third, we are deeply biological creatures. Our emotions, thoughts, outlooks, thinking patterns are at the mercy of our neurobiochemistry. And its changes.

While sudden withdrawal of T3 is certainly not generalizable to many others, all this does beg the following question. How would my life have turned out if my brain state at the time of my panic attack would have been my baseline?

Most likely I would have developed a severe anxiety disorder quite early in my life. Always trying to battle my neurobiology, realizing I am powerless and stand no chance against these forces. Eventually being put onto psychiatric drugs. If I was lucky.

How would my life have turned out if my brain state from very early on would have been more like the weeks of optimism?

While most of you likely can´t relate to what it feels like going from euthyroidism into severe hypothyroidism within only a few days, here is something the more audacious of you might be able to relate with: MDMA.

MDMA: every conscious state emerges from a brain state.

Let´s embark on a thought experiment. Let´s imagine you live in a country where MDMA is legal and in a couple of days you plan on taking MDMA for the first time.

(Note: If you have never taken MDMA before, think about a time when you tried to beat your addiction to weed or caffeine. Battered by the side effects, perhaps after only a few days giving in. Let your first puff (or the first sip of coffee) be the PG-13 version of MDMA.)

Let the days before this legal experience represent your baseline in how you normally feel on a daily basis. The baseline in how you normally view your life and future, ranging anywhere from depressed to optimistic.

Finally, in eager anticipation, you lawfully pop the pill. After around 90 minutes or so, you are coming up, rolling.

During this time your neurobiochemistry starkly changes. All your thoughts and outlooks follow suit. All of a sudden, your thoughts and thinking are utterly transformed and you are thinking about your life and future in very different ways.

An upwards shift in valence by many orders of magnitude. Utter euphoria. You feel invincible. You are sooo grateful to be alive and you feel pure love for yourself and others.

Many of your problems disappear. It is not that they are hiding somewhere and thus you don´t remember them. In fact, on MDMA you are quite lucid and very aware of your problems, but now you are full of energy, euphoria and motivation and view these problems through a completely different lens. The “what” does not change, but the “how you see it”.

You even see putative “solutions” to your problems and you are eager to tackle these in the future.

Let´s fast forward 24h or so hours. Your neurobiochemistry has again changed, but now in the opposite direction. Many of your monoamine stores have been depleted.

Whereas just hours ago all your thoughts and outlooks about your life are were filled with euphoria and grandiosity, suddenly, you feel depressed. You almost start to cry for seemingly no reason. You feel empty. You might even ask “What is the point?”. Welcome to Suicide Tuesday.

In both of these instances, your thoughts and outlooks on life are secondary. A consequence of your neurobiochemistry, not a cause. A puppet. Radically different, even though the factual and objective information about your life has not changed at all within the span of just hours.

But what has changed is how you view things, how you frame them, your tendency to be optimistic or pessimistic about your life and future.

Some of you will say all this doesn’t matter because it is all substance-induced and thus “artificial”. Well, while not as illustrative as the example with MDMA, try this one.

Sickness. Sleep. Fasting. Running. Cold shower. And coffee.

Have you ever been sick and felt sad/lethargic/pessimistic for seemingly no reason? Well, that´s a reduction in all 3 monoamines caused by inflammatory mediators in your body.

Have you ever had an exceptionally bad night of sleep and on the following day you are moody, anxious, pessimistic? Well, your HPA-activity and sympathetic tone are quite high whereas your serotonergic state quite low.

Has ever euphoria crept up after your first bite of food after a long time of not eating? Your brain is flooded with serotonin and this acute change in monoamines is reflected in your thoughts about life in general.

Have you ever gone for a long, heavy run in the morning? Being just one workout away from a good mood, this mood boost often lasts for many hours. The whole day it feels as if you are seeing the world through differently colored lenses. And here again, the reason is a prolonged rise in your serotonergic tone (which evolutionarily serves a protective function: “Hey you vertebrate, don’t overdo it. Chill down.”). You get the point.

Have you ever felt like a million bucks right after a cold shower? And has this suddenly changed the way you think? Your outlook now on the world is likely different, despite the factual information not having changed. Here again, the changes in your thoughts and outlooks are a consequence of instant neurochemical change, playing puppet with your higher, your more rational mental centers.

Has ever the euphoria crept up after your first sip of coffee? If you ever tried to wean yourself off caffeine, you know the opposite to be true. And once you take that first teeny-tiny sip of coffee again, the grey world turns color-TV again. You are excited about life, even though just minutes ago you were semi-depressed and your outlook was dull and grey. Again, just because you make this first sip of coffee any factual/objective information about your life doesn´t change. But your monoamines do. And so do your thoughts and outlooks, but secondarily, now reflecting your new neurobiochemical state.

The point I am trying to make is this. The quality of your life depends on the quality of your mind. Your mind emerges from your brain. Every specific conscious state emerges from a specific brain state. Said another way, the mind is what a brain does. (Science doesn’t care whether you believe otherwise.)

Well, but what does have to do with chronic, lasting depression?

From these examples, it is easy to predict that our individual baseline neurobiochemistry goes far beyond how we are simply feeling in each moment.

How you tend to feel in each moment affects the decisions you made, the things you did and didn’t do. The thinking patterns you evolved over the years. Ramifications on every domain in your life. It had far-reaching consequences on why your life turned out the way it did. (For more: The most important lesson I have learned from replacing my hormones.)

To better understand the chronic effects of these “chemical imbalances” I think the following disorder illustrates my point quite perfectly.

Bipolar Disorder

If you can´t think of anyone with bipolar disorder choose one of the following: Wilson Churchill, Jimi Hendrix, Curt Cobain, Marilyn Monroe, Ernest Hemingway, Vincent Van Gough. Or Kanye West. Briefly, bipolar disorder is a condition where the afflicted person cycles between periods of mania (the “high”) and depression (the “low”).

These changes are brought about by fluctuating levels of monoamines. When monoamines are high, so are they. When they get low, they do as well.

During their “high” period (high monoamines), they feel more than well. They feel more than well, often exuberantly happy. They are motivated. They are creative. They do. They come up with countless projects. They start companies. This often goes so far that they do things that are irrational and stupid to the outside observer.

As their monoamines oscillate downward again, so does their energy and motivation. At this point, they are depressed, listless, a pale reflection of what they were only a few months ago.

Kanye West from running for president to breaking down sobbing like a child. Ernest Hemingway from writing The Old Man and the Sea in one go to shooting himself in the head. Curt Cobain from nirvana to blasting himself into the real version of that.

On a neurobiochemical basis this is very similar to my introduction to T3, its cold-turkey withdrawal, its reinstatement. It is also quite similar to MDMA vs. Suicide Tuesday, with the only major difference being that the cycles are of much longer duration.

Well, what does all this have to do with you?

People with bipolar disorder have a “baseline” that is dynamic, fluctuating. Most of us however have a “baseline” that is more or less constant. Our energy, mood, motivation, in general, don´t cycle much but are more or less stable (unless you are an ovulating female).

This state of baseline neurobiochemistry determines (or at least strongly influences) how we feel on a daily basis (e.g. depressed, listless, motivated, enthusiastic). Thus, it influences our actions, which in turn determine how our life has turned out and where it will go in the future. Our “baseline” has guiding effects on both our inner and outer lives.

(Note: Of course slight changes in our baseline are happening to some degree all the time (but no comparison to bipolar disorder): for example, whenever we get sick, whenever seasons are changing (SAD), whenever we make significant changes to diet/sleep/exercise, whenever we add any substance (or hormone) that influences our monoamine signaling.)

My point is this: Positive vs. negative thoughts/moods/outlooks are more often caused by your underlying neurochemistry rather than itself being the cause for you to feel good vs. bad as a consequence. Most people assume the following sequence of events: conceptual changes (neg. thoughts) → feeling. In reality, though it is just as often the other way around: feeling (changes in monoamines due to whatever reason) → conceptual changes.

This means if you are (biologically) in a shitty mood (first and foremost low monoamines) your thoughts/outlooks will follow suit.

And if our neurobiochemistry changes, so do not just our inner lives (hours to days) but our outer lives as well (weeks to months).¹ 

(Side note: Single nucleotide polymorphisms and other gene variants associated with hypomania (the “high”) are much more common in US citizens, espescially in direct descendants of early founders. Why? Because these early founders on average had greater energy and motivation compared to the people they left behind in their home country. Energy and motivation necessary to set for a brave new world. Leaving their genetic legacy to their descendants. These descendants than initiated one of the most dramatic rises of a nation state ever seen in history. Descendants having a reputation for motivation, “action”, for moving things forward. Well, there is in part a biological reason for that.)

Biology and happiness.

Science claims happiness is supposed to be 60–80% “genetic”. This was determined by continuously sampling the happiness-level of monoecious twins separated at birth (to correct for any nonbiological factors). While prone to confounders, this is the best science can do. What these studies tell us is that if one were able to magically derive an equation that predicts people's happiness best, biology accounts for over one half.

This means biological factors (genes → biological factors) are by far the most heavy-weighted factor that determines determining someone's happiness level. While there are many exceptions, for the average human being, biological factors are more important than all the other factors combined

But the effects are to a large extent indirect. Genes/biochemistry does not just affect our moment-to-moment wellbeing, but also our thinking patterns, the way we act and through all of this over time our overall life situation (wealth, relationships, status, profession, etc.).

Genes' effect on happiness is not by making you “happy” the same way recreational drugs do. The effects are to a large extent indirect. Genetic/biological factors ripple through your life the same ways an earthquake does through the Earth's crust but also affect your life the same way the flaps of a butterfly in Mexico can cause a hurricane in Texas. (For more, read the introduction of The Most Important Lesson Learned From Replacing All Of My Hormones.)

Summary: Depression is not just a chemical imbalance: ultimately, it is about the story we tell ourselves (but biological factors are most important, mostly because of their countless indirect effects on your thinking patterns, thus the way you act and consequently your life situation.

The ripple effects of biology

No domain of our life is out of the purview of biology. From brain wiring, thinking patterns, to which personality traits we evolved over the years. All these indirectly affect the lifestyle choices we make, our decision-making, likeability, our emotional reactions, drive, motivation, concentration, energy levels, sleep needs, immunological health, our level of neuroticism, how outgoing we are, our looks, etc.. All these together then over time influence every aspect of our life, every single day.

People high up in the social and economic ranks, people with impressive conventional “life success” (wealth, status, relationships), on average, were in many cases quite lucky genetics. This luck in terms of their biological “baseline” (genetics) contributed a large share to their success in life.

Of course, they worked hard, but great energy, mood, health, drive, concentration, etc. allowed them to be motivated and work hard in the first place. Whatever the value they got from this, this value was reinvested daily. And compound interest is the most powerful force in the universe.

The opposite holds for people not having achieved “much” in life. If your energy and mood are low all the time, on average you are more likely to procrastinate, withdraw, sleep in, not exercise, choose the easy things, etc., forcing you to settle for the mediocre (or less) quite early.

Many lives are screwed from very early on by genetic or developmental aberrances in neurobiochemistry.³ 

Variants of SERT, MAO, COMT, D2R (and many others) all quite strongly correlate not only with subjective levels of happiness, but objective life success as well. From very early on, carriers of these alleles have their lives nudged into a different direction compared to the life of their cloned self in an alternate parallel universe who by chance happened to be the carrier of a different version of these genes homozygote for the major allele. (The same way an SNP for MAOA or COMT or SERT or D2R would ripple out to affect your brain wiring and thus your personality (as well as every aspect of your outer and inner life), so does any substance you take on a regular basis.)

Being a medical student I knew this before. But I “knew” it in a way medical students “know”. During my adventure with T3, now though I could feel it. Far beyond any textbook knowledge.

Viscerally experiencing what this actually mean for someone’s subjective micro-universe. The anxiety, the self-doubt, the choking. Not just cold statistical correlations detached from any tangible reality.

Practical: If you want to change your thoughts/mood, focus on your body first (even if this “just” means sleep, exercise, nutrition)! Why? Neurobiochemistry -> Feelings -> Thoughts. If you feel lethargic and unmotivated it is just a matter of time until your biochemical profile is reflected in your thoughts and thinking patterns. Going for a run, eating some good food, getting a good night´s sleep are sometimes all that is needed. At the very least, they put you in a state of mind from which you can more calmly and objectively look at whatever problems you have.

How antidepressants really work

Some background:

Depression is a catch-all term for countless different syndromes, all quite distinct from each other. The only common denominator is “prolonged subjective suffering”. Not liking the story you tell yourself about your life and not liking the character you play in it.

At the root of a lot of depression is this concept that there is no light at the end of the tunnel. That it will never get better (hopelessness) and there is nothing you can do about it (helplessness).

All common antidepressants increase one or more of the three monoamines (noradrenaline, dopamine, serotonin).⁴ Monoamines affect the way we feel. Well, this is an understatement. They mostly determine how you feel.

Briefly, dopamine feels like “I am motivated”, serotonin like “I am calm and relaxed.” and noradrenaline “I am alert and awake”. Your setpoint and balance between these monoamines had a major effect on why you are the way you are and why your life is the way it is, starting perhaps already in the second month of pregnancy.

As I was changing my hormones around, my monoamines were all over the place. My energy, mood, motivation, etc. were all swinging quite a bit. Unless you are using any neuropharmaceutical drug on a daily basis, the main factor that determines the individual level of any of the monoamines at any given point is your hormones (as well as the balance between them). As your hormones change so do your monoamines.

Let´s look at the examples from above. As I withdrew active thyroid hormone, dopamine and serotonin dropped, whereas noradrenaline soared. With MDMA dopamine and noradrenaline accumulate in the synaptic cleft, while serotonin is released in addition. With bipolar disorder, monoamines fluctuate from high to low (esp. dopamine). In each of these instances, the changes in how the person feels and thinks are reflecting these changes quite instantly.

How antidepressants really work

There is a common misconception about how antidepressants work.

A pill to feel well? Drugs do help. But not in a way most people think (“taking a pill and feeling well”). It is their indirect effect on your life that is more important.

If you take MDMA you immediately feel wonderful. Antidepressants work differently. While there certainly is a slight increase in wellbeing (how you feel on a moment-to-moment basis) the indirect changes are as important, perhaps even more important.

With an SSRI for example, due to an increase in serotonin in certain “stress”-populations in various points of your brain (serotonin is an inhibitory transmitter mostly), such as your amygdala or limbic cortices, your propensity for these populations to be active is lower. They are not overactive and triggered as easily anymore. All else being equal your tendency to stress and worry is now lower (the mind is what the brain does).

Over time, this then catalyzes the development of new thinking patterns, new outlooks on life. You are less stressed. Calmer. You might view things differently. You might ruminate less. Because of this you also act differently. You might contact that friend you haven´t in a long time building the high-quality relationships all of us need so deeply, you might take on that hobby of yours you stopped for years. You now finally have the energy and motivation necessary to go out and productively tackle whatever needs to be tackled.

Because of all of this, not just your inner life changes (the way it does with the one-time administration of recreational drugs) but also your outer life, your objective life situation.

And gradually over time this combined effect of a changed inner life (for example a change in thinking patterns and how you tend to frame things) and a changed your outer life (e.g. relationships, how you spend your time etc.) the story you tell yourself changes. Now you tend to like your story and you like the character you play in it.

So, in a way, taking an antidepressant is like tuning up the motor, but if the car doesn´t go anywhere, it won´t matter much.

Again, drugs do help. But not in a way most people think. It is mainly their indirect effects that are important. Over time this allows you to have the necessary energy and motivation and mindset to go out and productively tackle your shitty life situation or shitty thinking patterns, which is almost impossible if you are chronically anxious/lethargic/unmotivated (all of which are predominantly biological issues).

Their combined effect of a) your moment-to-moment wellbeing and b) their indirect effect on your thinking patterns and thus eventually on your actions and thus c) your life situation gradually and over time, will cause many (not all people) to alter the story they tell themselves, which is the only important thing for happiness or unhappiness/depression.

Knowing all of this we can now summarize how antidepressants really work. Treatment (whether genetic or environmentally/pharmacologically/hor-monally affected doesn´t matter) -> monoamines change (hours to days) -> acute wellbeing changes (days-to weeks) -> thinking patterns change (months)-> behavioral changes (months) -> life situation changes (months to years) -> the story you tell yourself changes (months to years)-> the combination of all of these changes your level of happiness/depression over time (months to years).

Should you take antidepressants?

Let´s make an analogy. Let´s say you are a chronic insomniac. You tried out countless different things and “hacks” and “natural” supplements but other than transient short-term improvement nothing really seems to work.

The lack of sleep makes you fatigued during the day, you can’t focus, your willpower is low and thus your propensity to make bad food choices and to forgo any exercise is high. Your metacognition is crap and your attention span non-existent. Because of your terrible sleep you are much less efficient and effective at your work. You are more withdrawn but also markedly more irritable in social interaction.

Let alone all the negative effects from increased sympathetic drive and chronic hypercortisolemia wreaking havoc on your metabolic health, which along with your suboptimal diet and exercise regime cause you to border on metabolic syndrome.

You know how “bad” all this is and that it is supposed to drastically increase your risk for neurodegeneration, cardiovascular disease and cancer, the three of which constitute around 80% of causes of death in Western civilization.

You thought about sleeping pills, but after doing some research online, you decided against them. They just seem to have many side effects, cause tolerance, interfere with memory consolidation, people can´t get off them. They are just straight out “very bad” for you.

True, all of these are legitimate concerns and relying on sleeping pills is “bad”. But bad compared to what?? The question shouldn’t be, whether something is “good” or “bad”, but what is worse? For your health, your wellbeing, your life? Sleeping badly for years on end (including all the ripple effects it entails) or taking sleeping pills?

It is always a complex calculation of tradeoffs, but many of us usually just look at the risks associated with doing something. Well, there are risks from doing nothing as well. The last point is often dismiss

(Note: All this is regardless of the fact that you certainly don´t need to take the drug for life. You can always try to come back off, after things have stabilized somewhat.)

There certainly are risks involved. But there are also risks involved with doing nothing. Perhaps you don’t like the place you are at in life. Perhaps you have been suffering for a long time. Likely you were also dragging down loved ones.

You got one single life in this universe. In this only life you have got, do not just consider the risk of intervention, but also consider the risk of inaction. The risk of doing nothing is simply too high.

The right or wrong neuropharmaceutical can completely change your outer and inner life over time. So did hormones for me. And not just for me but the many people I will interact with. Directly, indirectly or intangibly.

A neurobiochemical disease?

But relationships are what is all about, I hear you say. Well, if you are chronically lethargic or anxious or unmotivated, you don´t want to interact with others in the first place. Neither do others want to interact with you.

But the way we tell our story is what it is all about! Well, if your energy and mood are always crap, so will your thinking patterns and outlooks on life follow suit.

But purpose and meaning are what it is all about! Well, why do you think people in their early twenties (when their hormones are at their peak) have purpose and are much more prone to dreaming? They have zest for life, ready to conquer the world. And why do you think midlife crisis happens around the time when certain hormones experience major drops?

Of course, you can´t “biohack”/treat yourself out of every negative state. For example, while most of the time I feel great (biologically speaking), when my girlfriend recently left me for someone else, I was down for weeks, despite feeling “great”. All the antidepressants of hormones in the world couldn´t have changed that. But my point is this: a great vitality and neurobiochemistry change how you view it and how you respond, helping you to make the best out of it.

BECOMING different

The right intervention (e.g. hormone, antidepressant) can change equilibria in a certain way to completely change your life. For the better.

A friend of mine was started on lisdexamphetamine for unrecognized ADHD in his mid-twenties. During the first few days after commencing treatment, something quite funny happened. One morning he dropped his jelly sandwich and it fell jelly-side up on the floor.

Normally, he told me, this simple, laughable instance would have peppered his whole morning, even though he perfectly knew there wasn´t any need to be pissed about the universe, because the jelly side is simply heavier than its counterpart). But normally it didn’t matter what he knew, what he felt took over. But now on treatment, he remained calm and rational (as a “normal” person would do) and simply made himself a new one.

Overall, he is more focused, less rigid, less judgmental, a little more empathetic, ruminates less, able to be present without anxiety and worries constantly interrupting. The mind is what the brain does.

Without knowing anything, just by altering neurobiochemistry, he is becoming different. This goes beyond conceptual knowledge from self-help books. These changes are automatic. No effort required on his part.

If you make sustained alterations to your neurobiochemistry, whether “naturally” through daily lifestyle changes (e.g. sleeping more/less/better, exercise, keto diet, meditation, etc.) or whether through more “artificial” deliberate intervention (e.g. hormones, antidepressants, stimulants), over time you become different.

Gradually your personality changes. Often without you being aware. Often it is not even you who notices the change, often it is other people you meet after a long time of no seeing each other. They can tell something is different.

This automatic change to your personality and behavior is quite unlike the intentional changes you try to make, perhaps after picking up various concepts from reading self-help “literature”. Lists of to-dos and to-not-dos about how to be more mindful, compassionate, self-confident or dominant.

You can think, talk and even write about it, but in real-life all this conceptual knowledge doesn´t help you that much. Real tangible change is meager at best. You can read all the self-help blah you want, but quite likely you are still the same old mindless asshole when somebody is rude to you. Having acted in your habitual autopilot-mode, long before you can pull out your nice and neat little list of things about how to win friends and influence people.

However, if certain aspects of your (neuro)biochemistry change, then your autopilot mode, your baseline, your natural spontaneous intrinsic self, changes. You become different. You don´t have to know anything.

For illustration let’s say, some vicious scientist injected you secretly with testosterone or a serotonin reuptake inhibitor (or what have you) while you sleep. He keeps track of the changes happening to you and compares it to your identical placebo-treated clone in an alternate parallel universe.

For sure, your personalities, as well as your alternate futures, will be different. Ever larger differences the longer the experiment runs.

As old habits die hard, change is slow. But relentless. Cumulative. Given enough time will elapse, slowly brain wiring is altered, thinking and habit patterns change. These spin off many behavioral changes affecting your “outer” life (e.g. relationships, hobbies).

So even if you stopped treatment (e.g. hormones, antidepressants), due to a combined effect of all these (the changes in brain wiring, thinking patterns, habits, life) the changes quite likely last for some time, certainly months, perhaps years, maybe even longer if mental and behavioral habits are maintained by additional conscious effort on your side.

This can be compared to building muscle with steroids: even if you stopped the steroids, just maintaining the muscles only requires low-level effort and is much easier than building it in the first place. Though steroids by themselves will cause change if combined with a proper exercise and nutrition regime the gains are synergistic. Your physique -or your personality — will show signs for a long time.

All this is regardless of the fact that changing one's neurobiochemistry also changes our consciousness, our experience, the subjective micro-universe each one of us is living in on a daily basis. And many people have no problem engineering this micro-universe to our liking, this is what for example recreational drug use is all about.

The downsides of feeling “too” well

While feeling well all the time might sound tempting and desirable, there are downsides to feeling “too” well.

You might be overly confident and do shit you later regret. In times of mania, bipolar people often take out loans and to open a business they didn’t adequately prepare for.

You might be more impulsive and say or do something you wish you didn’t. You might feel so well that you just can´t see how others could possibly be suffering and you become unempathetic and insensitive.

After my hormone replacement protocol was more or less complete (How I fixed my hormones: The only guide you need) I had times where I just felt “great” (especially considering the stark contrast I was coming from). During these times I made a risky investment in stocks and lost around 10.000 Euro. Despite still being a student it didn´t even bother me at all that I lost this much money. I simply didn´t care.

One time, I said something to my girlfriend that hurt her. In fact, it hurt her so much that it broke her heart. Because I felt so well, I was too impulsive to be considering the consequences of my actions nor could I even see how what I said could possibly hurt someone.

Worst of all, as she was crying into my shoulder I felt nothing. For me, this was a red flag. Was I becoming a psychopath?

Fortunately, as my neurobiochemistry stabilized and the “honeymoon”-phase was over, my impulsivity, emotionality, empathy all returned to normal. But reflecting on this period was a wake-up call. Before, maximizing my biological well-being was my main goal. Now though, I have seen that while “engineering” yourself to feel very well all the time is tempting, it is also dangerous. Both for you, your loved ones and society as a whole.

And there is one more thing most people don´t consider. If you feel amazing all the time, you might unintentionally eliminate periods of suffering. And periods of suffering CAN be very “productive”. In fact, in retrospect, many say their worst times were the times they grew the most. These gave them identity and meaning.

While it is true that for many of us lots of growth happens reactively (as a reaction to suffering), proactive growth (growth through positive action from intrinsic motivation) is certainly possible. And such growth is certainly more likely if you feel somewhat well.

Thus, long periods of time where you feel “amazing” also have their upsides: you can be incredibly productive, you don’t worry about anything and thus you are much more ready to take action. Whatever you do or create during these periods stays (e.g. open a company, write a book, study lots of material, earn a lot of money, the Nazis on amphetamines doing their Blitzkrieg-thing).

In fact, many writers and artists did their greatest works in times of (hypo)mania.

Another upside of feeling well is that you simply enjoy life as it is now (why else would recreational drug use be this rampant?). Although perhaps at the price of both suffering being a catalyst for growth and you making tradeoffs with your future (e.g. hippies often stumble towards failure and regret, despite being genuinely happy during the few years when they “do their thing”.)

So, how “well” is optimal? How “well” does strike the right balance between you doing things that are conducive to your future life while you can also enjoy your life at the moment? What degree of “well” does maximize the area under the curve happiness?

Well, there is no way to tell. The second-or third-order consequences can’t be predicted. In my opinion, feeling “quite” well has net benefits overall. Although there are tradeoffs and dangers.


1. The earlier in life these changes the more powerful the effects.

2. Many of these genetic factors which have been found out to be correlated to happiness are genes associated with monoamines and hormones. Monoamines and hormones then among other things determine your energy levels and mood.

3. Any number of receptors for neurotransmitters, the many enzymes involved in their synthesis pathways, the countless relay proteins in the subsequent intracellular signaling cascade. The same also holds for every step of hormonal expression, regulation, signaling, number of cells involved at every step along the way. Rarely do these people know. A life altered. Either for the better or the worse.

4. Ketamine -and some others- seems to be an exception. Psychedelic drugs also are unconventional antidepressants but they work more like “psychotherapy for a year compressed into a single afternoon”.

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