Author: Altizen

  • Caffeine - Our Favorite Legal Stimulant

    Caffeine - Our Favorite Legal Stimulant

    (Note: This article is from the archive and was written c. 2022.)

    Caffeine is the most used drug in the world. It is a stimulant that works primarily by blocking adenosine receptors.

    Some of you may remember cellular respiration from biology. This is where our cells take glucose (food) and use it plus water and oxygen to create energy in the form of ATP — adenosine triphosphate. This and other adenosine compounds are used to cause actions in cells. Need to walk a protein to another part of the cell? Bam! ATP to the rescue. Reading RNA and need to build a protein? Bam! ATP makes it happen. Need to trigger a Rube Goldberg style intercellular cascade? Bam! ATP can do that.

    And as the cells in your body work, as you burn through your glucose stores to create ATP to make actions happen, you’ll have a build up of adenosine. All this adenosine then will connect with adenosine receptors, telling your body you’ve been busy and should get some sleep.

    …and this is where caffeine comes in.

    Caffeine puts the brakes on that process. It antagonizes the adenosine receptor, meaning it blocks or dampens them from functioning correctly. So you have all this adenosine building up, ready to tell your body you need some rest, and caffeine interferes with the message from getting through. This tricks your body into an alert state, and staves off sleep.

    But that’s not all caffeine does. It has downstream effects on serotonin, dopamine, and norepinephrine. These are powerful mood hormones, and also the primary hormones found in the original antidepressants. Sure enough, studies show that caffeine intake can help with mild depression.

    One of the ways this happens is that these adenosine receptors are linked to dopamine receptors. When the adenosine binds to its receptor, telling the body you’ve been working and need to rest, it kicks the dopamine off the adjacent dopamine receptor, so the body gets less of the dopamine response. But when we intake caffeine, the adenosine receptor is blocked, so the dopamine continues to activate its dopamine receptor, and we keep getting the infamous “dopamine hit.”

    Of course, there’s a catch. Too much dopamine can increase irritability. Caffeine can also exacerbate anxiety. It does this partially through hindering sleep; partially through keeping body cortisol — stress hormones — high; and partially through inhibiting our body’s GABA system, which is our body’s natural way of relaxing.

    In other words, a little caffeine can help fight against subclinical depression, too much caffeine can increase your anxiety and irritability.

    Caffeine also seems to potentiate acetylcholine, which is tied to increased memory and learning. Oh, and increased urination, too. Doesn’t help that it’s generally consumed as a liquid, either.

    Other benefits to drinking coffee seem to be lowered risk of dementia, lowered risk of Parkinson’s disease, and possibly even lowering incidences of type 2 diabetes.

    On the other hand, it is a mild contributor to hypertension, can increase episodes of acid reflux largely due to its acidity when imbibed as coffee, and can be harmful in pregnancy if not kept at low doses.

    So what to do? The answer for most people seems to be just keep your consumption low. 1–2 cups of coffee in the morning will equate to about 100–200 mg caffeine total, assuming about 100 mg of caffeine per 8 oz cup. Caffeine has an average half life of 4–6 hours. So it takes the average person between 20 to 30 hours to get caffeine out of their system. That’s a full day including the night. For this reason, it’s better not to have coffee as the day progresses, but to keep it to early parts of your day. Additionally, a coffee-free day here and there to make sure your body gets it out of the system, that it’s not accumulating, is a good idea if you find your anxiety levels getting too high.

    Consider also switching to tea. Green tea especially has been found to have incredible health benefits, from being more calming due to included l-theanine compounds to helping reduce blood sugar levels. It also has less than half the amount of caffeine compared to an average cup of coffee.

    If you stop coffee altogether, be aware of rebound headaches if you were a chronic coffee consumer. We mentioned that caffeine has downstream effects on norepinephrine, and norepinephrine is a vasoconstrictor. This causes your blood vessels to get smaller. If you drink a lot of coffee, your body will use mechanics to compensate and get your vessels a little larger again. Then, when you suddenly stop drinking coffee, there is no longer the extra norepinephrine causing the vasoconstriction, but the balancing mechanics countering the norepinephrine will still be in place, meaning your vessels will get even larger…

    …and you’ll get a headache from the extra pressure in your brain.

    So take it easy.

    At the end of the day, you know your body. But watch out for negative effects from excess caffeine consumption, usually found in the form of poor sleep, increasing anxiety, and/or increasing irritability. If that is happening to you, consider cutting down and replacing much of your coffee habit with teas. And consider having the occasional caffeine-free day.

    PS~ If you want to nerd out a bit, caffeine is metabolized by the CYP1A2 system, and some researchers are looking at genetic links with consumption and health benefits.

  • Surfing Difficult Emotions with RAIN

    Surfing Difficult Emotions with RAIN

    (Note: This article is from the archive and was written c. 2022.)

    One of the most useful techniques in the mindfulness arsenal is the exercise called RAIN. This English acronym was created in the late 90s by Michele McDonald, an insight meditator who I believe is currently teaching in Burma. It takes a core mindfulness concept of gently exploring feelings in a way that is self-compassionate and non-identifying, as opposed to fighting them and trying to suppress them. It has been successfully used to deal with negative thoughts and emotions, and addictions such as smoking and overeating. It is also a technique suggested by the SMART Recovery (Self-Management and Recovery Training) organization.

    So this is a tool to use when you are dealing with cravings and difficult emotions. Maybe you are irritable or angry. Maybe you are sliding into sadness and despair. Maybe you just really want that cigarette or drink or some other unhealthy craving. Generally in these times, people will indulge the feeling. They may fixate on it, and amplify it. (“Heck yeah I’m angry!”) Or, they may try to push the feelings down, try to ignore them. They may punish themselves, as if they are a poor human being for having these feelings. That is of course very far from the truth.

    The first thing to recognize is that you are not your thoughts, and you are not your feelings. Our minds are hard-wired to think about and anticipate problems. When a thought pops in your head, that does not mean “you” are doing it. Instead, you are experiencing your mind automatically generating this thought. When a feeling suddenly comes to you, that does not mean “you” are doing it. Your body will remember stressors, maybe trauma, and autogenerate feelings. You are experiencing your body and mind generating these feelings. Your biology is designed to do these things, largely as antiquated defense mechanisms. They do not define you.

    Similarly with addictions, our minds are wired to avoid pain (a defense!) and seek things that are pleasing. Many things exist around us that reinforce these pleasure centers, creating stronger and stronger pathways until the point that we may find ourselves automatically reaching for these pleasing things without even thinking about what we are doing. We become automata ruled by an addiction. Some chemicals are incredibly powerful in this regard, quickly building addictive pathways in the mind–especially nicotine and many illegal substances.

    RAIN asks you to take a pause when these feelings and cravings come, to investigate them gently and be self-compassionate.

    stands for recognize. This is the first step. You recognize what you are feeling, and step outside of that automatic mind. This is happening. This is how I am feeling.

    A stands for accept and allow. Let the feeling be. Accept that it is there, gently. Don’t worry about how you “should” be feeling, which can be a rabbit hole-like ruse. Instead, allow the experience to come, to be. Accept it as it is.

    I stands for investigate. Explore the feeling. Experience it. Where is it in your body? Do you feel tension? Where? Is the feeling moving around? What other feelings are behind it? Just like a cloud is more than the color white (also containing for example gray, blue, yellow), our emotions tend to have other emotions inside them, mixing together. Is this feeling trying to teach you something? You are an investigator and an observer. You are the experiencer. Allow yourself to feel, to experience, without fixating, without indulging, and without judging. You are not your thoughts. You are not your feelings. You are the one experiencing these thoughts and feelings.

    N stands for non-identification, for natural awareness, and for nurturing. Allow yourself to rest here, gently feeling the emotion, gently experiencing it, with recognition that it is not you. This is a place of self-compassion. You have recognized these automatic emotions. You have accepted them as a part of being human. You have investigated what is in them, what they want and are teaching, where they are and what they truly feel like. And now you apply self-compassion as you gently experience the feeling. Dr. Judson Brewer talks about RAIN as a technique to surf feelings and cravings, to experience them as they are and ride them to shore. The source of this idea may come from Dr. John Kabat-Zinn, who said, “You can’t stop the waves, but you can learn to surf.”

    Some people tack on an S here for self-compassion, but others see self-compassion as part of the N stage.

    I want you to recognize again that emotions and thoughts many times just come. Rumi spoke of them as guests arriving. They are not you, they are not the house. They are guests that will come. Open the door, let them in, and let them pass:

    The Guest House

    This being human is a guest house.
    Every morning a new arrival.

    A joy, a depression, a meanness,
    some momentary awareness comes
    As an unexpected visitor.

    Welcome and entertain them all!
    Even if they’re a crowd of sorrows,
    who violently sweep your house
    empty of its furniture,
    still treat each guest honorably.
    He may be clearing you out
    for some new delight.

    The dark thought, the shame, the malice,
    meet them at the door laughing and invite them in.

    Be grateful for whoever comes,
    Because each has been sent
    As a guide from beyond.

    — Jalaluddin Rumi, translation by Coleman Barks

    And from Victor Frankl:
    “Between the stimulus and the response there is a space, and in this space lies our power and our freedom.”

  • Biocentrism, Buddhism, and the Brain

    Biocentrism, Buddhism, and the Brain

    (Note: This is part of the archive and was written c. 2022.)

    Last year I read The Grand Biocentric Design, which to me was a modern follow up to older classics such as The Tao of Physics and The Dancing Wu Li Masters. Building on replications of the (in)famous double-slit experiment in physics, and experiments which have been done since then that on a whole continue to confirm extrapolations such as “there is no true separation of subject and observer,” “observation changes the result” and “observation creates,” biocentrists in essence posit that consciousness itself creates life, creates matter.

    This is not a new concept. Not by a long shot. However, one of the first questions raised is “what then is consciousness?” Biocentrists are quick themselves to state that they are not limiting the definition to human consciousness, but instead that it is “all of consciousness.” To which, the question remains.

    Consciousness is often spoken of in synonymy with sentience, that consciousness means to perceive and/or to feel. Fine, but where to draw that line? Plants respond to external stimuli. They send messages to each other. Is this not perception? Communication? What about single-cell organisms? They too respond to stimuli and send messages to each other. See how bacteria communicate with each other. See how they share new defense mechanisms they’ve built, making each other stronger. Viruses — this is a taxonomy on which biologists oft disagree: “Life” has been defined by metabolism, and yet viruses do not metabolize. It is as if they are machines. That goal post has been moved by at least one group to state life is defined by reproduction, which is something viruses most definitely do.

    Is life synonymous with consciousness? Take for example the person with a brain injury, said to be unconscious. Experience shows they still may be receiving information, perceiving it, on what we call an unconscious or subconscious level. In The Hidden Spring — A Journey to the Source of Consciousness, Mark Solms writes about a trip he took with families and their children with hydranencephaly to Disney World. Hydranencephaly is a disorder in which there is an absence of brain hemispheres, an absence of cortex, where most all of what are considered conscious processing centers lay. I say “conscious” because we know that in the brain stem are processed many biofunctional processes, e.g. temperature regulation, breathing, sleep, etc. — things done sans “conscious” thought. So these children are essentially considered to be in a vegetative state — unable to see, hear, recognize tactile sensations and more, and unable to consciously give responses.

    What was the result of the trip? The children were delighted. They seemed to have a grand time, these unconscious, “vegetative” children. (It was noted that “It’s a Small World” was a favorite of the child group.) There are other experiences that gave the same result, such as when a hydranencephalic child had her baby sibling put in her lap and clearly showed an excitation response. Or how about a man without an occipital/visual cortex, thus “blind,” but who would navigate objects in a hallway he was walking down. When asked about dodging objects, he had no idea he was doing so. Or a person unable to make memories who was taught a new skill. This person could recall no knowledge of the training nor knowledge of the skill, and yet when tested, continued to develop ability in the skill along with the training. What’s remarkable about these is that they suggest that beyond our “normal conscious” experience is something that not only receives input but has an emotional and functional response to it. (Granted, neuroscience has shown that, at least with cortical zones, when one area is lacking, especially in early development, other areas of the brain can take on some of the missing functions. I have yet to finish Solms’ book, and look forward to reading what else he has to show.)

    Where to draw the line?

    Perhaps it is at the “raw” forces of nature, such as found in chemistry and physics — elements and compounds; valence and gravity; the thermodynamics of chlorine ice, cloudbursts of liquid iron and the hydrogen maelstrom of stars. Perhaps these are the non-conscious to which consciousness gives rise. (And by definition, consciousness would also give rise to itself.)

    So hypothesis one: “Life, the universe, and everything” is created by Consciousness, which is Life (hello paradox), which itself is defined by a) that which metabolizes or b) that which replicates itself.

    Scientifically, this is supported mostly by physics experiments (of which there are many, and replicated) that show different results and different states of being (e.g. matter vs waveform, and/or different pathways traveled) depending on, and modified by, whether or not the experiments are being observed.

    The most obvious problem here is that Life as we know it came into existence after the Universe and Everything. What science gives us are biochemical development and a Big Bang. Beyond this lie mostly intricate mathematical excitations.

    What the ideas we are exploring here imply is that “consciousness” is something that lies then beyond Life itself, in a place where the term “consciousness” is perhaps misleading, a la “The Tao that can be named is not the eternal Tao.”

    Let’s wax romantic for a tad and take a look at religion.

    In the Old Testament of the Christian bible, God calls himself “I Am.” In Exodus 3:14 he instructs his messenger, “Tell them I Am has sent you.” This term is used over 300 times in the Bible in reference to divinity. The Tetragrammaton yahweh/yehwah/ יהוה appears itself to be derivative of the Hebrew verb “to be.”

    I admit my imagination plays a scene in which one hears “I am,” and then bang! — really Big Bang.

    And in Buddhism is the famous metaphor of the source of life, the ultimate Consciousness, being like an ocean, and the manifestations of Life, e.g. birds, fish, lizards, beetle, humans (or “hoomyns” as a friend calls us) are waves on the surface of the ocean. Forces give rise to the waves, which have their existence traveling in space and time, and then we ultimately run our course and return to the ocean, the Great Consciousness. Although the Buddhists don’t often use the word “consciousness,” which we have already seen can generate confusion. Translations of their texts frequently use the word “awareness.”

    There is an imaginative space-time parallel to the ocean metaphor, that of bended space being the result of mass and matter. The mass of an object creates gravitational pulls and “bends” space, in turn potentially adding to mass and thus pull. It is fun to juxtapose the ocean with a blanket of space, and waves with space-bending mass.

    The psychologist-monk Jack Kornfield in The Wise Heart — A Guide to the Universal Teachings of Buddhist Psychology discusses this topic of ocean-wave consciousness directly when he writes, “Buddhist psychology posits that consciousness is the condition for life, and that the physical body interacts with consciousness but is not its source.” The metaphor here, like waves of the ocean, is that the body is then a sort of conduit for consciousness, for the Great Awareness. The body itself is not consciousness, it is not awareness. Consciousness does not come from the body. The body is a way for consciousness to be, to experience. See: “I Am,” and “Bang!”

    Bada-bing, bada-boom.

    And you know what? I’ll take it. This is a philosophy of life rooted in both science and religion. It does not judge. It does not try to define “good” vs “evil.” (Relative terms if e’er there were ones.) It does create a sort of unification, where all of life comes from the same source, where all of being is familial — I, you, they all being nothing more than utilitarian terms outside of which practicality meaning breaks down and they are rendered inconsequential.

    And if a seeker comes forth and plays Jeopardy on “42,” a la “what does it all mean?” Perhaps the answer is simply to be aware. Maybe just “to be.” Maybe it’s relative. Quite frankly being aware is a taller order than most realize, definitely something often taken for granted.

    My interpretation?

    1) We are all family. No question about it. That includes crazy Uncle Hitler, yes that sadistic schmuck, and it also includes sharks who bite limbs off surfers. (As many of us know, it’s our family who have the capacity to hurt us the most.)

    2) We are here to be. If possible, to be aware. If possible, to feel. And if possible, to learn and to grow.

  • Homeostasis, Allostasis, Allostatic Load, and Rebound

    Homeostasis, Allostasis, Allostatic Load, and Rebound

    (Note: This article is from the archive and was written c. 2022.)

    Homeostasis (“similar/same” + “standing still/state”) as a concept has been around for a very long time. In medicine, the concept is that there is a certain set point of health that is optimal or necessary. Furthermore, if there is deviation from this state, processes are in place to shift the deviation back towards the optimal state and thus avoid disease.

    The easiest place to see this is with fundamental physiological processes. For example, our body in general needs to have an acid-base balance, known as pH, of around 7.35–7.45. Our blood has an amazing pH balancing system built in using bicarbonate, HCO3–. If the pH starts getting out of range, our kidneys and lungs will start working overtime to bring it back within range.

    Allostasis (“other” + “standing still/state”) was defined in the late 80s, but has a varying definition, sometimes seeming to supplant homeostasis, sometimes seeming to compliment it. In psychological and psychiatric literature, I tend to read it in a complimentary fashion, and that’s how I’ll address it here. Essentially, allostasis is when that balancing set point moves. Something is happening in your body that requires a change in physiological dynamic to meet new demands. So your body is still trying to stay in balance, but it can come at a price.

    Let’s first consider going for a jog. When you first start moving, you can breathe easily. But as you continue, your breathing becomes harder and harder. If you keep going and push yourself, eventually your muscles will start to tire. All the tissues in your body require a certain amount of oxygen and nutrients to keep functioning. When you are sitting, lying, or walking, it’s usually easy for your body to maintain this homeostasis. When you begin jogging, your muscles start to require a lot more oxygen and nutrients. This creates a new set point, a new point needing to be met to keep the body in balance. This would be our allostatic point. The first thing your body does is make you start breathing faster in order to meet this new set point. You breathe faster, and your tissues are once again properly perfused.

    Of course, you are still burning nutrients at a faster rate, and eventually you’ll exhaust that supply as well. Eventually, you will tire out. This brings us to allostatic load, namely the wear and tear that happens on your body as it tries to meet allostasis. Allostasis requires pushing our body outside of a state it can easily maintain. The longer our body is forced to maintain allostasis, the more the cost, and eventually, we burn out. Maybe we collapse to the ground, heaving and trying to recover our breath. Maybe we get sick. Maybe we have a heart attack. Or a panic attack. Maybe we develop anxiety, inflammation issues, depression.

    But not from jogging.

    Let’s then consider our body’s excitatory ready mode, popularly known as the fight-or-flight state. When your body senses danger, the primary stress hormone released is cortisol from the adrenal glands atop the kidneys. Cortisol is a steroid. Cortisol is going to want you to have energy fast, so it’s going to help break down glycogen stores into glucose, raising your blood sugar level. It’s going to suppress systems it thinks are non-essential for the immediate situation, such as parts of your immune system. (Remember that corticosteroids are used as anti-inflammatories.) It’s going to raise your blood pressure, to make sure all of your muscles and tissues can get the resources they need quickly.

    So this is an allostatic state, an allostasis, that our body has moved into in order to quickly react to danger. Maybe it does it because you’re about to be eaten by a tiger. Maybe you’re about to be “eaten” by your boss, or a difficult client, or a bully. Maybe it’s an enemy soldier. Or a car accident. Or your parents.

    People, especially those who are dealing with trauma, can get sort of stuck in allostasis. They have a hard time bringing themselves out of this fight-or-flight mode. Of course, over time with allostatic load, that wear and tear, the chronically stressed fight-or-flight mode itself becomes damaged. It doesn’t function quite the same anymore. Plus their body is having to deal with this allostatic load over years, maybe decades. The body may start having blood sugar issues, weight issues, hypertension, heart problems, neurological problems. The person may be considered “high-strung” or have chronic anxiety. Maybe they have a short temper. Maybe they resort to drugs and/or alcohol to try to calm themselves. Quite often some combination of lifestyle changes, therapy, and medication are required to get them back to a healthier state and stave off the wear and tear of the allostatic load.

    Lastly, let’s consider the chronic alcoholic. Alcohol is a suppressant. Its primary mechanism is to activate our body’s natural calming system. A little bit of alcohol can do this. But drinking too much (which is essentially overdosing), and drinking too frequently moves the body’s healthy set point. The body will respond to this by releasing more excitatory hormones and less calming hormones. Given enough time, it will create more excitatory cellular receptors, too, and remove some of the suppressing/calming receptors. It is trying to achieve balance. The alcoholic in part recognizes this as needing more alcohol to relax. And so goes the downward spiral.

    But then there is a moment of clarity, and the alcoholic decides to quit. So now, there is no longer alcohol in the system there to activate the calming receptors. What will happen?

    If we’re only talking one night of maybe partying and drinking too much (which again, is an overdose), then that person will later have symptoms such as a fast heart rate. Maybe sweating. Maybe increased anxiety.

    Why? Because their body is flooded with more excitatory hormones in order to balance out the excess suppressive drug they just saturated their system with.

    Now remember that over time, the body will not only change its hormonal response, but will actually modify the cells so that they are more receptive to excitatory signals, and less receptive to suppressive, calming signals. This is the chronic drinker. When that person suddenly stops drinking, they are going to feel very bad. Their hands will shake, their heart will beat hard and fast, they will sweat, they will worry. They might become delusional.

    …And they can straight up have a seizure.

    All of this is known as a rebound effect. When your body is working hard to reattain a balanced physiological state by countering a drug in your system, and suddenly that drug is removed, your body will then bounce back way in the opposite direction, to an exaggerated out-of-balance point on the other end of the spectrum. And sometimes this rebound can kill. Chronic hard drinkers who quit cold-turkey without medical help often have to be hospitalized.

    This is why substance abusers often have to be put on a medication similar to their drug of choice, and then tapered off. (With therapy.) This is why people who have been on cardiovascular medications and certain psychopharmaceuticals cannot just suddenly stop taking their pill, but must allow the dose to slowly be lowered over time before it’s removed. Patience is required.

    And I’ll tell you something else, babies born to opioid abusing mothers? They are born with their bodies in withdrawal shock. I spent some time with these adorable little creatures, but it’s heartbreaking. They have to be maintained in the hospital, getting enough of an opioid to get their body out of shock. And they stay in the hospital, being monitored while the opioid level is steadily tapered, steadily dropped, until homeostasis is restored as well as possible.

    So there we go.
    Homeostasis. Allostasis. Allostatic load. Rebound effect.


  • The Monoamine Theory of Antidepressants

    The Monoamine Theory of Antidepressants

    (Note: This article is from the archive, written when exploring the history of psychopharmaceuticals.)

    This hypothesis has its origins with some of the old SSRIs, and tries to explain:

    • Why it takes time for antidepressants to work
    • How side effects come before the antidepressant works
    • How the side effects go away over time

    Here is a sketch of a serotonergic neuron:

    From Stahl’s Guide to Essential Pharmacology

    On the left side are dendrites. Think of these as arms that receive input. On the right is the axon. This is the output arm. The end of the axon is called the presynapse, and the half circle to the right of that is the postsynapse. The little yellow bars are serotonin hormones. The blue blocks on the dendrites and the postsynapse are serotonin receptors.

    What we don’t see is the neuron getting the message to release serotonin. You might be thinking the receptors on the dendrites are for that since they’re input, but they’re actually autoreceptors. Their job is to apply brakes to the serotonin release.

    When the neuron gets a message from another neuron or neurons to release serotonin, it becomes an electrical message that shoots down the neuron and releases serotonin at the presynaptic site. The serotonin then diffuses over to the postsynaptic receptors and BAM! That serotonin makes something happen. Maybe you get happier. But then maybe you get anxious. Weird, right?

    Those serotonin receptors are called 5-HT receptors (5-hydroxytryptamine, the “other” name of serotonin*). There are many 5-HT receptors, involved in mood, blood pressure, sexual activity, headaches, anxiety, memory, nausea, sleep… the list goes on and on.

    So this monoamine hypothesis states that depression is in part cause by that serotonergic neuron not releasing very much serotonin from its axon anymore. When that happens, the postsynaptic neuron wonders what’s going on, why it’s not getting much serotonin anymore, and it up-regulates, it creates more serotonin receptors. These new receptors will be many kinds of receptors, not just the ones that help you feel better. So now it’s not just that there is less serotonin, but there are a greater spread of receptor types to be triggered by what little serotonin there is.

    Enter an SSRI. This person starts taking an SSRI, a selective serotonin reuptake inhibitor. Look again at the picture above and you’ll see five “Do Not Enter” type circles. These are all on reuptake pumps. While the neuron releases serotonin, it also has reuptake pumps to try to get the serotonin back after it does its job of triggering a receptor. Well, the SSRI interferes with these pumps working. So where we had very little serotonin, now we have more serotonin hanging around these neurons.

    Remember the arms on the left, the dendrites, get input. When the uptake pumps shut down over there, the autoreceptors start getting really busy. They become too active, too sensitive. When this happens, the dendrites begin to downregulate the receptors there.

    Now, here’s one of the odd things. Those autoreceptors are supposed to help the neuron understand how much serotonin to release. Of course, we have a dysfunctional neuron here, and we’re trying to get it to change, literally trying to change you on a cellular level. When these autoreceptors downregulate due to being over stimulated, there are now fewer receptors receiving serotonergic messages. The result is that the neuron will begin to create more serotonin, and release more from the axon.

    Those postsynaptic receptors also have been being flooded with serotonin, and so they too are going to downregulate. Ultimately, this should be the natural state of the neurons: the presynaptic neuron releasing a healthy flow of serotonin when needed (not stunted, not too little), and the postsynaptic neuron having the right amount of proper receptors to receive the serotonin stimuli.

    Let’s go back to our original questions:

    • Why it takes time for antidepressants to work
    • How side effects come before the antidepressant works
    • How the side effects go away over time

    Why does it take time for the antidepressant to work?
    Because that up and downregulation of the receptors takes time, and that’s a big part of the neuronal change we’re looking for the medication to make.

    How come there are side effects before the antidepressant even helps?
    Because the synaptic zone gets flooded with serotonin while all those extra receptors are there. Many of the receptors do things we don’t want them to do like cause anxiety, give stomachaches, cause sexual issues. For this reason, it is recommended that SSRIs be started at a low dose and increased gradually, as the neurons begin to change.

    How do the side effects go away over time?
    I think you can answer this one by now. As the postsynaptic zone downregulates, removes, 5-HT receptors over time, less side effects will be felt.

    So that is a nutshell summary of the monoamine hypothesis of antidepressants. Obviously, things are more complicated than this. Serotonin, as mentioned before, has many receptors all over the place and a very wide range of capabilities. There are many questions not answered, such as the function of antidepressants in OCD and eating disorders. Personally, I think the hypothesis is a little rough, but it helps us start forming an idea of functions.

    This hypothesis grew over time and was dominant, but largely has become superseded by other things such as research on brain-derived neurotropic factors. Regardless, it’s good information to be aware of.