“The fox provides for himself. but God provides for the lion.”
- William Blake
There is a subtle zero-sum game that people worldwide play. Because good things, such as money, usually come from labor, we link suffering to gain.
If a drug makes you feel good, you must build tolerance, and you must go through withdrawal. In receptor biology, if you activate a receptor, it will eventually down-regulate and the drug will lose its effect.
SSRIs were originally thought to increase serotonin in the synapse by stopping neurons from taking serotonin back up out of the synaptic cleft. Since serotonin is thought of as the “happy chemical,” and serotonin’s action is thought to be specific to the receptor in the synapse, SSRIs would be a perfect anti-depressant agent with few side effects.
Zero-sum receptor biology forbids this. Since the receptor can change expression in response to substrate levels, the serotonin receptors should down-regulate in response to the increased extracellular serotonin. Likewise, the auto-receptors on the neuron that is releasing the serotonin (presynaptic) sense the increased release and down-regulate both serotonin synthesis and serotonin release.
Both the presynaptic and postsynaptic neurons work to counter the effects of the SSRI.
Since there is a time delay, when starting or stopping SSRIs, the patient experiences a period with great serotonergic effects, and then the patient returns to a baseline that is relatively unchanged. While human studies are lacking, we know that long term SSRI usage in rats decreases serotonin levels. [1]
SSRIs were meant to be specific to serotonin uptake, but we now know they interact with a host of other targets, such as acid sphingomyelinase — a potential anti-neuroinflammatory mechanism.
The methods by which modern pharma companies make small-molecule drugs (things that go in a pill) are known as “fragment-based screening” and “structure-based drug design.” These methods pick out a specific protein target — in the case of the SSRI, it would be the serotonin transporter — and then try to make a molecule stick to it.
Proteins are like gears in an engine, and drugs are like gum. Drug developers try and stick gum into the engine’s gears to “fix” it.
Humans have around 20,000 protein-coding genes, and may have up to 400,000 variants if the genes are read in different ways. Modern drug developers choose one protein to test and select one molecule that sticks.
This is akin to taking a gum, seeing that it sticks to one gear in the engine, and then assuming that it does not stick to the 400,000 other gears. Drug developers may test one or two other gears, but they surely are not testing 400,000.
Evolution likes to double-dip. Why make a new molecule when you can repurpose an old one? Every molecule introduced into biology performs multiple actions because there is strong incentive for this to happen.
Receptor biology forbids that drugs work, because the receptors will always adjust levels to reach a new homeostasis. But — we do have drugs that work. Drug development has been successful for many diseases. How can this be?
Biology is not always a zero-sum game.
Receptor biology is not the best way to think about drug action.
If biology is thought of as a process of phase transitions between metastable states, per GN Ling and H Frohlich, cellular health can be improved by stabilizing a favored state, destabilizing a disfavored state, or by inducing a phase transition to a favored state by providing activation energy.
Drugs can have actions that create phase transitions, not through ‘gumming up’ a metabolic process, but by changing the state of components inside of the cell.
These states can have varying levels of sustainability.
Coffee makes people feel good. Population mortality studies suggest coffee is positively associated with lifespan.
Salt tastes good. Population mortality studies suggest that higher salt intake is better for lifespan.
The only robustly validated life-extending drug (Footnote A) is L-Deprenyl, or Selegiline, which increases dopamine and makes you feel more alert and alive.
The thyroid responds drastically to iodine deficiency, multiplying in size seemingly boundlessly. Taking thyroid hormones causes the thyroid to shrink, but temperatures can be pushed to >99F consistently, so the adaptive thyroid down-regulation does not fully mitigate the pro-metabolic effects. The thyroid restores its size after supplementation is ceased.
Anabolic steroids cause nearly permanent increases in number of myonuclei, potentially creating a long-term anabolic environment that lasts after cessation.
Gilbert Ling saw the action of life as an electronic phase transition in proteins. When a small molecule would associate with a protein, the protein’s electrons would change positions relative to the environment around them (Footnote B). This makes the protein interact with the outside world in a vastly different way: it structures more or less water depending on the molecule’s presence. The structuring of the water changes the state of many more adjacent proteins.
If drugs work as Ling believed, drugs can cause a cascade of effects that changes the state of every protein in the cell.
Slices of this can be seen in epigenetics: drugs can cause vast epigenetic changes — altering the expression of hundreds of proteins — which extend far past the canonical “target.”
Positive-sum drugs would create cascades that cause the cell to enter the preferred metastable state, or would stabilize the preferred metastable state. I think candidates for positive-sum drugs include thyroid, naltrexone, glucose, carbon dioxide, caffeine, DHT, progesterone, and urea.
Positive-sum drugs create sustainable positive changes.
Zero-sum drugs create transient metastable states that vanish, or completely invert, once the drug is removed. Strong candidates include opioids.
Zero-sum drugs are unsustainable.
Both exist, and we should be making more positive-sum drugs. Nature is a good first place to look.
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Footnote A: More than 3 high-quality lifespan studies, including a higher mammal — dogs. Only Rapamycin has a similar level of research, but nothing in higher mammals yet.
Footnote B: This is a standard concept in organic chemistry, “induction,” which explains why trifluoroacetic acid is a stronger acid than acetic acid. In TFA, the fluorines pull electrons away from the acidic carboxylic group, and the hydrogen more readily dissociates. Ling argued adsorbed molecules can have inductive effects on proteins, thereby changing carbonyl, carboxyl, and amino group affinities for their respective counter-ions.