Serotonin

Serotonin
Abbreviation	5-HT (5-hydroxytryptamine)
Molecular formula	C₁₀H₁₂N₂O
Type	Monoamine neurotransmitter
Administration	Endogenously produced, SSRIs increase extracellular activity by blocking reuptake.
Bioavailability	Movement between brain and blood is bidirectional, serotonin injected into the brain quickly increased blood levels, free passage from brain into blood.
Synonyms	Thrombotonin, thrombocytin, enteramine, and 5-HT
Source	~90% is produced in the gut (tryptophan hydroxylase type 2), driven by gut bacteria. Brain serotonin is synthesized separately by tryptophan hydroxylase type 1. Free fatty acids displace tryptophan from albumin, increasing brain uptake and synthesis.
Ray's verdict	Negative. Serotonin inhibits mitochondrial respiration and is involved in torpor and hibernation. In hibernating animals, stress causes increased serotonin production; in humans, winter stress causes similar changes. Serotonin lowers temperature by decreasing metabolic rate. Cold, dark, and even minor stresses cause increased serotonin. A progesterone or thyroid deficiency, or estrogen and PUFA excess, causes serotonin to increase.

Introduction

Serotonin is a whole-body, primarily non-brain, primarily non-neuronal coordinator of energy metabolism according to shifts in demands for mitochondrial oxygen-dependent ATP production. Despite only ~2% being found in the brain, the "happiness chemical" narrative dominated after SSRI marketing began in 1987. Ray Peat has called the idea that serotonin is a "happy hormone" one of the most destructive myths of our society, strictly created as a marketing ploy by the pharmaceutical industry about 50–60 years ago.

History/Etymology

• 1935: Serotonin was first discovered but named enteramine because it was found in the gut. Enterocytes are gut cells; serotonin is a tryptophan-derived amine, hence "enteramine."
• 1948: Serotonin was independently discovered in blood with its role being to constrict blood vessels. It was named serotonin "sero" for serum (blood), and "tonin" for its regulation of vascular tone.
• 1951: It was discovered that enteramine and thrombotonin were a single substance.
• 1953: 5-hydroxytryptamine in the brain was discovered to be identical to the previously known enteramine, which causes the intestine to contract, and the vasoconstrictor substance named serotonin.
• 1950s: The blind diabetic researcher D.W. Woolley first associated serotonin with the brain by noting it as an anti-metabolite of LSD. This fascination with psychedelics produced the neurotransmitter-centric model of brain operations.
• 1987: SSRIs are approved, and SSRI marketing extracted the neurotransmitter role of serotonin from its historical scientific context, completely leaving out the original discoveries about peripheral serotonin.

Structure/Chemical properties

Serotonin, tryptophan, and melatonin all share a chemical structure known as an indole group. The indole structure is widely used by plants, animals, and the simplest organisms in some of the most basic functions of life, including photosynthesis, movement, perception, structural maintenance, and regulation of water. The excitability of its electron system makes it essential for the formation of the most highly interactive systems.

Antiserotonin drugs like lisuride and ondansetron are based on the same indole molecular structure that serotonin is, but are tuned in a different way by additives. For example, adding bromine produces bromocriptine.

Although serotonin is much more water-soluble than tryptophan, the positive charge of its ionized amino group can form a link with the negative charge of a phosphate group in cellular phospholipids (such as lecithin), allowing the pair to be very mobile in the lipophilic cytoplasm.

Function/Mechanism of Action

Serotonin acts as a "traffic cop" in the lungs. It is released in response to hypoxia, hypoxic segments of the lungs make more serotonin, which constricts blood vessels in those segments, redirecting blood away from poorly-oxygenated areas and into oxygen-rich segments. This is how we achieve efficient oxygen extraction with every breath.

It acts directly on serotonin receptors in the smooth muscle cells of the vasculature to cause them to contract, this is not a neuronal effect of serotonin.

"It's a defensive chemical everywhere. It's one of the primitive protective reactions, for example, in the bowel. It causes spasms that clean out the bowel when you eat something poisonous, and so it causes diarrhea and that's protective." - Ray Peat

Serotonin activates prolactin and cortisol. When you're low in thyroid, serotonin goes up, and TSH is partly increased by the rising serotonin. Low thyroid people very often have increased prolactin as well as TSH - those both are increased by rising serotonin.

Serotonin activates glycolysis, forming lactic acid. Excess lactic acid tends to decrease efficient energy production by interfering with mitochondrial respiration.

Medical uses/Effects

More in SSRIs

Serotonin itself has no therapeutic use. Rather, anti-serotonin drugs have the therapeutic applications:

"As a class, the serotonin antagonists have a very interesting place in pharmaceutical medicine, because the broad spectrum of their therapeutic activity suggests the great variety of problems caused by excess serotonin." - Ray Peat

Anti-serotonin drugs and their uses:

• Ondansetron - the most popular anti-nausea, antiserotonin drug
• Lisuride - used against diabetes, cancer, and other serious degenerative diseases; a non-hallucinogenic LSD equivalent
• Bromocriptine - an ergot-derived drug that cures pituitary tumors by blocking serotonin's stimulating effects
• Tianeptine (brand: Stablon) - a serotonin reuptake promoter (the opposite of SSRIs).
• LSD
• Lidocaine
• Cyproheptadine
• Famotidin

"It promotes the uptake of serotonin, so it's less active, and it turns out to have lots of beneficial effects on bodily health for arthritis and diabetes and lots of inflammatory things." - Ray Peat

You can even prevent sunburn with an antiserotonin drug.

Dosing

Don't

For anti-serotonin interventions:

• Cyproheptadine: ~1-4mg doses, titrated
• Famotidin: 10–20mg shown to inhibit serotonin synthesis and can treat serotonin syndrome

Side/Adverse effects

"Any excess of it produces nausea, diarrhea, high blood pressure, tumor growth, fibrosis, arthritis, dementia, and so on." - Ray Peat "Serotonin constricts limits perspectives... Calcification goes with contraction and micro-blood vessel damage in aging and stress is one of the things too much serotonin does." - Ray Peat

Acute serotonin syndrome:

Overdose with serotonin reuptake inhibitors, or with 5-hydroxytryptophan, can cause the sometimes fatal "serotonin syndrome." Symptoms can include tremors, altered consciousness, poor coordination, cardiovascular disturbances, and seizures. Treatment with anti-serotonin drugs can alleviate the symptoms and usually can prevent death.

Chronic excess serotonin (carcinoid syndrome model):

Symptoms include flushing, sweating (sometimes dark-colored), diarrhea, nausea, anxiety, reduced urination, muscle and joint pains, and in late stages very often cardiovascular disease (especially inflammation, fibroma, and calcification of the valves in the right side of the heart) and aggressive behavior and psychosis.

Other documented effects:

• Prolonged intestinal irritation causing fibrous deterioration of the valves on the right side of the heart and pulmonary artery hypertension
• Heart failure, hypertension, muscle hyperalgesia, some panic reactions
• Learned helplessness: "an excess of serotonin helps to create the state of learned helplessness"
• Violence and aggression: "In an epidemiological study, a record of violence was clearly associated with above-average blood serotonin levels"
• Emotional numbness, decreased libido and the ability to love