Adrenaline

Adrenaline
Abbreviation	ADR, EPI
Molecular formula	C₉H₁₃NO₃
Type	Catecholamine (hormone and neurotransmitter)
Administration
Bioavailability
Synonyms	(−)-Adrenalinem L-Adrenaline, Epinephrine, Eppy, Adrenalin (brand name), (R)-(−)-3,4-Dihydroxy-α-[(methylamino)methyl]benzyl alcohol
Source	Produced by adrenal medulla, Small amounts also synthesized in certain neurons in the central nervous system Medicinal/commercial source: synthetic or formerly extracted from animal adrenal glands
Ray's verdict	Acute adrenaline with adequate thyroid = adaptive and beneficial. Chronic adrenaline compensating for low thyroid = destructive. The problem isn't adrenaline itself, it's the metabolic context forcing its overproduction.

Introduction

Adrenaline, also known as epinephrine, is one of the body's principal catecholamine hormones and neurotransmitters. It is the classic "fight or flight" hormone, produced primarily in the adrenal medulla and released during acute stress. While often portrayed as purely stimulatory, adrenaline's effects are highly context-dependent, with small amounts producing different physiological outcomes than large amounts.

History/Etymology

The samurai chemist Jokichi Takamine (1854-1922) crystallized adrenalin, the first hormone to be isolated in the twentieth century, from the adrenal medulla, in the summer of 1900.

The active principle of suprarenal extract that produces its pressor effects was isolated by the joint research of John Abel in 1899 and Jokichi Takamine in 1901. This active principle was referred to by British physiologists as "adrenaline" and named "Adrenalin" by Takamine, and it was discovered to be released from sympathetic nerve terminals to act on smooth muscle cells.

However, it was not until 1946 that von Euler showed that demethylated adrenaline (noradrenaline) rather than adrenaline is a sympathetic transmitter.

The name "adrenaline" derives from the Latin ad (near) + renes (kidneys), referring to the adrenal glands sitting atop the kidneys. "Epinephrine" comes from the Greek epi (upon) + nephros (kidney). The dual naming persists due to trademark disputes; in the United States, "epinephrine" is preferred in medical contexts, while "adrenaline" remains common in British and international usage.

Structure/Chemical properties

Adrenaline is classified as a catecholamine, a class of molecules containing a catechol group (a benzene ring with two hydroxyl groups) and an amine side chain. Its molecular formula is C₉H₁₃NO₃, with a molecular weight of approximately 183 g/mol.

Biosynthesis pathway:

Julius Axelrod described the catecholamine synthesis pathway in his Nobel Prize work. All catecholamines are synthesized from the amino acid L-tyrosine according to the following sequence:

1. L-Tyrosine → L-DOPA (via tyrosine hydroxylase, the rate-limiting enzyme)
2. L-DOPA → Dopamine (via DOPA decarboxylase)
3. Dopamine → Noradrenaline (via dopamine-β-hydroxylase)
4. Noradrenaline → Adrenaline (via phenylethanolamine N-methyltransferase, or PNMT)

The enzyme PNMT, which methylates noradrenaline to form adrenaline, is "highly localized in the adrenal gland" according to Julius Axelrod's research.

Metabolism:

Adrenaline is metabolized through two primary pathways:

"As a result of these and other experiments, it was proposed that adrenaline or noradrenaline was metabolized by two pathways: the first by O-methylation via catechol-O-methyltransferase (COMT) which I isolated and characterized, and the other by deamination by monoamine oxidase."

After intravenous injection, epinephrine is rapidly metabolized, with a precipitous fall in plasma levels within 5 minutes. The O-methylated metabolite metanephrine is produced quickly, reaching peak plasma levels within 2 minutes after injection.

Function/Mechanism of Action

"The adrenaline system has been maligned; it's the fight or flight immediate response stress hormone, but it does activate other stress hormones, cortisol and so on. So it can, if it persists, be harmful. But the history of maligning that has led people to overemphasize the opposite parasympathetic part of the nervous system." - Ray Peat

Adrenaline is central to the sympathetic nervous system's acute stress response.

Key mechanisms:

1. Blood sugar regulation: When blood sugar falls, "the first reaction is for adrenaline to increase to try to squeeze more glycogen into your circulation for your brain primarily. And when the glycogen is absolutely gone, the adrenaline keeps activating the breakdown of fat and provides increased amounts of circulating fat to make up for the lack of sugar."
2. Mitochondrial effects: On the cellular level, "adrenaline increases the rate of oxygen consumption" while acetylcholine increases efficiency of energy conservation. Critically, "the effects of a little adrenaline, and a lot of adrenaline, are very different, with a high concentration of adrenaline decreasing the efficiency of phosphorylation."
3. Anti-proliferative effects: "Adrenaline, and the sympathetic nerves, have the opposite function [to the parasympathetic], of restraining cell division, and they also oppose the pro-inflammatory functions of those parasympathetic agents."
4. Compensatory role in hypothyroidism: Low thyroid function leads to chronically elevated adrenaline. Ray Peat has observed that hypothyroid individuals can produce "30 or 40 times more adrenaline than normal," using this as emergency compensation for low cellular energy.

Medical uses/Effects

Emergency applications:

Adrenaline injections directly into the heart remain "the only currently approved treatment for cardiac arrest." However, research has revealed complications: "This new study found that it is actually the adrenaline administered as part of the revival protocol that damaged the brain. The adrenaline group did have a higher survival rate, so its use in this case is probably justified." Alternative protocols combining adrenaline with progesterone or T3 have been proposed to mitigate brain damage.

Cardiovascular effects:

"In the stressed heart, this effect of excess adrenaline can be fatal, especially when it is combined with adrenaline's acceleration of clotting, liberation of fatty acids, and frequently of calcium, and constriction of blood vessels."

Ray Peat notes: "Under some conditions adrenaline does increase circulation to the heart, but extreme stress doesn't seem to be among those conditions."

Adrenaline in heart disease:

"Adrenaline chronically contributes to this sickness field by elevating the levels of free fatty acids, and adrenaline itself is also a negatively ionotropic hormone."

Dosing

Standard emergency doses of epinephrine for cardiac arrest typically range from 0.3-0.5 mg intramuscularly for anaphylaxis, with 1 mg IV given every 3-5 minutes during cardiac resuscitation protocols.

However, context matters enormously. As discussed above, large doses have fundamentally different effects than small doses, with high concentrations actually decreasing phosphorylation efficiency in stressed tissues.

Side/Adverse effects

Acute effects of excess adrenaline:

The harmful effects of elevated adrenaline relate largely to its mobilization of free fatty acids (FFA). "Prior studies (and Peat's articles) have established that other organ damage is most likely caused by the elevation of FFA driven by adrenaline."

Excess adrenaline can cause:

• Coronary artery spasms
• Cardiac arrhythmias
• Accelerated blood clotting
• Increased intracellular calcium (excitotoxicity)
• Vasoconstriction
• Neurological damage (in acute high-dose situations)
• Impaired mitochondrial respiration

Chronic elevation:

Chronically elevated adrenaline, typically seen in hypothyroidism, creates what Ray Peat calls a "high adrenaline state" that "creates a terrible amount of confusion among doctors and patients both because as an adaptation it makes people feel like they're on speed sometimes."

This leads to:

• Insomnia and sleep disturbances
• Anxiety and irritability
• Depression
• Tissue catabolism (via secondary cortisol elevation)
• Accelerated aging

"When you have been in that low thyroid state too long, you are living on adrenaline and cortisone which are destroying all of your essential tissues."

Managing excess adrenaline:

Ray Peat recommends several strategies for reducing chronically elevated adrenaline:

1. Sugar and Salt: "Sugar and salt happen to be two of the nutrients that will limit uncontrolled production of the adrenaline system."
2. Thyroid Support: Correcting hypothyroidism reduces the compensatory need for adrenaline. However, "to prevent the overexcited adrenaline action, it takes weeks of adapting to a slowly increasing level of thyroid."
3. Magnesium: "Magnesium is one of the most important nutrients because when your thyroid function is slow and you're running on adrenaline, these cells are not making ATP quickly in the hypothyroid state. And the ATP is what holds magnesium in your cells."