The term “hormesis” derives from Greek hórmēsis for “rapid motion, eagerness”, itself from ancient Greek hormáein to excite. The same Greek root provides the word hormone.

September 2, 2024
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Hormesis is a two-phased dose-response relationship to an environmental agent whereby low-dose amounts have a beneficial effect and high-dose amounts are either inhibitory to function or toxic. Within the hormetic zone, the biological response to low-dose amounts of some stressors is generally favorable. An example is the breathing of oxygen, which is required in low amounts (in air) via respiration in living animals, but can be toxic in high amounts, even in a managed clinical setting.

A low dose of a chemical agent may trigger from an organism the opposite response to a very high dose.

In toxicology, hormesis is a dose-response phenomenon to xenobiotics or other stressors. In physiology and nutrition, hormesis has regions extending from low-dose deficiencies to homeostasis, and potential toxicity at high levels. Physiological concentrations of an agent above or below homeostasis may adversely affect an organism, where the hormetic zone is a region of homeostasis of balanced nutrition. In pharmacology, the hormetic zone is similar to the therapeutic window.

  1. Mattson, M. P (2007). “Hormesis defined”. Ageing Research Reviews. 7 (1): 1–7. doi:10.1016/j.arr.2007.08.007. PMC 2248601. PMID 18162444.
  2. Hayes, D. P. (2007). “Nutritional hormesis”. European Journal of Clinical Nutrition. 61 (2): 147–159. doi:10.1038/sj.ejcn.1602507. ISSN 1476-5640. PMID 16885926.

The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include theophylline, digoxin, lithium, and warfarin.

  • Rang H, et al. (2015). “Pharmacokinetics”. Rang & Dale’s Pharmacology (8th ed.). Churchill Livingstone. p. 125. ISBN 978-0-7020-5362-7.

The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect. The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

  • Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). “Chapter 2: Pharmacodynamics”. Pharmacology Examination & Board Review (10th ed.). New York: McGraw-Hill Medical. p. 17. ISBN 978-0-07-178924-0. The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose–response curves.

Drug titration is the process of adjusting the dose of a medication for the maximum benefit without adverse effects. When a drug has a narrow therapeutic index, titration is especially important, because the range between the dose at which a drug is effective and the dose at which side effects occur is small. Some examples of the types of drugs commonly requiring titration include insulin, anticonvulsants, blood thinners, anti-depressants, and sedatives.

  • Maxwell S (2013). “Chapter 2: Therapeutics and Good Prescribing: Choosing a Dosing Regime”. In Walker BR, Colledge NR, Ralston SH, Penman ID (eds.). Davidson’s Principles and Practice of Medicine. Elsevier Health Sciences. p. 34. ISBN 978-0-7020-5103-6.
  • Schachter M, Pirmohamed M (2012). “General Pharmacology”. In Bennett PN, Brown MJ, Sharma P (eds.). Clinical Pharmacology (11 ed.). Elsevier. pp. 74–109. ISBN 978-0-7020-4084-9.
  • Roden DM (2014). “Chapter 5 : Principles of Clinical Pharmacology”. In Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J (eds.). Principles of Clinical Pharmacology (19th ed.). New York, NY: McGraw-Hill. ISBN 978-0-07-180215-4.
  • Olson KR, Anderson IB, Benowitz NL, Blanc PD, Clark RF, Kearney TE, Kim-Katz SY, Wu AH, eds. (11 December 2017). “Section III: Therapeutic Drugs and Antidotes”. Poisoning & Drug Overdose (7th ed.). New York, NY: McGraw-Hill. ISBN 978-0-07-183979-2.
  • Kruidering-Hall M, Campbell L (30 November 2017). “Chapter 27: Skeletal Muscle Relaxants”. In Katzung BG (ed.). Basic & Clinical Pharmacology (14th ed.). New York, NY: McGraw-Hill. ISBN 978-1-259-64115-2.

Titrating off of a medication instead of stopping abruptly is recommended in some situations. Glucocorticoids should be tapered after extended use to avoid adrenal insufficiency.

Drug titration is also used in phase I of clinical trials. The experimental drug is given in increasing dosages until side effects become intolerable. A clinical trial in which a suitable dose is found is called a dose-ranging study.

In the context of toxicology, the hormesis model of dose response is vigorously debated. The biochemical mechanisms by which hormesis works (particularly in applied cases pertaining to behavior and toxins) remain under early laboratory research and are not well understood.

Etymology

The term “hormesis” derives from Greek hórmēsis for “rapid motion, eagerness”, itself from ancient Greek hormáein to excite. The same Greek root provides the word hormone. The term “hormetics” is used for the study of hormesis. The word hormesis was first reported in English in 1943.

hormone (n.) “organic compound produced in animal bodies to regulate activity and behavior,” 1905, from Greek hormon “that which sets in motion,” present participle of horman “impel, urge on,” from horme “onset, impulse,” from PIE *or-sma-, from root *er- (1) “to move, set in motion.” Used by Hippocrates to denote a vital principle; modern scientific meaning coined by English physiologist Ernest Henry Starling (1866-1927). Jung used horme (1915) in reference to hypothetical mental energy that drives unconscious activities and instincts. Related: Hormones.

In Greek mythology, Horme (/ˈhɔːrmiː/; Ancient Greek: Ὁρμή) is the Greek spirit personifying energetic activity, impulse or effort (to do a thing), eagerness, setting oneself in motion, and starting an action, and particularly onrush in battle. She had an altar at Athens, where mainly the divine servants and relations of Zeus (including Pheme and Aidos, as well as Athena) had altars. Her opposite character is Aergia, a goddess of sloth and apathy. The word “horme” is also used to refer to the philosophical concept represented by the goddess.

  • Pausanias, Graeciae Descriptio 1.17.1
  • Cicero, P.G. Walsh (2000) On Obligations

The name ‘horme’ was adopted by Sir Percy Nunn, to refer to all the purposive behaviours (drives or urges) of an organism – whether conscious or not. He based this on a suggestion by Jung but saw it as having a wider significance than Jung’s idea of relating the term to psychological values. Maria Montessori made this a central point of her later thinking, stressing that the behaviour of the child was driven by an inner urge to self construct, to become the adult they were destined to be. This idea of the future drawing the child on (as opposed to child development being just driven by causality) was related to the Aristotelian concept of entelechy which would have formed an implicit part of her Thomist education as a devout Catholic. The concept, but not the name, has been developed by writers such as James Hillman where he applies the idea to adults and refers to it as ‘destiny’ or the individual’s daemon.

  • Nunn, P. (1923) Education: its data and first principles. London: Edward Arnold
  • Jung, C.G. (1916) Analytic Psychology. p. 348 footnote, as cited by Nunn
  • Montessori, M. (1948). The Absorbent Mind. Oxford: Clio
  • Stoops, J.A. (1987), “Maria Montessori: an intellectual portrait”, Paper presented at the AMS meeting in Boston, available from ERIC
  • Hillman, J. (1996) The Soul’s Code: in search of character and calling. New York: Random House

In On Obligations, Cicero contrasts horme with reason as one of two aspects of the soul. He seems to be using [clarification needed] where one would expect to see the word “passion” or “emotion″. In the Walsh translation it is rendered “appetite”.

  • Cicero, P.G. Walsh (2000) On Obligations

The Greek writer Arrian of Nicomedia owned a much-loved greyhound called Horme, whose character and name he recorded for posterity in his Kynēgetikos.

  • Arrian (1831). Arrian on coursing. Translated and with commentary by “A Graduate of Medicine”. London: J. Bohn. pp. 78–82.

References

A herma (Ancient Greek: ἑρμῆς, pl. ἑρμαῖ hermai), commonly herm in English, is a sculpture with a head and perhaps a torso above a plain, usually squared lower section, on which male genitals may also be carved at the appropriate height. Hermae were so called either because the head of Hermes was most common or from their etymological connection with the Greek word ἕρματα (érma, meaning blocks of stone), which originally had no reference to Hermes at all. The form originated in ancient Greece, and was adopted by the Romans (called mercuriae), and revived at the Renaissance in the form of term figures and atlantes.

  • Anatole Bailly, Abrégé du dictionnaire Grec-Français, Hachette, Paris, 1901, p. 361.
  • One or more of the preceding sentences incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). “Hermae“. Encyclopædia Britannica. Vol. 13 (11th ed.). Cambridge University Press. p. 365.

Origin

In the earliest times Greek divinities were worshipped in the form of a heap of stones or a shapeless column of stone or wood. In many parts of Greece there were piles of stones by the sides of roads, especially at their crossings, and on the boundaries of lands. The religious respect paid to such heaps of stones, especially at the meeting of roads, is shown by the custom of each passer-by throwing a stone on to the heap or anointing it with oil. Later there was the addition of a head and phallus to the column, which became quadrangular (the number four was sacred to Hermes).

  • Nicand. Ther. 150; Theophrast. Char. 16.
  • Paus. vii. 22. § 2; Aristoph. Plut. 1121, 1144; Hom. Od. xiv. 435, xix. 397; Athen. i. p. 16.

Uses

Herma with the head of Herakles (Hermherakles). Museum of Ancient Messene, Greece.
Herma with the head of Herakles (Hermherakles). Museum of Ancient Messene, Greece

In ancient Greece the statues were thought to ward off harm or evil, an apotropaic function, and were placed at crossings, country borders and boundaries as protection, in front of temples, near to tombs, outside houses, in the gymnasia, palaestrae, libraries, porticoes, and public places, at the corners of streets, on high roads as sign-posts, with distances inscribed upon them. Before his role as protector of merchants and travelers, Hermes was a phallic god, associated with fertility, luck, roads and borders. His name perhaps comes from the word herma, referring to a square or rectangular pillar of stone, terracotta, or bronze; a bust of Hermes’ head, usually with a beard, sat on the top of the pillar, and male genitals adorned the base. The surmounting heads were not, however, confined to those of Hermes; those of other gods and heroes, and even of distinguished mortals, were of frequent occurrence. In this case a compound was formed: Hermathena (a herm of Athena), Hermares (of Ares), Hermherakles (of Herakles), Hermaphroditus (of Aphrodite—not to be confused with the son of Hermes and Aphrodite with the same name, Hermaphroditus, who had the genitals of both sexes), Hermanubis, Hermalcibiades, and so on. In Athens, where the hermai were most numerous and most venerated, they were placed outside houses as apotropes for good luck. They would be rubbed or anointed with olive oil and adorned with garlands or wreaths. This superstition persists, for example the Porcellino bronze boar of Florence (and numerous others like it around the world), where the nose is shiny from being continually touched for good luck or fertility.

  • Brunck, Anal. 3.197, no. 234
  • The image of a youthful, beardless Hermes was a development of the 5th century BCE.
  • Thuc. 6.27; Aelian, Ael. VH 2.41; Suid. s.v. Pollux, 8.72; Athen. 10.437b
  • Theophrast. Char. 16; comp. Genesis 28.18, 22, 31.45-48
  • One or more of the preceding sentences incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). “Hermae“. Encyclopædia Britannica. Vol. 13 (11th ed.). Cambridge University Press. p. 365.

In Roman and Renaissance versions (termini), the body was often shown from the waist up. The form was also used for portrait busts of famous public figures, especially writers like Socrates and Plato. Anonymous female figures were often used from the Renaissance on, when herms were often attached to walls as decoration.

See also

Copilot says:

The terms “hormesis” and “hormone” are related through their roots and their roles in biological processes:

  1. Etymology: Both words derive from the Greek root “hormaein,” which means “to set in motion” or “to stimulate.” This reflects their fundamental roles in initiating and regulating biological responses.
  2. Biological Function:
  3. Adaptive Responses: Both hormesis and hormones involve adaptive responses. Hormesis triggers beneficial adaptive responses at low doses of stressors, while hormones regulate adaptive physiological processes to maintain homeostasis and respond to environmental changes.

In summary, while hormesis and hormones operate in different contexts, they share a common theme of stimulating and regulating biological functions to promote health and adaptation.

Copilot also says any similarity between hormetic and hermetic is primarily phonetic:

The words “horme” and “herme” have distinct meanings and origins, though they sound similar:

  1. Horme:
    • Etymology: Derived from the Greek word “hormē,” meaning “impulse” or “urge.”
    • Meaning: In psychology, horme refers to the innate drive or impulse that motivates behavior and action. It is often associated with the concept of instinctual energy that propels organisms towards goals or activities.
  2. Herme:

While “horme” pertains to psychological impulses, “herme” is connected to the mythological figure Hermes and concepts of boundaries and communication. The connection between them is primarily phonetic rather than conceptual (and said roughly the same for hormetic and hermetic).

hermetic (adj.) 1630s “dealing with occult science or alchemy,” from Latin hermeticus, from Greek Hermes, god of science and art (among other things), who was identified by Neoplatonists, mystics, and alchemists with the Egyptian god Thoth as Hermes Trismegistos “Thrice-Great Hermes,” who supposedly invented the process of making a glass tube airtight (a process in alchemy) using a secret seal. Hence, “completely sealed” (c. 1600, implied in hermetically).

Controversy

Hormesis suggests dangerous substances have benefits. Concerns exist that the concept has been leveraged by lobbyists to weaken environmental regulations of some well-known toxic substances in the US.

History

A form of hormesis famous in antiquity was Mithridatism, the practice whereby Mithridates VI of Pontus supposedly made himself immune to a variety of toxins by regular exposure to small doses. 

Mithridate and theriac, polypharmaceutical electuaries claiming descent from his formula and initially including flesh from poisonous animals, were consumed for centuries by emperors, kings, and queens as protection against poison and ill health.

In the Renaissance, the Swiss doctor Paracelsus said,

“All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison.“

German pharmacologist Hugo Schulz first described such a phenomenon in 1888 following his own observations that the growth of yeast could be stimulated by small doses of poisons. This was coupled with the work of German physician Rudolph Arndt, who studied animals given low doses of drugs, eventually giving rise to the Arndt–Schulz rule. Arndt’s advocacy of homeopathy contributed to the rule’s diminished credibility in the 1920s and 1930s.

The term “hormesis” was coined and used for the first time in a scientific paper by Chester M. Southam and J. Ehrlich in 1943 in the journal Phytopathology, volume 33, pp. 517–541.

In 2004, Edward Calabrese evaluated the concept of hormesis. Over 600 substances show a U-shaped dose–response relationship; Calabrese and Baldwin wrote: “One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria [of a U-shaped response indicative of hormesis]”

Examples

Carbon monoxide

Carbon monoxide is produced in small quantities across phylogenetic kingdoms, where it has essential roles as a neurotransmitter (subcategorized as a gasotransmitter). The majority of endogenous carbon monoxide is produced by heme oxygenase; the loss of heme oxygenase and subsequent loss of carbon monoxide signaling has catastrophic implications for an organism. In addition to physiological roles, small amounts of carbon monoxide can be inhaled or administered in the form of carbon monoxide-releasing molecules as a therapeutic agent.

Regarding the hormetic curve graph:

Oxygen

Many organisms maintain a hormesis relationship with oxygen, which follows a hormetic curve similar to carbon monoxide:

Physical exercise

Physical exercise intensity may exhibit a hormetic curve. Individuals with low levels of physical activity are at risk for some diseases; however, individuals engaged in moderate, regular exercise may experience less disease risk.

Mitohormesis

See also: Antioxidant § Health research

The possible effect of small amounts of oxidative stress is under laboratory research. Mitochondria are sometimes described as “cellular power plants” because they generate most of the cell’s supply of adenosine triphosphate (ATP), a source of chemical energy. Reactive oxygen species (ROS) have been discarded as unwanted byproducts of oxidative phosphorylation in mitochondria by the proponents of the free-radical theory of aging promoted by Denham Harman. The free-radical theory states that compounds inactivating ROS would lead to a reduction of oxidative stress and thereby produce an increase in lifespan, although this theory holds only in basic research. However, in over 19 clinical trials, “nutritional and genetic interventions to boost antioxidants have generally failed to increase life span.”

Whether this concept applies to humans remains to be shown, although a 2007 epidemiological study supports the possibility of mitohormesis, indicating that supplementation with beta-carotene, vitamin A or vitamin E may increase disease prevalence in humans.

Alcohol

Main articles: Alcohol consumption and health, Alcohol and cancer, and Alcohol and cardiovascular disease

Alcohol is believed to be hormetic in preventing heart disease and stroke, although the benefits of light drinking may have been exaggerated. The gut microbiome of a typical healthy individual naturally ferments small amounts of ethanol, and in rare cases dysbiosis leads to auto-brewery syndrome, therefore whether benefits of alcohol are derived from the behavior of consuming alcoholic drinks or as a homeostasis factor in normal physiology via metabolites from commensal microbiota remains unclear.

In 2012, researchers at UCLA found that tiny amounts (1 mM, or 0.005%) of ethanol doubled the lifespan of Caenorhabditis elegans, a roundworm frequently used in biological studies, that were starved of other nutrients. Higher doses of 0.4% provided no longevity benefit. However, worms exposed to 0.005% did not develop normally (their development was arrested). The authors argue that the worms were using ethanol as an alternative energy source in the absence of other nutrition, or had initiated a stress response. They did not test the effect of ethanol on worms fed a normal diet.

Methylmercury

In 2010, a paper in the journal Environmental Toxicology & Chemistry showed that low doses of methylmercury, a potent neurotoxic pollutant, improved the hatching rate of mallard eggs. The author of the study, Gary Heinz, who led the study for the U.S. Geological Survey at the Patuxent Wildlife Research Center in Beltsville, stated that other explanations are possible. For instance, the flock he studied might have harbored some low, subclinical infection and that mercury, well known to be antimicrobial, might have killed the infection that otherwise hurt reproduction in the untreated birds.

Radiation

Ionizing radiation

See also: Radiation hormesis

Hormesis has been observed in a number of cases in humans and animals exposed to chronic low doses of ionizing radiation. A-bomb survivors who received high doses exhibited shortened lifespan and increased cancer mortality, but those who received low doses had lower cancer mortality than the Japanese average.

In Taiwan, recycled radiocontaminated steel was inadvertently used in the construction of over 100 apartment buildings, causing the long-term exposure of 10,000 people. The average dose rate was 50 mSv/year and a subset of the population (1,000 people) received a total dose over 4,000 mSv over ten years. In the widely used linear no-threshold model used by regulatory bodies, the expected cancer deaths in this population would have been 302 with 70 caused by the extra ionizing radiation, with the remainder caused by natural background radiation. The observed cancer rate, though, was quite low at 7 cancer deaths when 232 would be predicted by the LNT model had they not been exposed to the radiation from the building materials. Ionizing radiation hormesis appears to be at work.

Chemical and ionizing radiation combined

No experiment can be performed in perfect isolation. Thick lead shielding around a chemical dose experiment to rule out the effects of ionizing radiation is built and rigorously controlled for in the laboratory, and certainly not the field. Likewise the same applies for ionizing radiation studies. Ionizing radiation is released when an unstable particle releases radiation, creating two new substances and energy in the form of an electromagnetic wave. The resulting materials are then free to interact with any environmental elements, and the energy released can also be used as a catalyst in further ionizing radiation interactions.

The resulting confusion in the low-dose exposure field (radiation and chemical) arise from lack of consideration of this concept as described by Mothersill and Seymory.

Nucleotide excision repair

Veterans of the Gulf War (1991) who suffered from the persistent symptoms of Gulf War Illness (GWI) were likely exposed to stresses from toxic chemicals and/or radiation. The DNA damaging (genotoxic) effects of such exposures can be, at least partially, overcome by the DNA nucleotide excision repair (NER) pathway. Lymphocytes from GWI veterans exhibited a significantly elevated level of NER repair. It was suggested that this increased NER capability in exposed veterans was likely a hormetic response, that is, an induced protective response resulting from battlefield exposure.

  • Latimer JJ, Alhamed A, Sveiven S, Almutairy A, Klimas NG, Abreu M, Sullivan K, Grant SG. Preliminary Evidence for a Hormetic Effect on DNA Nucleotide Excision Repair in Veterans with Gulf War Illness. Mil Med. 2020 Feb 13; 185(1–2):e47–e52. doi:10.1093/milmed/usz177. PMID 31334811; PMC PMC7353836.

Applications

Effects in aging

One of the areas where the concept of hormesis has been explored extensively with respect to its applicability is aging. Since the basic survival capacity of any biological system depends on its homeostatic ability, biogerontologists proposed that exposing cells and organisms to mild stress should result in the adaptive or hormetic response with various biological benefits. This idea has preliminary evidence showing that repetitive mild stress exposure may have anti-aging effects in laboratory models. Some mild stresses used for such studies on the application of hormesis in aging research and interventions are heat shock, irradiation, prooxidants, hypergravity, and food restriction. Such compounds that may modulate stress responses in cells have been termed “hormetins”.

Radiation controversy

Main article: Health effects of radon § Intentional exposure

The hypothesis of hormesis has generated the most controversy when applied to ionizing radiation. This hypothesis is called radiation hormesis. For policy-making purposes, the commonly accepted model of dose response in radiobiology is the linear no-threshold model (LNT), which assumes a strictly linear dependence between the risk of radiation-induced adverse health effects and radiation dose, implying that there is no safe dose of radiation for humans.

Nonetheless, many countries including the Czech Republic, Germany, Austria, Poland, and the United States have radon therapy centers whose whole primary operating principle is the assumption of radiation hormesis, or beneficial impact of small doses of radiation on human health. Countries such as Germany and Austria at the same time have imposed very strict antinuclear regulations, which have been described as radiophobic inconsistency.

The United States National Research Council (part of the National Academy of Sciences), the National Council on Radiation Protection and Measurements (a body commissioned by the United States Congress) and the United Nations Scientific Committee on the Effects of Ionizing Radiation all agree that radiation hormesis is not clearly shown, nor clearly the rule for radiation doses.

A United States-based National Council on Radiation Protection and Measurements stated in 2001 that evidence for radiation hormesis is insufficient and radiation protection authorities should continue to apply the LNT model for purposes of risk estimation.

A 2005 report commissioned by the French National Academy concluded that evidence for hormesis occurring at low doses is sufficient and LNT should be reconsidered as the methodology used to estimate risks from low-level sources of radiation, such as deep geological repositories for nuclear waste.

Policy consequences

Hormesis remains largely unknown to the public, requiring a policy change for a possible toxin to consider exposure risk of small doses.

  • Poumadere, M. (2003). Hormesis: public health policy, organizational safety and risk communication. Human & experimental toxicology, 22(1), 39-41

See also

References

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  2. Calabrese EJ (2014). “Hormesis: a fundamental concept in biology”. Microbial Cell. 1 (5): 145–9. doi:10.15698/mic2014.05.145. PMC 5354598. PMID 28357236.
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