Peter R. Martin: Historical Dictionary of Addiction
Tolerance

The noun tolerance originates from the French tolerance, first used in the 14^th century (Hatzfeld and Darmesteter: Dictionnaire général de la langue française, 1895-1900), which in turn was derived from the Latin verb tolerāre, to tolerate (OED Online 2017). The medical meaning of tolerance corresponds to one of the definitions of the word found in the Oxford English Dictionary, Third Edition, November 2010: “The power, constitutional or acquired, of enduring large doses of active drugs, or of resisting the action of poison, etc.; hence diminution in the response to a drug after continued use” (OED Online 2017). However, specific reference to diminished response to a drug or resistance to a poison is not the primary meaning of tolerance in the current OED, nor is it the earliest use of the word in history. Evolution of the meaning of the word is of interest in gaining understanding of its meaning in neuropsychopharmacology and with respect to addiction (Martin 2016).

The earliest recorded reference to the word tolerance in the English language, according to OED, occurred in Middle English in 1412-20 as tolleraunce (John Lydgate: History of Troy II. 7014, “Riȝt so convenient Is to þe wyse…with suffraunce, In al his port to haue tolleraunce”), where the word was employed in its original meaning: “The action or practice of enduring or sustaining pain or hardship; the power or capacity of enduring; endurance.” This very early reference to the word tolerance refers to elements of emotional life/experience (thoughts or inclinations) rather than the capacity of an individual for intake of an exogenous entity such as a pharmacological agent, especially a psychoactive drug. The currently used medical meaning of the word tolerance is attributed to Horatio Curtis Wood (1841-1920), the American physician, educator and editor in his pioneering contribution to medicine and science (A Treatise on Therapeutics, comprising Materia Medica and Toxicology, with especial reference to the application of the physiological action of drugs to clinical medicine, 1874: “By the aid of opiates and careful dilution a species of tolerance was often obtained for these heroic doses”). This mention of tolerance as a mechanism of the pharmacological action of a drug actually precedes establishment of pharmacology as a discipline by Wood’s student John Jacob Abel beginning in the 1890s (Swann 2017).  

The notion of tolerance as presented by Curtis Wood broadens understanding of pharmacology beyond simply pharmacognosy to elucidation of the interaction between a drug and the organism to which the drug is administered.  Accordingly, individual attributes, including both constitutional characteristics and neurobiological adaptations upon administration of a given drug over time, not chemical/physiological characteristics of the administered molecule alone, became the purview of pharmacology.  While the interaction of drug and host adds considerably to the scope of pharmacology, it is nevertheless incomplete. A further conceptual leap, especially relevant for the sub-discipline neuropsychopharmacology, involves another level of analysis, namely, the influence of the environmental milieu and its accommodation by brain mechanisms of the individual who is administered the pharmacological agent.

While recognizing that tolerance has these tripartite determinants, the term itself has been parsed and qualified in various ways (Martin and Patel 2017). The term can be readily dichotomized into: i) initial (also called innate) tolerance which refers to inter-individual variation in sensitivity to a drug (i.e., variations that are present before the first administration of drug to an individual) typically arising from genetic variation of receptors at which the drug acts or differences among individuals in drug absorption, metabolism, or excretion; and ii) acquired tolerance which refers to tolerance as a consequence to repeated drug exposure comprising pharmacokinetic, pharmacodynamic and learning-related components. The meaning of initial tolerance is not well understood and continues as an exciting area of research in elucidation of risk for drug use disorders or addiction. Acquired tolerance can occur due to identifiable changes in capacity of the organism to dispose of the drug or due to changes in pharmacological effect of the same amount of drug at its site of action.  The former, termed metabolic or pharmacokinetictolerance typically is due to induction of the enzyme systems responsible for biotransformation of a drug prior to elimination from the body resulting in shortened duration of presence of the drug at its site of action.  The latter, termed pharmacodynamic tolerance is typically due to changes in signal transduction at the site of action of the drug. Indeed, persistent adaptations to drug use both modify existing synapses and create new synapses, effectively “rewiring” the brain.  Pharmacodynamic tolerance also involves another element of tolerance which has been termed learned tolerance.  In behavioral tolerance, a form of learned tolerance, drug use results in compensatory changes in behavior that are not directly related to the pharmacologic action of the drug but rather to accommodation to drug effects through learning acquired while the person is intoxicated or in the environment in which the intoxication occurred.  Conditioned tolerance occurs when environmental cues associated with exposure to a drug induce preemptive, reflexive compensatory changes, called a conditioned opponent response. The influence of these adaptive brain mechanisms were addressed, parceled and integrated by Kalant and colleagues (1971) when they proposed the term behaviorally augmented tolerance as being preferable to dichotomizing tolerance into learned and physiological components.  Such long-lasting molecular and cellular adaptations of the brain are likely involved in the cravings and relapses that can occur in individuals with drug use disorders even long after drug use has ceased.

Changes in response to a psychoactive drug resulting from prior exposure(s) of which tolerance is a component, now commonly termed neuroadaptation (American Psychiatric Association, 1987), have become understood as neurobiologically related to learning and memory formation (Kalant, LeBlanc and Gibbins 1971). Thus, exposure to drugs alters the individual and thereby the individual’s experience of the environment in which the drug is administered.  The current century’s scientific agenda of elucidating epigenetic factors in drug action and learning (Sweatt 2016; Francis et al. 1999) is the fruit of an early seed planted by Mendel, watered by Garrod and Galton and reaped by Scriver among others (Scriver and Clow 1980).  The term epigenetics was originally coined by Waddington in 1942 to describe the examination of “causal mechanisms” whereby “the genes of the genotype bring about phenotypic effects” (Waddington 2012). Epigenetic mechanisms are admirably suited to elucidate our understanding of the multi-faceted responses of the unique organism to different drugs of abuse within a given environment, including development of tolerance (Malvaez et al. 2009). Conceptualization of tolerance using these three interactive factors makes perfect sense, especially because this neuropharmacological action of drugs can play a fundamental role in drug use disorders (Martin 2016).  In fact, a tripartite model, historically derived from the epidemiologic perspective (agent/host/environment) of infectious diseases (Snow 1855), seems especially suited for drug use disorders because, contrary to other mental disorders, the causal agent (a drug of abuse) is of necessity defined. 

There continues to be a striking inconsistency between the meanings of the word tolerance in medical/scientific and other realms. The original (non-medical) understanding of tolerance is of a positive attribute, the power or capacity to endure pain or suffering, presumably strength of character.  However, tolerance in the medical sense, a diminution in the response to a pharmacologic agents after continued use, especially drugs that possess dependence liability, does not necessarily connote a desired characteristic and may be considered to bear stigma if associated with addiction (Martin 2016).  Although in some cultures the capacity to “drink someone under the table” is viewed as a sign of masculinity and strength, presumably a positive attribute, there is accumulating research indicating that increased innate tolerance to central nervous system depressants, such as alcohol, actually may represent a significant risk factor for development of alcoholism (Schuckit and Rayses 1979).  Hence, while the earliest uses of the word tolerance connoted positive attributes strongly linked to mystical or religious contexts and even may have involved psychoactive agents, by the 20^th century, the description in medical science of a syndrome of self-destructive and out-of-control self-administration of various neuropsychopharmacological agents (Nathan, Conrad and Skinstad 2016) of which tolerance is an important mechanistic component has perhaps shed a new light on the debate about whether tolerance to drugs of abuse is good or bad.

REFERENCES:

American Psychiatric Association (1987). American Psychatric Association: Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Washington, DC.

Francis, D., Diorio, J., Liu, D., & Meaney, M. J. (1999). Nongenomic Transmission Across Generations of Maternal Behavior and Stress Responses in the Rat. Science, 286, 1155.

Kalant, H., LeBlanc, A. E., & Gibbins, R. J. (1971). TOLERANCE TO, AND DEPENDENCE ON, SOME NON-OPIATE PSYCHOTROPIC DRUGS. Pharmacological Reviews, 23, 135.

Malvaez, M., Barrett, R. M., Wood, M. A., & Sanchis-Segura, C. (2009). Epigenetic mechanisms underlying extinction of memory and drug-seeking behavior. Mammalian Genome, 20, 612-623.

Martin, P. R. (2016). Historical Vocabulary of Addiction: Addiction. inhn.org/home/central-office-cordoba-unit/peter-r-martin-historical-vocabulary-of-addiction/addiction.html [On-line]. Available: inhn.org.

Martin, P. R. & Patel, S. (2017). Pharmacology of drugs of abuse. In D.E.Golan, E. J. Armstrong, & A. W. Armstrong (Eds.), Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy (Fourth ed., pp. 308-334). Philadelphia: Wolters Kluwer Health.

Nathan, P. E., Conrad, M., & Skinstad, A. H. (2016). History of the Concept of Addiction. Annual Review of Clinical Psychology, 12, 29-51.

OED Online (2017). "tolerance, n.". www.oed.com/view/Entry/202979 [On-line].

Schuckit, M. A. & Rayses, V. (1979). Ethanol Ingestion: Differences in Blood Acetaldehyde Concentrations in Relatives of Alcoholics and Controls. 203, 54-55.

Scriver, C. R. & Clow, C. L. (1980). Phenylketonuria: Epitome of Human Biochemical Genetics. New England Journal of Medicine, 303, 1336-1342.

Snow, J. (1855). On the Mode of Communication of Cholera. (2nd ed.) London: John Churchill.

Swann, J. P. (2017). Wood, Horatio C, Jr. American National Biography Online (Feb.2000) [On-line]. Available: www.anb.org/articles/12/12-00998.html.

Sweatt, J. D. (2016). Neural plasticity and behavior -  sixty years of conceptual advances. Journal of Neurochemistry, 139, 179-199.

Waddington, C. H. (2012). The Epigenotype. International Journal of Epidemiology, 41, 10-13.

February 1, 2018