Peter R. Martin: Historical Vocabulary of Addiction, Vol. II

Inflammation

According to the electronic version of the Oxford English Dictionary (OED), the noun inflammation is a borrowing from Latin.  The word is derived from inflammātiōn-em which is a noun of action of the verb inflammāre (meaning “to set on fire”).  The Latin inflammāre is constructed from the prefix in- (“In combinations formed in Latin and frequently maintained through Old French… with the sense ‘in, into; to, towards’.”) combined with the noun flamma (meaning flame, defined as “Vapour heated to the point of combustion; ignited gas.”).

The meaning of inflammation that is most relevant to this discussion was derived from the field of Pathology.  The word was first used in the English language around 1541 and is defined in OED as: “A morbid process affecting some organ or part of the body, characterized by excessive heat, swelling, pain, and redness; also, a particular instance or occurrence of this.” 

A later definition of inflammation in OED may represent a psychological consequence of the previous (pathological) meaning or may simply be independent of that meaning: “The action of inflaming mentally, of firing the mind, passions, senses, etc. (…with liquor); the condition of being so inflamed; excitement, fervour.”  An early example of this psychological meaning of inflammation is from Henry IV by William Shakespeare (1564 –1616), the English playwright, poet and actor (Shakespeare 1600): “They are generally fooles and cowards, which some of vs should be too but for inflammation.”  This meaning of inflammation refers to temper, anger, passion or enhanced motivation or elevated mood, not necessarily any attempt to define the causation of these emotional states, which is the purpose of the present discussion.

Inflammation had been clinically described as a pathological concept well before it was first employed in English, as indicated by the well-known quotation of the Roman encyclopedist Aulus Cornelius Celsus (c.25 BCE – c.50 CE) in his treatise De Medicina, a primary source on diet, pharmacy, surgery and related fields and one of the best sources concerning medical knowledge in the Roman world (Celsus, Targa, Lee et al. 1836): “Notae vero inflammationis sunt quattuor: rubor [redness] et tumor [swelling] cum calore [heat] et dolore [pain].”   

A very early English example of this use of inflammationis by the diplomat and scholar Sir Thomas Elyot (c.1496 – 26 March 1546) in The Castel of Helth a popular treatise on medicine, intended to place a scientific knowledge of the art within the reach of those unacquainted with Greek (Elyot 1539): “Much sleepe augmenteth heate, more than is necessary, wherby hot fumes and inflamacions are often ingendred.”  This quote links the ideas of body heat and manifestation of fever with inflammation.

John Hunter (1728 –1793), a Scottish surgeon and early advocate of scientific methods in medicine, described in A treatise on the blood, inflammation, and gun-shot wounds (Hunter and Home 1794) his studies of the composition of blood derived through bloodletting of patients with various diseases.  He developed a novel theory that inflammation was a bodily responseto disease and was not itself pathological.  In one of his experiments, among the first to examine the pathophysiological changes in blood due to inflammation, he compared the rates at which blood corpuscles from individuals with and without inflammation sedimented (Russell 1939):  

“As the coagulation hinders any comparative experiment respecting the weight of the red globules of each, I tried to see if they sank in serum faster in the one kind of blood than in the other; I took the serum of inflammatory blood, with some of the red part, and also some serum of blood free from inflammation, with nearly the same quantity of the red part; they were put into phials of the same size; I shook them at the same time, then allowed them to stand quiet, and observed that the red globules subsided much faster in the inflammatory blood than in the other. To ascertain whether this arose from the red globules being heavier, or the serum lighter, I poured off the serum from each, as free from red blood as possible, then put the red part of the one into the serum of the other, and shook them to mix them well; and, upon letting them stand quiet, the red globules appeared to fall equally fast.”

These studies pointed to alterations in the molecular constituents of blood serum as a result of inflammation within the body, thereby advancing beyond and attempting to explain the clinical signs described by Celsus.  Moreover, Hunter provided the foundation for a method that is still employed with some modifications in the modern era as nonspecific evidence of the presence of inflammation in the body (Grzybowski and Sak 2011).

Nevertheless, for some years still, studies of inflammation relied mostly on clinical observation and did not go beyond the observations of Celsus as suggested by a quotation from John Thomson (1765–1846), president of the Royal College of Physicians of Edinburgh, who was considered “the most learned physician in Scotland,” in his Lectures on inflammation: exhibiting a view of the general doctrines, pathological and practical, of medical surgery (Thomson 1813):  “The term Inflammation has long been employed by medical men, to denote the existence of an unusual degree of redness, pain, heat, and swelling, in any of the textures or organs of which the human body is composed.”  The important point made by this quotation is that inflammation can occur anywhere in the body, complementing Hunter’s observation that inflammation is reflected in the composition of the blood.

It was not until the past century that the molecular mechanisms underpinning inflammation became the focus of research.  An early example of a molecular pathogenic process that is fundamental to how the clinical signs of inflammation arise is the alteration of capillary permeability that occurs in inflamed tissues (Spector 1958):

“The capillary wall is a barrier freely permeable to water and electrolytes but only very slightly permeable to protein.  The term “increased capillary permeability” therefore refers normally to an alteration in the capillary wall leading to an accelerated rate of passage of plasma proteins into the tissues… Increased capillary permeability is one of the cardinal features of acute inflammation, i.e., the local reaction of living tissue to injury.  It is in this and in other pathological states… and in relation to the mode of action of vaso-active compounds that the importance of the phenomenon lies.

This early interest in elucidating how capillary changes underpin inflammation remains vital to our understanding of the process and has continued to the present day (Hasegawa, Lee, Hotchen et al. 2024).

It seems quite intuitive that physical injury and infectious diseases can cause inflammation throughout the body expressed by the classical signs discussed above.  However, considering molecular inflammatory processes in the pathogenesis of mental disorders (not necessarily with any of the classical clinical signs of inflammation) is a relatively recent idea in the history of psychiatry (Müller 2024; Yirmiya 2024). 

An early example of the recognition that psychiatric illness and immune functions can influence each other is from the late 19th century.  The Austrian psychiatrist Julius Wagner-Jauregg (1857–1940) — the first psychiatrist to win the Nobel Prize in Physiology or Medicine in 1927 “for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica” — noticed that patients in a mental asylum were less likely to be infected with typhus, a bacterial disease spread by fleas and lice, than were their mentally healthy guards (Wagner von Jauregg 1926).  Emil Kraepelin (1856 –1926), the German psychiatrist considered the founder of modern scientific psychiatry, observed that in some of his patients influenza infection was a precursor of psychiatric symptoms (Kraepelin 1890). 

The varied neuropsychiatric signs of syphilis — now termed neurosyphilis and recognized to be due to systemic spread of T. pallidum infection to the central nervous system — were found in the early 20^th century to be among the most common causes for admissions to mental asylums (about one-third of admissions).  More recently, it was reported that 28% of acutely disturbed mentally ill patients admitted to a mental hospital had serum substances, probably protein, which were found to react immunologically with a brain constituent (Fessel 1962).  These observations were consistent with the idea that inflammatory (immune) responses within the central nervous system or elsewhere in the body may be expressed as mental disorders.

All the same, as a result of the serendipitous discoveries of lithium, chlorpromazine and imipramine in the middle of the 20^th century, research on these highly effective treatments for mental disorders came to the forefront as exciting opportunities for better understanding the pathogenesis of psychiatric diseases (Ban 1969).  As the presumed mechanism of action of these medications was via the biogenic amines, these neurotransmitters became the thrust of psychiatric research for several decades (Cooper, Bloom and Roth 1970) and the early insights concerning inflammation fell by the wayside for several decades. 

Interest in the role of inflammation in the pathogenesis of psychiatric disorders was eventually revived for a number of reasons.  Early studies that demonstrated interactions between biogenic amines and inflammatory processes naturally led the way in the direction of immunological mechanisms in mental disorders (Besedovsky, del Rey, Sorkin et al. 1983).  Second, it was recognized that immune responses to various viral infections could reproduce psychiatric symptoms, reminiscent of the observations originally made by Kraeplin (Cappel, Gregoire, Thiry et al. 1978; King and Cooper 1989).  Third, overlapping immunologic changes and psychopathologic manifestations were identified in individuals affected by chronic pain (Cahill and Taylor 2017) as well as depressive disorders (Sternbach 1975; Colpaert 1987; Irwin and Miller 2007).   Fourth, it was reported that treatment of patients, especially those with hepatitis, with certain immune modulating medications (antivirals) were often complicated by severe depressive symptoms (Yates and Gleason 1998; Leserman 2008).  Fifth, accumulating evidence from studies of molecular underpinnings of inflammatory processes suggested overlapping predisposing factors and pathophysiologic mechanisms were also involved in psychiatric disorders, in particular, depression (Schleifer, Keller, Meyerson et al. 1984; Kiecolt-Glaser, Derry and Fagundes 2015; Herzog, Bartlett, Zanderigo et al. 2023; Singh, Lee, Sealock et al. 2024).  Finally, autoimmune response to an anti-N-methyl-d-aspartate receptor (a synaptic autoimmune disorder in which IgG auto-antibodies recognize the GluN1 subunit of NMDAR) was reported in some individuals with psychosis (Dalmau, Tüzün, Wu et al. 2007).  This observation supported an important bridging notion in pathogenesis of psychiatric disorders — that abnormalities in either immune functioning or neurotransmitter (glutamatergic) signaling can have psychopathological consequences (Kayser and Dalmau 2016).

Stress responses within the body, widely studied in animals and humans, became linked to the neurobiology of mental illnesses (Martin, 2020, 2021b).  Stress resulted in activation of the hypothalamic-pituitary-adrenal axis and release into the circulation of steroids from the adrenals, which are also involved in regulation of inflammation (Selye 1955; Chrousos 1995). 

Genetic predispositions and epigenetic modifications can influence both inflammation and addiction risk as certain genetic variants may make individuals more susceptible to stress, inflammation and, thereby, to addictive behaviors (Gould 2023).  Various neuro-humeral responses to emotional or physical stressors have been demonstrated to influence immune functioning (Dantzer and Kelley 1989; Pawlikowski, Stepien and Komorowski 2010), and together, these have been proposed to play a role in pathogenesis and symptomatology of the majority of psychiatric disorders (Rubin and Mandell 1966; Atkinson, Kremer, Risch et al. 1983; Nemeroff and Evans 1989; Yirmiya 2024).  In particular, functioning of the hypothalamic-pituitary axis was reported to contribute to both the pathogenesis and clinical expression of depression (Carroll, Curtis and Mendels 1976).

Inflammation can play a significant role in alcoholism and drug use disorders and it can influence the development, progression, and consequences of these conditions (Crews, Zou and Qin 2011; Crews, Lawrimore, Walter et al. 2017; Mayfield, Ferguson and Harris 2013; Loftis and Janowsky 2014).  Moreover, any inflammatory effects are heightened when there is concomitant exposure to stress, which is a typical component of the addictive lifestyle (Wills, Schwartz, McGuffin et al. 2025).  

Chronic use of drugs like cocaine, methamphetamine and alcohol as well as some addictive behaviors have been associated with the release of pro-inflammatory cytokines and other inflammatory mediators.  These result in the activation of microglia, the resident immune cells in the central nervous system, a process that has been termed as neuroinflammation (Harricharan, Abboussi and Daniels 2017).  On the other hand, the effects of opioid use on the immune system can be rather more complex because these drugs can have both inflammatory and anti-inflammatory effects (Sibinga and Goldstein 1988; Butelman, Huang, Cathomas et al. 2024).  

Inflammatory molecules, as suggested above, can directly affect neurotransmitter systems (such as dopamine, serotonin and others) that are involved in reinforcement of behaviors via brain  circuits and conditioning (see Martin 2023, 2019), fundamental to addiction (Cazettes, Cohen, Yau et al. 2011). 

Changes in neuroinflammatory signaling can also result in neuronal injury (Erickson, Grantham, Warden et al. 2019; O’Sullivan, Malahias, Park et al. 2019) and disrupted functioning of brain regions involved in reward, decision-making, impulse control and affective regulation all of which contribute to the development and maintenance of addictive disorders (Koob and Volkow 2010; Melkumyan, Randall and Silberman 2025). 

Many individuals with alcohol/drug use disorders have multiple co-occurring conditions, most of which are potentially associated with inflammation.  These include psychiatric disorders such as depression and fear- and anxiety-based disorders (Michopoulos, Powers, Gillespie et al. 2017)and medical maladies like liver, cardiovascular and metabolic disorders, as well as chronic infections due to HIV and various forms of viral hepatitis often a complication of an addiction-associated lifestyle (Buch, Yao, Guo et al. 2011; Corcorran and Kim 2023).  These multiple contributory factors can synergize and result in intense systemic inflammation.

Pharmacologic actions of substances of abuse on the peripheral and central nervous systems can activate neuro-immune modulators (Chapman and Goodell 1964).  These pharmacological effects augment preexisting elevated brain cytokine concentrations due to various causes of systemic inflammation (see above) to enhance the severity of neuronal and behavioral expressions of individual vulnerability traits for development of destructive out-of-control self-administration of abused substances (Carmon, Haley, Parikh et al. 2023).  The resulting increases in levels of pro-inflammatory cytokines in the bloodstream can exacerbate health complications associated with many substances of abuse and also of behavioral addictions like over-eating (see Martin 2025).  For example, systemic inflammation can foster development of liver disease (such as alcoholic hepatitis and cirrhosis), atherosclerotic cardiovascular disease and neurodegenerative disorders (Kaltschmidt, Uherek, Volk et al. 1997; Brenner, Galluzzi, Kepp et al. 2013 ; Leal-Lassalle, Estévez-Vázquez, Cubero et al. 2025; Mohammad Hosseini, Khaleghzadeh‐Ahangar and Rahimi 2025).  Thus, the presence in an individual of comorbid mental and medical conditions with alcohol/drug use disorders can be interactive with the inflammatory state of the body and evolution of addictive disorders.

Systemic inflammatory cells can penetrate the central nervous system as a result of disruption of the blood-brain barrier by drugs of abuse (Northrop and Yamamoto 2015; Morris, Fernandes, Puri et al. 2018).  Such effects on the blood-brain barrier differ for different drugs of abuse, e.g., increased permeability as a result of chronic alcohol consumption is not due to alcohol alone but also to the associated nutritional deficits (Martin, Singleton and Hiller-Sturmhöfel 2003).  Thus, alcohol and drug associated compromise of the integrity of the blood-brain barrier allows peripheral immune cells and inflammatory mediators to enter the brain more easily and thereby, can augment neuroinflammation and enhance the associated brain injury noted above.  

Another pathophysiological mechanism that can influence the interaction of brain/immune functioning associated with alcohol/drug use disorders involves the gut-brain axis (Morris, Voon and Leggio 2018; Qin, Hu, Wan et al. 2021).  The gut-brain axis is an interactive communication system between the brain and the gastrointestinal tract which involves neural, hormonal and immunological networks, increasingly recognized to be influenced by the microbial constituents of the gut, or microbiota (Cryan, O’Riordan, Cowan et al. 2019).

The gut-brain axis helps maintain homeostasis and can influence many aspects of the clinical course of alcohol/drug use disorders.  For example, chronic alcohol consumption can disrupt the gut microbiota, leading to dysbiosis and increased gut permeability.  This can result in the translocation of bacterial endotoxins into the bloodstream, triggering systemic inflammation and affecting brain function as indicated above.  Drug use can also modify gut microbiota and gut-brain axis, leading to similar inflammatory effects which can influence addiction-related behaviors.

In summary, there is a complex and bidirectional relationship between inflammation and addictive disorders with respect to both the pathogenesis and treatment of each.  Specifically, addressing either one via prevention or treatment approaches can improve outcomes for both.  For example, addressing both addiction and inflammation can be accomplished through healthful modifications of lifestyle (Martin 2021a,c, 2025) and more specific approaches aimed at stress reduction (Buchowski, Meade, Charboneau et al. 2011; Kohno, Link, Dennis et al. 2019).  

Recent research on pharmacological treatment of addiction has revealed that medications such as the glucagon-like peptide-1 (GLP-1) receptor agonists developed initially for treatment of obesity may also have significant benefits in management of alcohol and drug use disorders as well as of the many comorbid conditions that enhance inflammatory insults (Drucker 2024).  Importantly, addiction treatment is best delivered in combination with an integrated pharmacopsychosocial approach which incorporates and must highlight lifestyle changes (Martin, Weinberg and Bealer 2007).  Further research is needed to fully understand the role of inflammatory mechanisms in addictive disorders, which have historically been considered independent of each other, but now are recognized to be synergistic and requiring novel interventions that target both realms.

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February 20, 2025