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Summary
Many aspects of health and disease are modeled using the abstraction of a “pathway”—a
set of protein or other subcellular activities with specified functional linkages
between them. This metaphor is a paradigmatic case of a deterministic, mechanistic
framework that focuses biomedical intervention strategies on altering the members
of this network or the up-/down-regulation links between them—rewiring the molecular
hardware. However, protein pathways and transcriptional networks exhibit interesting
and unexpected capabilities such as trainability (memory) and information processing
in a context-sensitive manner. Specifically, they may be amenable to manipulation
via their history of stimuli (equivalent to experiences in behavioral science). If
true, this would enable a new class of biomedical interventions that target aspects
of the dynamic physiological “software” implemented by pathways and gene-regulatory
networks. Here, we briefly review clinical and laboratory data that show how high-level
cognitive inputs and mechanistic pathway modulation interact to determine outcomes
in vivo. Further, we propose an expanded view of pathways from the perspective of basal cognition
and argue that a broader understanding of pathways and how they process contextual
information across scales will catalyze progress in many areas of physiology and neurobiology.
We argue that this fuller understanding of the functionality and tractability of pathways
must go beyond a focus on the mechanistic details of protein and drug structure to
encompass their physiological history as well as their embedding within higher levels
of organization in the organism, with numerous implications for data science addressing
health and disease. Exploiting tools and concepts from behavioral and cognitive sciences
to explore a proto-cognitive metaphor for the pathways underlying health and disease
is more than a philosophical stance on biochemical processes; at stake is a new roadmap
for overcoming the limitations of today’s pharmacological strategies and for inferring
future therapeutic interventions for a wide range of disease states.
The bigger picture
Disorders ranging across drug addiction, injury, and cancer have proven difficult
to definitively repair by focusing on the molecular hardware inside cells. Drug design
and genomic editing face fundamental limitations of context, complexity, and cellular
resistance. Fortunately, computer science and behavioral science are beginning to
point the way to a transformative regenerative medicine in which pharmaceutical efforts
focused on molecules will be complemented by top-down approaches that exploit the
collective intelligence of cells and the native control mechanisms that establish
form and function.
Powerful methods of controlling complex body systems include taking advantage of their
newly discovered cognitive properties: memory, problem solving, and reprogrammability.
Emerging advances in placebo research, non-neural bioelectric networks, and the diverse
intelligence of cells, tissues, and organs suggest that the medicine of the future
may look more like a kind of somatic psychiatry than chemistry or genetics. Therapeutic
interventions will communicate and behavior-shape body processes, exploiting the software
of life for novel solutions to disease, injury, and aging.
Abstract
Biomedical approaches that target cellular pathways as hardwired mechanisms face significant
limitations with safety and efficacy. Here, we provide a framework for recognizing
and exploiting the proto-cognitive aspects of molecular networks and cell behavior.
This enables top-down control of complex system-level functions through the use of
tools and concepts adapted from cybernetics and behavioral neuroscience. Through recognizing
the learning capacities of cellular pathways and their sensitivity to high-level cognitive
context, biomedical problems ranging across addiction, pharmaceutical resistance,
and regeneration after injury can be addressed.
Adaptation in the face of potentially stressful challenges involves activation of neural, neuroendocrine and neuroendocrine-immune mechanisms. This has been called "allostasis" or "stability through change" by Sterling and Eyer (Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition and Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an essential component of maintaining homeostasis. When these adaptive systems are turned on and turned off again efficiently and not too frequently, the body is able to cope effectively with challenges that it might not otherwise survive. However, there are a number of circumstances in which allostatic systems may either be overstimulated or not perform normally, and this condition has been termed "allostatic load" or the price of adaptation (McEwen and Stellar, Arch. Int. Med. 1993; 153: 2093.). Allostatic load can lead to disease over long periods. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. Examples will be given for each type of allostatic load from research pertaining to autonomic, CNS, neuroendocrine, and immune system activity. The relationship of allostatic load to genetic and developmental predispositions to disease is also considered.
This paper presents a biopsychological theory of drug addiction, the 'Incentive-Sensitization Theory'. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether 'wanting' drugs (drug craving) is attributable to 'liking' drugs (to the subjective pleasurable effects of drugs)? The theory posits the following. (1) Addictive drugs share the ability to enhance mesotelencephalic dopamine neurotransmission. (2) One psychological function of this neural system is to attribute 'incentive salience' to the perception and mental representation of events associated with activation of the system. Incentive salience is a psychological process that transforms the perception of stimuli, imbuing them with salience, making them attractive, 'wanted', incentive stimuli. (3) In some individuals the repeated use of addictive drugs produces incremental neuroadaptations in this neural system, rendering it increasingly and perhaps permanently, hypersensitive ('sensitized') to drugs and drug-associated stimuli. The sensitization of dopamine systems is gated by associative learning, which causes excessive incentive salience to be attributed to the act of drug taking and to stimuli associated with drug taking. It is specifically the sensitization of incentive salience, therefore, that transforms ordinary 'wanting' into excessive drug craving. (4) It is further proposed that sensitization of the neural systems responsible for incentive salience ('for wanting') can occur independently of changes in neural systems that mediate the subjective pleasurable effects of drugs (drug 'liking') and of neural systems that mediate withdrawal. Thus, sensitization of incentive salience can produce addictive behavior (compulsive drug seeking and drug taking) even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family. We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.
Deaths involving synthetic opioids other than methadone (synthetic opioids), which largely consist of illicitly manufactured fentanyl; psychostimulants with abuse potential (e.g., methamphetamine); and cocaine have increased in recent years, particularly since 2013 ( 1 , 2 ). In 2019, a total of 70,630 drug overdose deaths occurred, corresponding to an age-adjusted rate of 21.6 per 100,000 population and a 4.3% increase from the 2018 rate (20.7) ( 3 ). CDC analyzed trends in age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, heroin, and prescription opioids during 2013–2019, as well as geographic patterns in synthetic opioid- and psychostimulant-involved deaths during 2018–2019. From 2013 to 2019, the synthetic opioid-involved death rate increased 1,040%, from 1.0 to 11.4 per 100,000 age-adjusted (3,105 to 36,359). The psychostimulant-involved death rate increased 317%, from 1.2 (3,627) in 2013 to 5.0 (16,167) in 2019. In the presence of synthetic opioid coinvolvement, death rates for prescription opioids, heroin, psychostimulants, and cocaine increased. In the absence of synthetic opioid coinvolvement, death rates increased only for psychostimulants and cocaine. From 2018 to 2019, the largest relative increase in the synthetic opioid-involved death rate occurred in the West (67.9%), and the largest relative increase in the psychostimulant-involved death rate occurred in the Northeast (43.8%); these increases represent important changes in the geographic distribution of drug overdose deaths. Evidence-based prevention and response strategies including substance use disorder treatment and overdose prevention and response efforts focused on polysubstance use must be adapted to address the evolving drug overdose epidemic. Drug overdose deaths were identified in the National Vital Statistics System multiple cause-of-death mortality files* by using International Classification of Diseases, Tenth Revision (ICD-10) underlying cause-of-death codes X40–44 (unintentional), X60–64 (suicide), X85 (homicide), or Y10–14 (undetermined intent). Drug categories were defined using the following ICD-10 multiple cause-of-death codes: synthetic opioids other than methadone (T40.4), psychostimulants with abuse potential (T43.6), cocaine (T40.5), prescription opioids (T40.2 or T40.3), and heroin (T40.1). Deaths involving more than one type of drug were included in the rates for each applicable drug category; categories are not mutually exclusive. † Annual age-adjusted death rates § were examined during 2013–2019 and stratified by drug category and synthetic opioid coinvolvement. The percentage of 2019 drug overdose deaths and change in 2018–2019 age-adjusted death rates involving synthetic opioids and psychostimulants were examined by U.S Census region ¶ and state. States with inadequate drug specificity, too few deaths to calculate stable estimates, or too few deaths to meet confidentiality requirements were excluded from state-level analyses.** ,†† Analyses of rate changes used z-tests when deaths were ≥100 and nonoverlapping confidence intervals based on a gamma distribution when deaths were 80% of drug overdose death certificates named at least one specific drug in 2019 and ≥10 deaths occurred in 2019 in the specific drug category. † Rate per 100,000 population age-adjusted to the 2000 U.S. standard population using the vintage year population of the data year. § Z-tests were used if the number of deaths was ≥100 in both 2018 and 2019, and p 80% of drug overdose death certificates named at least one specific drug in 2018 and 2019 and ≥20 deaths occurred during 2018 and 2019 in the drug category examined. †† Deaths were classified using the International Classification of Diseases, Tenth Revision. Drug overdoses are identified using underlying cause-of-death codes X40–X44 (unintentional), X60–X64 (suicide), X85 (homicide), and Y10–Y14 (undetermined). §§ Drug overdose deaths, as defined, that involve synthetic opioids other than methadone (T40.4). ¶¶ Drug overdose deaths, as defined, that involve psychostimulants with abuse potential (T43.6). *** Because deaths might involve more than one drug, some deaths are included in more than one category. In 2019, 6.3% of drug overdose deaths did not include information on the specific type of drug(s) involved. The figure is a series of maps showing percent and relative change in age-adjusted rates of drug overdose deaths involving synthetic opioids other than methadone and psychostimulants with abuse potential in the United States during 2013–2019. From 2018 to 2019, the age-adjusted synthetic opioid-involved death rate increased 15.2%, from 9.9 to 11.4. In 2019, the Northeast had the highest percentage and rate of deaths involving synthetic opioids, but the smallest relative (5.2%) and absolute (1.0) rate increases from the previous year (19.1 in 2018 to 20.1 in 2019). In contrast, the West experienced the largest relative (67.9%) and absolute (1.9) rate increases from 2.8 in 2018 to 4.7 in 2019. From 2018 to 2019, a total of 20 states experienced relative increases in their synthetic opioid-involved death rate, with the highest rate in 2019 in Delaware (38.4). The largest relative rate increase occurred in Colorado (95.5%), and the largest absolute rate increase occurred in the District of Columbia (7.6). No state experienced a significant decrease. The percentage of deaths involving psychostimulants was highest in the West (43.5%) and lowest in the Northeast (7.9%) in 2019. The same geographic pattern was observed with psychostimulant-involved deaths that did not coinvolve synthetic opioids. In all northeastern states, fewer than 20% of drug overdose deaths involved psychostimulants. In 12 states, mostly in the West and Midwest, ≥40% of overdose deaths involved psychostimulants. Among these, the percentage was highest in Hawaii (70.2%) and Oklahoma (50.7%). The percentage was lowest in Maryland (3.3%). From 2018 to 2019, the age-adjusted rate of psychostimulant-involved deaths increased 28.2%, from 3.9 to 5.0. The Northeast experienced the largest relative (43.8%), but smallest absolute (0.7), rate increase. The Midwest (36.1%) and South (32.4%) experienced similar relative but slightly larger absolute (1.3 and 1.2, respectively) rate increases. Although the percentage of 2019 drug overdose deaths involving psychostimulants was highest in the West, the relative rate increase (17.5%) was lowest there. Twenty-four states experienced an increase in the rate of psychostimulant-involved deaths. Kansas experienced the largest relative increase (107.1%) and third largest absolute rate increase (3.0). West Virginia had the highest 2019 rate (24.4) and the largest absolute rate increase (5.1); New York had the lowest 2019 rate (1.3). No state had a significant decrease (Supplementary Table, https://stacks.cdc.gov/view/cdc/101757). Discussion In 2019, a total of 70,630 drug overdose deaths occurred in the United States; approximately one half involved synthetic opioids. From 2013 to 2019, the age-adjusted synthetic opioid death rate increased sharply by 1,040%, from 1.0 to 11.4. Death rates involving prescription opioids and heroin increased in the presence of synthetic opioids (from 0.3 to 1.8 and from 0.1 to 2.7, respectively), but not in their absence. Death rates involving psychostimulants increased 317% overall, regardless of synthetic opioid coinvolvement. Synthetic opioid- and psychostimulant-involved deaths shifted geographically from 2018 to 2019. From 2015 to 2016, states in the East had the largest increases in deaths involving synthetic opioids, and from 2016 to 2017, the Midwest had the largest increases in deaths involving psychostimulants ( 2 , 4 ). In contrast, from 2018 to 2019, the largest relative increase in death rates involving synthetic opioids occurred in the West (67.9%); the largest relative increase in death rate involving psychostimulants occurred in the Northeast (43.8%). Sharp increases in synthetic opioid- and psychostimulant-involved overdose deaths in 2019 are consistent with recent trends indicating a worsening and expanding drug overdose epidemic ( 1 , 2 , 4 – 6 ). Synthetic opioids, particularly illicitly manufactured fentanyl and fentanyl analogs, are highly potent, increasingly available across the United States, and found in the supplies of other drugs ( 7 , 8 ). Co-use of synthetic opioids with other drugs can be deliberate or inadvertent (i.e., products might be adulterated with illicitly manufactured fentanyl or fentanyl analogs unbeknownst to the user). Similarly, psychostimulant-involved deaths are likely rising because of increases in potency, availability, and reduced cost of methamphetamine in recent years ( 9 ). The increase in synthetic-opioid involved deaths in the West and in psychostimulant-involved deaths in the Northeast signal broadened geographic use of these substances, consistent with increases in the number of drug submissions to forensic laboratories in those regions during 2018–2019 ( 8 ). The findings in this report are subject to at least two limitations. First, forensic toxicology testing protocols varied by time and jurisdiction, particularly for synthetic opioids. Therefore, some of the increases in overdose deaths reported by drug categories could be attributed to the increases in testing as well as the use of more comprehensive tests. Second, geographic analyses excluded states with inadequate drug specificity or too few deaths to calculate stable rates. The worsening and expanding drug overdose epidemic in the United States now involves potent synthetic drugs, often in combination with other substances, and requires urgent action. As involved substances and geographic trends in drug overdose deaths change, timely surveillance and evidence-based prevention and response strategies remain essential. CDC’s Overdose Data to Action ¶¶ cooperative agreement funds health departments in 47 states, the District of Columbia, two territories, and 16 cities and counties to obtain high-quality, comprehensive, and timely data on fatal and nonfatal drug overdoses to inform prevention and response efforts. To help curb this epidemic, Overdose Data to Action strategies focus on enhancing linkage to and retention in substance use disorder treatment, improving prescription drug monitoring programs, implementing postoverdose protocols in emergency departments, including naloxone provision to patients who use opioids or other illicit drugs, and strengthening public health and public safety partnerships, enabling data sharing to help inform comprehensive interventions.*** Other approaches ††† should include expanded naloxone distribution and education that potent opioids might require multiple doses of naloxone, improved access to substance use disorder treatment (including medications for opioid use disorder or programs addressing polysubstance use), expanded harm reduction services, and continued partnerships with public safety to monitor trends in the illicit drug supply, including educating the public that drug products might be adulterated with fentanyl or fentanyl analogs unbeknownst to users. A comprehensive and coordinated approach from clinicians, public health, public safety, community organizations, and the public must incorporate innovative and established prevention and response strategies, including those focused on polysubstance use. Summary What is already known about this topic? Deaths involving synthetic opioids other than methadone, cocaine, and psychostimulants have increased in recent years. What is added by this report? From 2013 to 2019, the age-adjusted rate of deaths involving synthetic opioids other than methadone increased 1,040%, and for psychostimulants increased 317%. During 2018–2019, the largest relative increase in synthetic opioid-involved death rates occurred in the West (67.9%), and the largest relative increase in psychostimulant-involved death rates occurred in the Northeast (43.8%). What are the implications for public health practice? Evidence-based prevention and response strategies, including substance use disorder treatment and overdose prevention and response efforts focused on polysubstance use, must be adapted to address the changing drug overdose epidemic.
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