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Biological factor, barrier 1 of 6

Chronic and toxic stress

Prolonged activation of the stress response damages health and impairs learning, memory, and self-regulation. Shonkoff and Garner (2012) describe how repeated childhood adversity alters development in brain regions tied to planning and emotional control.

Evidence

  • Original ACE study. Among 9,508 adults, more than half reported at least one adverse childhood experience. Four or more categories carried 4 to 12 times the risk of alcoholism, drug abuse, depression, and suicide attempt compared with none (Felitti et al., 1998).
  • Graded relationship. The study found that the more categories of childhood abuse or household dysfunction a person reported, the higher the risk of adult heart disease, substance use, depression, and early death (Felitti et al., 1998).

Note: The adverse childhood experiences studies are retrospective self-reports, so they show strong associations rather than direct measurements of stress.

What can be done

Actions rated on the strength-rating scale (A strong and replicated, B solid but limited, C weak or debated, D contested or failed), applied to the specific claim made.

  • Trauma-focused cognitive behavioral therapy for children exposed to trauma (A). A network meta-analysis of 70 randomized trials with 5,528 patients found a large reduction in post-traumatic stress symptoms compared with no treatment (Hedges g = 1.06), with similar results 6 to 24 months later, though long-term data are thinner (Hoppen et al., 2025). It treats harm after exposure and does not prevent adversity.
  • Parent training programs such as Incredible Years (B). Across 50 studies, child disruptive behavior fell (d = 0.27 across informants). Effects were larger for children already showing problems (d = 0.50 by parent report) than in prevention samples (d = 0.13 to 0.20) (Menting, Orobio de Castro, and Matthys, 2013).
  • Video-feedback coaching for parents (B). Across 25 trials of VIPP-SD with over 2,000 caregivers, parenting improved (r = .18) and child attachment security improved (r = .23), but child behavior problems did not (r = .07). Two of the authors developed the program (van IJzendoorn et al., 2023). In one trial of the ABC program with children at risk of neglect, children showed healthier daily cortisol patterns (d = 0.48 for wake-up cortisol), one of the few trials to measure a stress hormone directly (Bernard et al., 2015).
  • School social-emotional learning (B). A meta-analysis of 213 programs with 270,034 students found gains in skills and behavior and an 11 percentile point gain in achievement (Durlak et al., 2011), and a larger review of 424 studies in 53 countries found similar benefits (Cipriano et al., 2023). Both include nonrandomized studies, and neither measured stress biology.
  • Coached play at home for young children (B for long-run earnings, C for lasting gains at scale). In Jamaica, two years of weekly home visits to stunted toddlers raised adult earnings by 25% about 20 years later in a small randomized trial (Gertler et al., 2014). A scaled version in Colombia raised cognitive scores by 0.26 standard deviations (Attanasio et al., 2014), but the gain had faded two years after the program ended (Andrew et al., 2018).
  • Not shown to work: cash alone to improve early child development. A randomized trial gave 1,000 low-income U.S. mothers $333 or $20 a month and found no significant effects on language, executive function, behavior, or brain activity at age 4 (Noble et al., 2025). An earlier report of brain activity changes at age 1 depended on the analysis chosen and was publicly disputed (D) (Troller-Renfree et al., 2022).

Proposed and experimental methods

Methods that are proposed, under trial, approved in some places, or tried and then failed. Each shows a stage label and an evidence rating. A stage label shows how far a method has progressed, not whether it works. The stage labels are explained on the biological factor page.

  • Guaranteed income as a stress buffer (Large trial, B). In the OpenResearch trial, 1,000 low-income U.S. adults aged 21 to 40 received $1,000 a month for three years versus 2,000 controls who received $50 a month (Miller et al., 2024). Stress and food security improved strongly but only in the first year, and the study ruled out improvements larger than 0.03 standard deviations in a mental health index, 0.02 in a physical health index, and 0.01 in a biomarker index that includes blood pressure, cholesterol, and A1c (a blood sugar measure) (Miller et al., 2024). Hospital and emergency department use rose, with about $20 a month more spent on medical care, though this spending effect narrowly missed statistical significance after adjusting for multiple comparisons. It is a single U.S. trial reported in a working paper (revised August 2026), and larger, longer, or permanent transfers might differ.
  • Hair cortisol as a marker to target or monitor stress care (Theoretical, C). Cortisol stored in hair gives a record of stress hormone output over several months. A meta-analysis of 66 studies (N = 10,289) found 22% higher hair cortisol in stress-exposed groups and 43% higher when stress was ongoing, but no consistent link with self-reported stress, depression, or mood disorders, and 17% lower levels in anxiety disorders such as PTSD (Stalder et al., 2017). A second meta-analysis of 28 studies found a small overall link with adversity (d = 0.213), with one subgroup of studies pointing the opposite way (Khoury et al., 2019). Age, sex, hair washing, hair treatment, and oral contraceptives also change levels, and no trial was found showing that cortisol-guided care improves outcomes.
  • Statewide ACE screening in primary care (Approved but not scaled, contested, C). Builds on the ACE screening entry in "Early-life adversity (preventing abuse and neglect)" in the biological factors, adding what happened at scale. California pays Medi-Cal clinicians to screen for adverse childhood experiences, and by June 30, 2025, 3,045,940 members had been screened 5,918,450 times, with 8% of those aged 0 to 17 and 20% of those aged 18 to 64 scoring 4 or more (ACEs Aware, 2026). An independent RAND evaluation found screening feasible and acceptable to clinicians but uneven, reaching about 31% of children and teens and 6.3% of eligible adults by March 2024, and stated that further evaluation is needed to learn whether screening improves health (RAND, 2025). No health outcome data have been reported.
  • Failed: CRF1 receptor antagonists for stress-related disorders (Failed or reversed, D). These drugs block the brain's main stress hormone receptor (corticotropin-releasing factor type 1). Despite strong animal evidence and sustained effort, none had reached the clinic for depression, anxiety, or addiction by 2017, and a review attributed this to poor early drug candidates, animal screens that did not match chronic human illness, and other causes, concluding that the drugs' scope appears narrower than hoped (Spierling and Zorrilla, 2017). One drug of this class, crinecerfont, lowered adrenal androgen levels in a trial in children with congenital adrenal hyperplasia, a hormonal disorder (Sarafoglou et al., 2024), and was approved for that condition in December 2024 (FDA, 2024), which does not show benefit for stress-related illness.

Sources cited on this page

  1. Shonkoff, J. P., & Garner, A. S. (2012). The lifelong effects of early childhood adversity and toxic stress. Pediatrics, 129(1), e232-e246. DOI B Moderate: for adversity harming health and learning, C for effects on specific brain regions
  2. Felitti, V. J., et al. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. American Journal of Preventive Medicine, 14(4), 245-258. DOI00017-8) B Moderate
  3. Andrew, A., Attanasio, O., Fitzsimons, E., Grantham-McGregor, S., Meghir, C., & Rubio-Codina, M. (2018). Impacts 2 years after a scalable early childhood development intervention to increase psychosocial stimulation in the home: A follow-up of a cluster randomised controlled trial in Colombia. PLOS Medicine, 15(4), e1002556. link B Moderate
  4. Attanasio, O. P., Fernández, C., Fitzsimons, E. O. A., Grantham-McGregor, S. M., Meghir, C., & Rubio-Codina, M. (2014). Using the infrastructure of a conditional cash transfer program to deliver a scalable integrated early child development program in Colombia: Cluster randomized controlled trial. BMJ, 349, g5785. link C Limited: for lasting benefit, B for the end-of-program effect
  5. Bernard, K., Dozier, M., Bick, J., & Gordon, M. K. (2015). Intervening to enhance cortisol regulation among children at risk for neglect: Results of a randomized clinical trial. Development and Psychopathology, 27(3), 829-841. link B Moderate
  6. Cipriano, C., Strambler, M. J., Naples, L. H., Ha, C., Kirk, M., Wood, M., Sehgal, K., Zieher, A. K., Eveleigh, A., McCarthy, M., Funaro, M., Ponnock, A., Chow, J. C., & Durlak, J. (2023). The state of evidence for social and emotional learning: A contemporary meta-analysis of universal school-based SEL interventions. Child Development, 94(5), 1181-1204. link B Moderate
  7. Durlak, J. A., Weissberg, R. P., Dymnicki, A. B., Taylor, R. D., & Schellinger, K. B. (2011). The impact of enhancing students' social and emotional learning: A meta-analysis of school-based universal interventions. Child Development, 82(1), 405-432. link B Moderate
  8. Gertler, P., Heckman, J., Pinto, R., Zanolini, A., Vermeersch, C., Walker, S., Chang, S. M., & Grantham-McGregor, S. (2014). Labor market returns to an early childhood stimulation intervention in Jamaica. Science, 344(6187), 998-1001. link B Moderate
  9. Hoppen, T. H., Wessarges, L., Jehn, M., Mutz, J., Kip, A., Schlechter, P., Meiser-Stedman, R., & Morina, N. (2025). Psychological interventions for pediatric posttraumatic stress disorder: A systematic review and network meta-analysis. JAMA Psychiatry, 82(2), 130-141. link A Strong
  10. Menting, A. T. A., Orobio de Castro, B., & Matthys, W. (2013). Effectiveness of the Incredible Years parent training to modify disruptive and prosocial child behavior: A meta-analytic review. Clinical Psychology Review, 33(8), 901-913. link B Moderate
  11. Noble, K., Magnuson, K., Duncan, G., Gennetian, L. A., Yoshikawa, H., Fox, N. A., et al. (2025). The effect of a monthly unconditional cash transfer on children's development at four years of age: A randomized controlled trial in the U.S. (NBER Working Paper No. 33844). National Bureau of Economic Research. link B Moderate
  12. Troller-Renfree, S. V., Costanzo, M. A., Duncan, G. J., Magnuson, K., Gennetian, L. A., Yoshikawa, H., Halpern-Meekin, S., Fox, N. A., & Noble, K. G. (2022). The impact of a poverty reduction intervention on infant brain activity. Proceedings of the National Academy of Sciences, 119(5), e2115649119. link D Contested: (contested)
  13. van IJzendoorn, M. H., Schuengel, C., Wang, Q., & Bakermans-Kranenburg, M. J. (2023). Improving parenting, child attachment, and externalizing behaviors: Meta-analysis of the first 25 randomized controlled trials on the effects of Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline. Development and Psychopathology, 35(1), 241-256. link B Moderate
  14. Khoury, J. E., Bosquet Enlow, M., Plamondon, A., & Lyons-Ruth, K. (2019). The association between adversity and hair cortisol levels in humans: A meta-analysis. Psychoneuroendocrinology, 103, 104-117. link C Limited
  15. Miller, S., Rhodes, E., Bartik, A. W., Broockman, D. E., Krause, P. K., & Vivalt, E. (2024, revised 2026). Does income affect health? Evidence from a randomized controlled trial of a guaranteed income (NBER Working Paper No. 32711). National Bureau of Economic Research. link B Moderate
  16. Sarafoglou, K., Kim, M. S., Lodish, M., Felner, E. I., Martinerie, L., Nokoff, N. J., et al. (2024). Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. New England Journal of Medicine, 391(6), 493-503. link B Moderate
  17. Spierling, S. R., & Zorrilla, E. P. (2017). Don't stress about CRF: Assessing the translational failures of CRF1 antagonists. Psychopharmacology, 234(9-10), 1467-1481. link B Moderate
  18. Stalder, T., Steudte-Schmiedgen, S., Alexander, N., Klucken, T., Vater, A., Wichmann, S., et al. (2017). Stress-related and basic determinants of hair cortisol in humans: A meta-analysis. Psychoneuroendocrinology, 77, 261-274. link C Limited
  19. Troller-Renfree, S. V., Costanzo, M. A., Duncan, G. J., Magnuson, K., Gennetian, L. A., Yoshikawa, H., et al. (2026). The impact of a monthly unconditional cash transfer on child brain activity: A 4-year follow-up. Developmental Cognitive Neuroscience, 78, 101673. link B Moderate

Every source for this factor is listed on the biological factor page.