# Effects of Early Life Adversity on Substance Use Problems in Adolescents: Biobehavioral Risk Mechanisms

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $722,597

## Abstract

Substance use disorders (SUDs) have substantial healthcare and economic costs as well as accidental deaths
from drug overdose. Adolescence is a critical period in which exposure to alcohol and other drugs markedly
increases the risk for SUD. Early-life adversity (ELA), including interpersonal trauma and loss, family dysfunction
and poverty, is highly prevalent and a well-established risk factor for SUD. Individuals with ELA have an earlier
age of onset for the initiation and transition to SUD, greater severity and a more pernicious course, marked by a
greater risk for relapse and poor treatment response, compared to counterparts without ELA. The neuroimmune
network hypothesis postulates that ELA sensitizes the brain circuits involved in threat and reward processing via
inflammation, initiating positive feedback loops between these systems. Also, inflammatory mediators engage
these neural circuits, predisposing individuals to emotional dysregulation, and “self-medicating” behaviors, such
as smoking and drug use. Such self-medicating behaviors in adolescence, a period of high neuronal plasticity,
can exacerbate the neurotoxic effects of ELA, with a quicker transition from use to disorder. To our knowledge,
this theory has not been tested empirically. Adolescent studies characterizing inflammatory processes in relation
to ELA focused on non-specific systemic markers of inflammation which may lack sensitivity in young, healthy
persons to detect the early signs of pathogenesis, and the mechanistic specificity to inform modifiable pathways,
by which health disparities emerge during this developmental period. The proposed investigation addresses
these theoretical and methodological issues in the following ways: (1) we will recruit adolescents, stratified based
on ELA and oversampling the high-ELA group, without a prior history of substance misuse or SUD, to examine
the probability of SUD onset over a 24-month prospective follow-up; (2) examine whether an inflammatory index
comprising of vertically integrated measures (namely upregulated proinflammatory and reciprocal downregulated
antiviral type 1 interferon genes, diminished intracellular glucocorticoid receptor signaling, increased circulating
cytokines, and c-reactive protein) accounts for, partly, the association between ELA and SUD onset; (3) assess
whether ELA interacts with certain clinical, biobehavioral and family-contextual factors in predicting vulnerability
to, or protection against, SUD; and (4) explore whether SUD onset has a modulating influence on psychiatric,
biobehavioral and family-contextual factors. By identifying the biobehavioral risk and protective factors during a
critical developmental period, the study findings may help shift ELA research toward prevention and resilience
and identify novel biobehavioral targets for clinical trials. The identified biobehavioral targets may elucidate for
whom the intervention programs engage the underlying psychobiological processes that precede...

## Key facts

- **NIH application ID:** 10719048
- **Project number:** 1R01DA058794-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** UMA RAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $722,597
- **Award type:** 1
- **Project period:** 2023-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10719048

## Citation

> US National Institutes of Health, RePORTER application 10719048, Effects of Early Life Adversity on Substance Use Problems in Adolescents: Biobehavioral Risk Mechanisms (1R01DA058794-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10719048. Licensed CC0.

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