# Impact of Cannabinoid Across the Lifespan (ICAL)

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $2,338,658

## Abstract

IMPACT OF CANNABINOIDS ACROSS THE LIFESPAN (ICAL): SUMMARY
Teenagers use cannabis more than any other recreational drug. Their developing brains may also be especially
vulnerable to its effects, as epidemiological and experimental evidence suggests that frequent cannabis use in
adolescence is associated with impairments in cognitive and affective functioning that continue in adult life.
Excessive stimulation of the endocannabinoid (ECB) system – the target of cannabis’s intoxicating constituent,
Δ9-tetrahydrocannabinol (THC) – is a plausible but still poorly understood mechanism for the lasting
consequences of cannabis use. The NIDA Center Impact of Cannabinoids Across Lifespan (ICAL), whose
renewal is proposed in this revised application, combines molecular, synaptic, and behavioral approaches to
determine whether adolescent THC exposure (‘ado-THC’) alters ECB signaling in a persistent manner thus
causing impairments in adult brain function and behavior. In the first funding period, which lasted 4 years, we
made substantive progress on our research and service goals. Research: (1) We systematically characterized
pharmacokinetics and metabolism of THC in adolescent and adult mice and rats of both sexes and validated a
THC treatment protocol that models daily cannabis consumption (an increasingly common use pattern among
teenagers). (2) We found that this protocol produces enduring neurobehavioral alterations, most (but not all) of
which appear to be rooted in persistent disruption of microglial homeostasis. (3) We uncovered unexpected
modifications in the adult metabolic and immune phenotype of male and female ado-THC mice. (4) We
published 29 articles in peer-reviewed journals, including Cell Metabolism, Biological Psychiatry, Nature
Communications, and Nature Neuroscience. Service: we (1) organized 2 international symposia (>1600
participants), 5 research seminars, and 4 workshops/webinars; (2) created and launched a public biobank, which
in ~12 months of service distributed >500 ado-THC tissue samples to 6 laboratories worldwide; (3) trained 9
graduate students (5 from underrepresented minorities, URM), 5 post-docs (2 from URM), and 51 undergraduate
students (26 from URM); and (4) funded 7 pilot research projects. In this renewal, we propose to test the highly
innovative hypothesis that ado-THC alters ECB signaling in microglia and, by doing so, disrupts both their
homeostasis and their interactions with neurons, ultimately causing persistent (but possibly correctable)
alterations in neuroplasticity, episodic memory, and vulnerability to opioids. This hypothesis, which is supported
by rigorous preliminary data generated by the close cooperation of ICAL’s three Projects, will be tested in Aim 1
using emerging molecular techniques (e.g., single-nuclei RNAseq, imaging mass cytometry) along with state-of-
the-art electrophysiological and behavioral methods. In Aim 2, we will continue our service mission by (1)
organizing symposia and workshops to ...

## Key facts

- **NIH application ID:** 10932775
- **Project number:** 2P50DA044118-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Daniele Piomelli
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,338,658
- **Award type:** 2
- **Project period:** 2018-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932775

## Citation

> US National Institutes of Health, RePORTER application 10932775, Impact of Cannabinoid Across the Lifespan (ICAL) (2P50DA044118-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10932775. Licensed CC0.

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