Project Details
Description
We propose to prospectively investigate the effects of cannabis—the most used illicit drug in teenagers—
on reward and pain neurocircuits in adolescents with depression. Converging data suggest that cannabis use
during adolescence results in long-lasting alterations in reward circuitry, as well as depression and substance
use. Alarmingly, epidemiological evidence indicates high use of cannabis among depressed adolescents to self-
medicate, potentially exacerbating reward dysfunction, leading to depression chronicity. However, research in
this particular cohort has been sparse due to the exclusion of cannabis use in most depression studies. This
research seeks to address this knowledge gap. Our proposed model is: (1) Reward dysfunction contributes to
depression chronicity. (2) The habenula (Hb), a small limbic hub within the pain circuitry, has been hypothesized
to play a role in depression due to its regulatory role in reward function, specifically, inhibiting reward signaling
following pain and loss. (3) Cannabis, particularly Δ9-tetrahydrocannabinol (THC), exerts psychoactive and
analgesic effects by binding to cannabinoid receptors throughout the reward and pain systems including in the
Hb; this leads to temporary relief of mood and pain symptoms but also to alterations in both neurocircuits that
may potentiate depression chronicity and substance use. (4) Advancements in fMRI resolution and our
novel imaging methods allow us to study the Hb and other small structures critical to reward and pain. In support,
we documented that among adolescents with depression, anhedonia—which reflects reward dysfunction—was
associated with worse outcomes, including suicidality and chronicity. Additionally, using the reward flanker (RFT)
and reward prediction error (RPET) fMRI tasks, we identified distinct brain activity during reward anticipation,
attainment, and prediction errors, and found that the latter predicted worse outcomes in depressed adolescents.
Further, our Hb imaging methodology allowed us to detect Hb activation during a pain fMRI task and to map Hb
intrinsic functional connectivity (iFC) during rest with regions critical to reward, pain, or both. Preliminary data
further suggest disrupted Hb connectivity with the default mode network in adolescents with depression and
cannabis use. Expanding upon this work, we will test the overall hypothesis that depression and cannabis use
in adolescents have an additive effect, inducing alterations in reward and pain neurocircuits, and that this pattern
will predict worse depression at 2-year follow-up. We will study 250 adolescents across a wide range of
depression and cannabis use severity, including those with subthreshold and no symptoms, as well as 30 healthy
controls. Comprehensive clinical evaluations, including daily surveys of cannabis use, as well as blood and urine
tests for quantification of cannabinoid metabolites (e.g., THC:CBD) will be conducted at baseline, 12-, and 24-
months. Neuroimaging (RFT, RPET, pain, rest) will be acquired at baseline and 12-months. Public health impact:
Understanding the relationships between cannabis use and depression in adolescence may inform prevention
and intervention strategies for this vulnerable population.
Status | Active |
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Effective start/end date | 9/30/24 → 5/31/25 |
Funding
- National Institute on Drug Abuse: $713,908.00
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