Buspirone, Stress, and Attentional Bias to Marijuana Cues

For nearly 40 years marijuana has remained the most widely used illicit drug in the US, with
more than 50% of first-time users < age 18. Marijuana accounts for ≈ 60% of illicit
substance use disorders (SUD) in the US, bearing by percent the largest US public health
burden among illicit substances. Across preclinical, human laboratory, and clinical
interview data, there is compelling evidence that the phenomenon of cue reactivity is
related to drug seeking and relapse. Attentional bias is a measurable component of cue
reactivity, and can be operationally defined as differential attention (e.g., reaction time
difference) towards drug-related stimuli vs. neutral stimuli. This phenomenon has been
demonstrated in SUD populations across many classes of abused drugs, including alcohol,
nicotine, stimulants, opiates, and - importantly - marijuana. Cue reactivity and attentional
bias are exacerbated by acute and chronic stress and anxiety. Notably, stress is a
well-documented predictor of marijuana abuse and marijuana relapse. Therapeutic
interventions that attenuate attentional bias to marijuana cues are a potentially important
component in the treatment of marijuana SUD. Due to the well-documented association with
stress, an intervention that simultaneously addresses both stress and attentional bias could
be uniquely efficacious. Currently, few pharmacotherapies exist for marijuana SUD, and none
are presently known to address attentional bias to marijuana cues. This application will
explore the potential of the anxiolytic buspirone to modify attentional bias and stress.
Buspirone is a unique compound marked by modulation of both serotonin (5-HT1A) and dopamine
D3 receptors. Importantly, the 5-HT1A receptor is known to play a key role in stress related
anxiety, and preclinical work indicates that D3 antagonists significantly decrease cue
reactivity to a number of abused drugs. This combination of effects suggests buspirone may
be advantageous in targeting both stress and attentional bias as factors that contribute to
problem marijuana use.

Accordingly, this application seeks to examine the effects of chronic buspirone
administration on attentional bias and stress/anxiety in marijuana SUD. Using
laboratory-based methodologies sensitive to attentional bias towards marijuana cues and well
validated measures of stress and anxiety, we will examine if buspirone's unique mechanism of
action will (a) produce an attenuation of attentional bias to marijuana cues, and (b) be
most pronounced under conditions in which attentional bias is related to high levels of
stress and anxiety.

Inclusion Criteria:

- Male and female subjects aged 18-45 years, with a marijuana substance use disorder
based on a score of ≥ 13 on the Cannabis Use Disorders Identification Test - Revised
(CUDIT-R); a score of ≥ 4 on the Cannabis Abuse Screening Test (CAST); and meeting
criteria for a marijuana substance use disorder based on the Structured Clinical
Interview for the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV).

Exclusion Criteria:

- Current DSM-IV Axis I disorder other than marijuana use disorder; (2) serious medical
illness requiring ongoing medical treatment, which could affect the central nervous
system, or any other medical contraindication (e.g., renal, cardiovascular,
pulmonary, blood) as determined by medical screening; (4) a positive pregnancy test
or breast feeding (females); (5) concomitant use of prescription medications that
could affect the central nervous system; (6) active suicidal ideation or Beck
Depression Inventory II score greater than 19; (7) positive urine drug screen for
drugs other than marijuana or positive breath alcohol screen; (8) Shipley-2 test of
cognitive aptitude score outside 2 SD units of the published composite score average;
(9) smoking > 10 nicotine cigarettes per day / Fagerstrom Score > 4; (10) taking meds
known to have significant drug interactions with buspirone.