Cognitive and Psychophysiological Effects of Delta-9-Tetrahydrocannabinol in Bipolar Disorder (THC-BD)

The overarching goal of this study is to characterize the acute cognitive and psychophysiological effects of the main psychoactive constituent of cannabis, 9-delta-tetrahydrocannabinol (THC) in individuals with euthymic bipolar disorder (BD), and to begin probing the mechanisms that may underlie its effects in this illness. This study is expected to contribute to a better characterization of specific effects of THC in individuals with BD compared to healthy controls (HC).

To compare the dose related acute effects of inhaled THC, administered through a vaporizer over approximately 20 minutes, between HC and euthymic BD individuals (referred to as eBD) on a range of subjective and objective parameters as described below: Primary Aims: Verbal memory, measured by a modified computer version of the Rey Auditory Verbal Learning Test (RAVLT) and/or the CogState battery, administered while EEG data is collected. Executive functioning measured by the CogState battery and/or Trails Making Test-Part B. Secondary Aims: Attention, measured by the Continuous Performance Test-Identical Pairs (CPT-IP). Working memory, measured by the Wechsler Memory Scale-3 Letter-Number Sequencing. Mood, measured by the Profile of Mood States (POMS). Psychotic-type experiences, measured by the Psychotomimetic States Inventory (PSI) and/or the Clinician Administered Dissociative Symptoms Scale (CADSS). Anxiety symptoms, measured by the Visual Analog Scale for Anxiety (VAS-A). Impulsivity, measured by the Balloon Analogue Risk Task (BART). Exploratory aims: •Serum prolactin, serum ACTH, serum cortisol and serum endocannabinoid levels.

The study is a double-blind, randomized, placebo-controlled, crossover laboratory evaluation of the acute subjective, cognitive and psychophysiological effects of 2 mg and 4 mg inhaled THC in Healthy Control individuals and individuals with euthymic Bipolar Disorder.

Subject will have 1/3 chance of receiving 4 mg THC administered through a vaporizer, over approximately 20 minutes, followed by approximately 45 minutes of neuropsychological and physiological testing.

Subject will have 1/3 chance of receiving 2 mg THC administered through a vaporizer, over approximately 20 minutes, followed by approximately 45 minutes of neuropsychological and physiological testing.

Subject will have 1/3 chance of receiving the inhaled placebo condition administered through a vaporizer, over approximately 20 minutes, followed by approximately 45 minutes of neuropsychological and physiological testing. The placebo condition will include no active cannabinoids.

Subject will have 1/3 chance of receiving 4 mg THC administered through a vaporizer, over approximately 20 minutes, followed by approximately 45 minutes of neuropsychological and physiological testing.

Subject will have 1/3 chance of receiving the inhaled placebo condition administered through a vaporizer, over approximately 20 minutes, followed by approximately 45 minutes of neuropsychological and physiological testing. The placebo condition will include no active cannabinoids.

Subject will have 1/3 chance of receiving 2 mg THC administered through a vaporizer, over approximately 20 minutes, followed by approximately 45 minutes of neuropsychological and physiological testing.

Verbal memory will be measured by a modified computer version of the Rey Auditory Verbal Learning Test (RAVLT) and/or the CogState battery, administered while EEG data is collected.

baseline, +35 mins after drug administration, +90 mins after drug administration and +210 mins after drug administration

baseline and +20 mins after drug administration, +90 mins after drug administration and +210 mins after drug administration

Psychotic-type experiences will be measured by the Psychotomimetic States Inventory (PSI) and/or the Clinician Administered Dissociative Symptoms Scale (CADSS).

baseline and +20 mins after drug administration, +90 mins after drug administration and +210 mins after drug administration

baseline and +20 mins after drug administration, +90 mins after drug administration and +210 mins after drug administration

baseline, +35 mins after drug administration, +90 mins after drug administration and +210 mins after drug administration

Blood serum hormonal levels • Serum prolactin, serum ACTH, serum cortisol and serum endocannabinoid levels. • Serum prolactin, serum ACTH, serum cortisol and serum endocannabinoid levels.

As an exploratory aim, serum prolactin (ng/mL), serum ACTH (pg/ml), and serum cortisol (μg/dL) levels will be measured to provide an objective measure of THC effects on the hypothalamic pituitary adrenal (HPA) axis.

baseline, +20 mins after drug administration, +30 mins after drug administration, +60 mins after drug administration, +90 mins after drug administration, +150 mins after drug administration, +210 mins after drug administration

Blood levels of THC and both its active and inactive metabolites will be assayed to explore the gender related differences in the metabolism of THC.

baseline, +20 mins after drug administration, +30 mins after drug administration, +60 mins after drug administration, +90 mins after drug administration, +150 mins after drug administration, +210 mins after drug administration

baseline, -60 mins before drug administration, +2, +4, +6, +8,+10, +20, +30, +35, +40, +45, +50, +60, +90, +150, +210 mins after drug administration.

baseline, -60 mins before drug administration, +2, +4, +6, +8,+10, +20, +30, +35, +40, +45, +50, +60, +90, +150, +210 mins after drug administration.

Blood samples for DNA extraction will be collected to examine whether any of the genes implicated in cognition in the response to cannabinoids (e.g., COMT, CNR1, FAAH, BDNF) modify the effects of THC.

Inclusion Criteria for individuals with Bipolar Disorder (BD) Men and women aged 18-55 years (extremes included). Able to provide informed consent in English. A diagnosis of BD type I or BD type II and good physical health. Current euthymic state for at least 4 weeks. Inclusion Criteria for Healthy Control (HC) individuals: Men and women aged approximately 18-55 years (extremes included). Able to provide informed consent in English. No psychiatric diagnoses and in good physical health. General exclusion criteria: Cannabis naïve Unwillingness to remain alcohol-free, cannabis-free for at least 1 week (in infrequent cannabis users) prior to each test day. Evidence of a hearing deficit. IQ less than 80. Positive pregnancy test, lactation, and refusal to practice birth control.