The aim of the research protocol is to evaluate cannabinoid-glutamate interactions in humans. As part of this aim the investigators will assess the safety and tolerability of the combination of NMDA antagonist, ketamine, and the cannabinoid, delta-9-tetrahydrocannabinol (THC), in healthy adult subjects, and characterize the interactive effects of ketamine and THC on various electrophysiological (EEG), cognitive, and behavioral outcomes.
The investigators will examine the contributions of the cannabinoid receptor (CB1R) and N-methyl D-aspartate receptor (NMDAR) systems to psychosis in healthy humans beings using THC and ketamine respectively (both alone and in combination). Healthy subjects (n=21) will receive THC (active or placebo) followed by ketamine (active or placebo) in a double blind, randomized, crossover (2x2) design. Psychotomimetic effects will be assessed before and at various time points after the drug infusions. EEG indices of information processing, specifically neural oscillations, will be assessed during peak drug effects.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
22
Active Delta-9-THC (0.015 mg/kg) given intravenously (IV)
A placebo dose given intravenously (IV)
Active Ketamine (0.2 mg/kg) given intravenously (IV)
VA Connecticut Healthcare System
West Haven, Connecticut, United States
EEG Measures 1
The primary EEG outcome 1 will be EEG event related potential voltage amplitude (microvolts).
Time frame: 0-60 minutes after the onset of drug infusion
EEG Measures 2
The primary EEG outcome 2 will be EEG event related potential latency (milliseconds).
Time frame: 0-60 minutes after the onset of drug infusion
EEG Measures 3
The primary EEG outcome 3 will be spectral power (microvolts squared).
Time frame: 0-60 minutes after the onset of drug infusion
EEG Measures 4
The primary EEG outcome 4 will be Intertrial Coherence (phase locking factor).
Time frame: 0-60 minutes after the onset of drug infusion
EEG Measures 5
The primary EEG outcome 5 will be neural noise (Lempel Ziv Complexity).
Time frame: 0-60 minutes after the onset of drug infusion
Neurochemical Measures: THC levels
THC blood levels (ng/mL) will be assayed to determine the relationships between blood levels and EEG measures (outcomes 1-5) and behavioral measures (outcomes 10-12). Blood sampled at 4 time-points will be centrifuged and the resultant plasma will be aliquoted into appropriate vials and stored at -80 degrees C until the time of the assay.
Time frame: -30, +25, +60, +120 minutes after start of drug infusion (0)
Neurochemical Measures: THC-COOH levels
THC-COOH blood levels (ng/mL) will be assayed to determine the relationships between blood levels and EEG measures (outcomes 1-5) and behavioral measures (outcomes 10-12). Blood sampled at 4 time-points will be centrifuged and the resultant plasma will be aliquoted into appropriate vials and stored at -80 degrees C until the time of the assay.
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A placebo dose given intravenously (IV)
Time frame: -30, +25, +60, +120 minutes after start of drug infusion (0)
Neurochemical Measures: ketamine/norketamine levels
Ketamine/norketamine blood levels (ng/mL) will be assayed to determine the relationships between blood levels and EEG measures (outcomes 1-5) and behavioral measures (outcomes 10-12). Blood sampled at 4 time-points will be centrifuged and the resultant plasma will be aliquoted into appropriate vials and stored at -80 degrees C until the time of the assay.
Time frame: -30, +25, +60, +120 minutes after start of drug infusion (0)
Genetics
Blood samples for DNA extraction will be collected to examine whether any of the genes e.g., calcyon, BDNF, neuregulin-1, dysbindin, NOTCH4, COMT and the 22q11 PRODH2/DGCR6 locus that have been associated with schizophrenia, modify the effects of delta-9-THC, ketamine or the combination.
Time frame: Collected at the screening visit.
Positive and Negative Symptoms Scale (PANSS)
Positive, negative, and general psychosis symptoms will be assessed using the Positive and Negative Syndrome Scale (PANSS). The PANSS is divided into three sub-scales: Positive Scale (7 items), Negative Scale (7 items), and General Psychopathology Scale (16 items). Each item is scored from 1 to 7 (1=absent, 2=minimum, 3=mild, 4=moderate, 5=moderate severe, 6=severe, 7=extreme). Scores range from 30 to 210, where higher scores indicate greater symptom severity.
Time frame: -60, +70, +120, +240 from baseline (0) (units in minutes).
Perceptual Alterations
Perceptual alterations will be measured using the Clinician Administered Dissociative Symptoms Scale (CADSS), a scale consisting of 19 self-report items and 8 clinician-rated items (0 = not at all, 4 = extremely) that we have shown to be sensitive to THC effects. The scale captures alterations in environmental/time/body perception, feelings of unreality, and memory impairment.
Time frame: -60, +70, +120, +240 from baseline (0) (units in minutes).
Cannabis Subjective Effects
Feeling states associated with cannabis intoxication will be measured using a self-reported visual analog scale of 3 feeling states ("high", "calm and relaxed", and "tired") associated with cannabis effects. Subjects will be asked to score the perceived intensity of these feeling states at that moment on a 100 mm line (0 = not at all, 100 = extremely).
Time frame: -60, +70, +120, +240 from baseline (0) (units in minutes).