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THC and Ketamine Effects in Humans: Relation to Neural Oscillations and Psychosis

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ClinicalTrials.gov Identifier: NCT04199468
Recruitment Status : Recruiting
First Posted : December 16, 2019
Last Update Posted : January 11, 2021
Sponsor:
Information provided by (Responsible Party):
Patrick D. Skosnik, Yale University

Tracking Information
First Submitted Date  ICMJE October 21, 2019
First Posted Date  ICMJE December 16, 2019
Last Update Posted Date January 11, 2021
Actual Study Start Date  ICMJE September 24, 2019
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 17, 2019)
  • EEG Measures 1 [ Time Frame: 0-60 minutes after the onset of drug infusion ]
    The primary EEG outcome 1 will be EEG event related potential voltage amplitude (microvolts).
  • EEG Measures 2 [ Time Frame: 0-60 minutes after the onset of drug infusion ]
    The primary EEG outcome 2 will be EEG event related potential latency (milliseconds).
  • EEG Measures 3 [ Time Frame: 0-60 minutes after the onset of drug infusion ]
    The primary EEG outcome 3 will be spectral power (microvolts squared).
  • EEG Measures 4 [ Time Frame: 0-60 minutes after the onset of drug infusion ]
    The primary EEG outcome 4 will be Intertrial Coherence (phase locking factor).
  • EEG Measures 5 [ Time Frame: 0-60 minutes after the onset of drug infusion ]
    The primary EEG outcome 5 will be neural noise (Lempel Ziv Complexity).
  • Neurochemical Measures: THC levels [ Time Frame: -30, +25, +60, +120 minutes after start of drug infusion (0) ]
    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.
  • Neurochemical Measures: THC-COOH levels [ Time Frame: -30, +25, +60, +120 minutes after start of drug infusion (0) ]
    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.
  • Neurochemical Measures: ketamine/norketamine levels [ Time Frame: -30, +25, +60, +120 minutes after start of drug infusion (0) ]
    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.
  • Genetics [ Time Frame: Collected at the screening visit. ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
  • EEG Measures 1 [ Time Frame: 0-60 Min after the onset of drug infusion ]
    The primary EEG outcome 1 will be EEG event related potential voltage amplitude (microvolts).
  • EEG Measures 2 [ Time Frame: 0-60 Min after the onset of drug infusion ]
    The primary EEG outcome 2 will be EEG event related potential latency (milliseconds).
  • EEG Measures 3 [ Time Frame: 0-60 Min after the onset of drug infusion ]
    The primary EEG outcome 3 will be spectral power (microvolts squared).
  • EEG Measures 4 [ Time Frame: 0-60 Min after the onset of drug infusion ]
    The primary EEG outcome 4 will be Intertrial Coherence (phase locking factor).
  • EEG Measures 5 [ Time Frame: 0-60 Min after the onset of drug infusion ]
    The primary EEG outcome 5 will be neural noise (Lempel Ziv Complexity).
  • Neurochemical Measures: THC levels [ Time Frame: -30, +25, +60, +120 minutes after start of drug infusion (0) ]
    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.
  • Neurochemical Measures: THC-COOH levels [ Time Frame: -30, +25, +60, +120 minutes after start of drug infusion (0) ]
    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.
  • Neurochemical Measures: ketamine/norketamine levels [ Time Frame: -30, +25, +60, +120 minutes after start of drug infusion (0) ]
    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.
  • Genetics [ Time Frame: Collected at the screening visit. ]
    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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 17, 2019)
  • Positive and Negative Symptoms Scale (PANSS) [ Time Frame: -60, +70, +120, +240 from baseline (0) (units in minutes). ]
    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.
  • Perceptual Alterations [ Time Frame: -60, +70, +120, +240 from baseline (0) (units in minutes). ]
    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.
  • Cannabis Subjective Effects [ Time Frame: -60, +70, +120, +240 from baseline (0) (units in minutes). ]
    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).
Original Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
  • Psychosis [ Time Frame: -60, +70, +120, +240 from baseline (0) (units in minutes). ]
    Positive, negative, and general psychosis symptoms will be assessed using the Positive and Negative Syndrome Scale (PANSS).
  • Perceptual Alterations [ Time Frame: -60, +70, +120, +240 from baseline (0) (units in minutes). ]
    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.
  • Cannabis Subjective Effects [ Time Frame: -60, +70, +120, +240 from baseline (0) (units in minutes). ]
    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).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE THC and Ketamine Effects in Humans: Relation to Neural Oscillations and Psychosis
Official Title  ICMJE An Electrophysiological Examination of CB1 and NMDA Receptors in Humans
Brief Summary 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.
Detailed Description 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE
  • Cannabis
  • Ketamine
Intervention  ICMJE
  • Drug: Active Delta-9-THC
    Active Delta-9-THC (0.015 mg/kg) given intravenously (IV)
  • Drug: Placebo Delta-9-THC
    A placebo dose given intravenously (IV)
  • Drug: Active Ketamine
    Active Ketamine (0.2 mg/kg) given intravenously (IV)
  • Drug: Placebo Ketamine
    A placebo dose given intravenously (IV)
Study Arms  ICMJE
  • Experimental: Active Delta-9-THC and Placebo Ketamine
    Active IV Delta-9-THC and Placebo Ketamine
    Interventions:
    • Drug: Active Delta-9-THC
    • Drug: Placebo Ketamine
  • Experimental: Active Delta-9-THC and Active Ketamine
    Active IV Delta-9-THC and Active Ketamine
    Interventions:
    • Drug: Active Delta-9-THC
    • Drug: Active Ketamine
  • Experimental: Placebo Delta-9-THC and Placebo Ketamine
    IV Placebo Delta-9-THC and Placebo Ketamine
    Interventions:
    • Drug: Placebo Delta-9-THC
    • Drug: Placebo Ketamine
  • Experimental: Placebo Delta-9-THC and Active Ketamine
    IV Placebo Delta-9-THC and Active Ketamine
    Interventions:
    • Drug: Placebo Delta-9-THC
    • Drug: Active Ketamine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 11, 2019)
21
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2021
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 18 to approximately 45 years old
  2. Good physical and mental health as determined by history, the Structured Clinical Interview for DSM-5 TR (SCID-NP) and collateral information, physical and laboratory examinations, ECG and vital signs.
  3. Weight of 100 kg (220.46 lbs.) or less (inclusive).

Exclusion Criteria:

  1. Unstable serious medical conditions. At the discretion of the investigator, subjects with unstable medical conditions that may necessitate changes in medical treatment and hence influence study outcomes will be excluded.
  2. Uncontrolled hypertension, long QT syndrome, and seriously abnormal EKG results. EKG abnormalities will be reviewed by the PI and eligibility decisions will be made at the discretion of the PI.
  3. A hearing deficit in greater than one band in an ear detected using a Welch-Allyn audioscope (500, 1000, 2000 and 4000 Hz threshold will be evaluated)
  4. Positive pregnancy test
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Leigh Taylor Flynn, BS 203-932-5711 ext 2557 leigh.flynn@yale.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04199468
Other Study ID Numbers  ICMJE 2000025927
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Patrick D. Skosnik, Yale University
Study Sponsor  ICMJE Yale University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Patrick D Skosnik, Ph.D. Yale University
PRS Account Yale University
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP