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

Ketamine

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.

Intervention / Treatment

  • Active Delta-9-THC (DRUG)
    Active Delta-9-THC (0.015 mg/kg) given intravenously (IV)
  • Placebo Delta-9-THC (DRUG)
    A placebo dose given intravenously (IV)
  • Active Ketamine (DRUG)
    Active Ketamine (0.2 mg/kg) given intravenously (IV)
  • Placebo Ketamine (DRUG)
    A placebo dose given intravenously (IV)

Condition or Disease

  • Cannabis
  • Ketamine

Phase

  • Phase 1

    • Study Design

    Study type: INTERVENTIONAL
    Status: Active, not recruiting
    Study results: No Results Available
    Age: 18 Years to 45 Years
    Enrollment: 21 (ESTIMATED)
    Funded by: Other
    Allocation: Randomized
    Primary Purpose: Basic Science

    Masking

    DOUBLE:
    • Participant
    • Investigator

    Clinical Trial Dates

    Start date: Sep 24, 2019 ACTUAL
    Primary Completion: Jun 21, 2022 ACTUAL
    Completion Date: Dec 01, 2023 ESTIMATED
    Study First Posted: Dec 16, 2019 ACTUAL
    Results First Posted: Aug 31, 2020
    Last Updated: Mar 31, 2023

    Sponsors / Collaborators

    Lead Sponsor: Yale University
    Responsible Party: N/A

    Location

    West Haven, Connecticut, USA

    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.

    Participant Groups

    • Active IV Delta-9-THC and Placebo Ketamine

    • Active IV Delta-9-THC and Active Ketamine

    • IV Placebo Delta-9-THC and Placebo Ketamine

    • IV Placebo Delta-9-THC and Active Ketamine

    Eligibility Criteria

    Sex: All
    Minimum Age: 18
    Maximum Age: 45
    Age Groups: Adult
    Healthy Volunteers: Yes

    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

    Primary Outcomes

    • The primary EEG outcome 1 will be EEG event related potential voltage amplitude (microvolts).

    • The primary EEG outcome 2 will be EEG event related potential latency (milliseconds).

    • The primary EEG outcome 3 will be spectral power (microvolts squared).

    • The primary EEG outcome 4 will be Intertrial Coherence (phase locking factor).

    • The primary EEG outcome 5 will be neural noise (Lempel Ziv Complexity).

    • 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.

    • 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.

    • 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.

    • 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.

    Secondary Outcomes

    • 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 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.

    • 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).

    More Details

    NCT Number: NCT04199468
    Other IDs: 2000025927
    Study URL: https://clinicaltrials.gov/study/NCT04199468
    Last updated: Sep 29, 2023