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

Phase 1

Completed

• Conditions: Cannabis; Ketamine
• Interventions: Drug: Active Delta-9-THC; Drug: Placebo Delta-9-THC; Drug: Active Ketamine; Drug: Placebo Ketamine

• Registration Number: NCT04199468
• Lead Sponsor: Yale University

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 Timeline

• Study Start: 2019-09-24
• Study First Submitted: 2019-10-21
• Study First Submitted QC: 2019-12-11
• Study First Posted: 2019-12-16
• Primary Completion: 2022-06-21
• Study Completion: 2022-06-21
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-21
• Last Update Posted: 2024-03-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

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).

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Active Delta-9-THC and Active Ketamine	Active Delta-9-THC	Active IV Delta-9-THC and Active Ketamine
Active Delta-9-THC and Active Ketamine	Active Ketamine	Active IV Delta-9-THC and Active Ketamine
Placebo Delta-9-THC and Placebo Ketamine	Placebo Delta-9-THC	IV Placebo Delta-9-THC and Placebo Ketamine
Placebo Delta-9-THC and Placebo Ketamine	Placebo Ketamine	IV Placebo Delta-9-THC and Placebo Ketamine
Placebo Delta-9-THC and Active Ketamine	Placebo Delta-9-THC	IV Placebo Delta-9-THC and Active Ketamine
Placebo Delta-9-THC and Active Ketamine	Active Ketamine	IV Placebo Delta-9-THC and Active Ketamine
Active Delta-9-THC and Placebo Ketamine	Active Delta-9-THC	Active IV Delta-9-THC and Placebo Ketamine
Active Delta-9-THC and Placebo Ketamine	Placebo Ketamine	Active IV Delta-9-THC and Placebo Ketamine

Primary Outcome Measures

Name	Time	Method
EEG Measures 2	0-60 minutes after the onset of drug infusion	The primary EEG outcome 2 will be EEG event related potential latency (milliseconds).
EEG Measures 5	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	-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	-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.
EEG Measures 4	0-60 minutes after the onset of drug infusion	The primary EEG outcome 4 will be Intertrial Coherence (phase locking factor).
Neurochemical Measures: ketamine/norketamine levels	-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	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.
EEG Measures 1	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 3	0-60 minutes after the onset of drug infusion	The primary EEG outcome 3 will be spectral power (microvolts squared).

Secondary Outcome Measures

Name	Time	Method
Positive and Negative Symptoms Scale (PANSS)	-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	-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	-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).

Trial Locations

Locations (1)

VA Connecticut Healthcare System; 🇺🇸 West Haven, Connecticut, United States