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

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Electrophysiological Examination of CB1 and NMDA Receptors in Humans

Conditions
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Cannabis, Ketamine

Intervention / Treatment
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* Drug: Active Delta-9-THC
* Drug: Placebo Delta-9-THC
* Drug: Active Ketamine
* Drug: Placebo Ketamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to approximately 45 years old 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. Weight of 100 kg (220.46 lbs.) or less (inclusive). Exclusion Criteria: 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. 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. 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) Positive pregnancy test

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Delta-9-THC and Placebo Ketamine<br>Active IV Delta-9-THC and Placebo Ketamine | Drug: Active Delta-9-THC<br>* Active Delta-9-THC (0.015 mg/kg) given intravenously (IV)<br>Drug: Placebo Ketamine<br>* A placebo dose given intravenously (IV)<br>|
| Experimental: Active Delta-9-THC and Active Ketamine<br>Active IV Delta-9-THC and Active Ketamine | Drug: Active Delta-9-THC<br>* Active Delta-9-THC (0.015 mg/kg) given intravenously (IV)<br>Drug: Active Ketamine<br>* Active Ketamine (0.2 mg/kg) given intravenously (IV)<br>|
| Experimental: Placebo Delta-9-THC and Placebo Ketamine<br>IV Placebo Delta-9-THC and Placebo Ketamine | Drug: Placebo Delta-9-THC<br>* A placebo dose given intravenously (IV)<br>Drug: Placebo Ketamine<br>* A placebo dose given intravenously (IV)<br>|
| Experimental: Placebo Delta-9-THC and Active Ketamine<br>IV Placebo Delta-9-THC and Active Ketamine | Drug: Placebo Delta-9-THC<br>* A placebo dose given intravenously (IV)<br>Drug: Active Ketamine<br>* Active Ketamine (0.2 mg/kg) given intravenously (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EEG Measures 1 | The primary EEG outcome 1 will be EEG event related potential voltage amplitude (microvolts). | 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). | 0-60 minutes after the onset of drug infusion | 
| EEG Measures 3 | The primary EEG outcome 3 will be spectral power (microvolts squared). | 0-60 minutes after the onset of drug infusion | 
| EEG Measures 4 | The primary EEG outcome 4 will be Intertrial Coherence (phase locking factor). | 0-60 minutes after the onset of drug infusion | 
| EEG Measures 5 | The primary EEG outcome 5 will be neural noise (Lempel Ziv Complexity). | 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. | -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. | -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. | -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. | Collected at the screening visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | -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. | -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). | -60, +70, +120, +240 from baseline (0) (units in minutes). |