Medical Cannabis and Behavior

All participants will complete a cognitive task battery measuring processes such as learning and memory. The Rey Auditory Verbal Learning Test requires individuals to learn a list of words across five learning trials followed by a distractor list then immediate recall of the initial word list then a 30-minute delayed recall. The minimum score on each trial is 0 and the maximum score on each trial is 15. Scores are tabulated for each of the eight trials. Scores on trials 1-5 reflect learning. Scores on trials 7 and 8 reflect immediate and delayed recall.

The digit span task is a measure of working memory and has a forward and a backward condition. On the forward condition, participants are presented with sequences of digits that are read aloud, beginning with two digits, which the participant must repeat in order. The sequence increases by one digit for each correct level of performance up to a maximum of 9 digits. On the backward condition, the presentation of digits is the same but participants must recall the digit sequences in backward order. The maximum forward and backward span that was correctly recalled is tabulated (min = 0; max = 9).

Participants are told that they will hear a letter (e.g. F) and must generate as many words as they can that begin with that letter in a one-minute period while adhering to certain task rules. Three letters are presented in total, and the total number of words generated without errors is recorded for each letter (min = 0; max = unspecified).

The spatial span task is a measure of working memory for locations and has a forward and a backward condition. On the forward condition, participants are presented with sequences of targeted locations, beginning with two, which the participant must repeat in order by touching those locations on a computer screen. The sequence increases by one location for each correct level of performance up to a maximum of 9 locations. On the backward condition, the presentation of locations is the same but participants must recall the spatial sequences in backward order. The maximum forward and backward spatial span that was correctly recalled is tabulated (min = 0; max = 9).

This task is a measure of fine motor coordination. Participants are provided with a board upon which 25 small holes are inserted. They are provided with small pegs to be inserted into the holes. They must place pegs one-by-one into the holes using first the dominant hand and then the non-dominant hand. Dropped pegs are recorded as errors (0 to 25). Completion time (in seconds; min = unspecified; max = 300) is recorded for each hand and is the primary metric that is examined to assess fine motor function and the presence of lateralized motor difficulties.

Participants view a computer screen on which some number of boxes is displayed in a circular pattern. Boxes are "opened" in a randomized order, one by one. One or more of them will contain a pattern. Participants must learn which patterns go in which boxes. After all box-pattern pairs are shown, the patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located. If the participant makes an error, the boxes are opened in sequence again to remind the participant of the locations of the patterns. Increased difficulty levels (arrays with a greater number of boxes) can be used. Specifically, participants complete up to 5 stages, which involve learning one, two, three, six or eight pattern-location pairings. Outcome measures include the errors made by the participant (max score is unspecified), the number of trials required to locate the pattern(s) correctly, and the number of stages completed.

This task is a computerized measure of planning ability. On each trial, the participant is shown two displays. In each of these displays, three columns - each containing three colored balls - are suspended from a beam. The two displays appear at the top and bottom of the screen. The balls are arranged in different patterns in each display.The participant must move the balls in the bottom display to match the pattern shown in the top display. The balls are moved one at a time by selecting the required ball, then selecting the position to which it should be moved. The participant is instructed to make as few moves as possible to match the two patterns and is told how many moves are optimal.

Trials increase in difficulty from 2-move to 5-move problems. Outcomes include the number of problems perfectly solved (max = 12), the number of moves used to execute each problem, and planning time (in milliseconds; how much time the participant waited before beginning to execute each problem).

On each trial of this working memory task, participants view an array of boxes on a computer screen. Participants search for tokens hidden inside of the boxes. Touching a box reveals whether a token is present. The array size varies from 2 to 8 boxes. When a token is found, it is placed at the side of the screen, and participants are instructed not to return to a location that was previously targeted. Returning to a previously targeted location is a forgetting error. Thus, they must remember where they have searched and found tokens on each trial. For each difficulty level (trials of 3, 4, 6 and 8 boxes), the number of forgetting errors is recorded (high scores = more error). Across 6 and 8-item searches, a strategy score is computed to reflect the extent to which the participant used an organized search strategy. High scores reflect decreased strategy use. Both scores are normed, yielding age-scaled percentiles. CANTAB documentation does not provide max values for the raw scores.

The IGT measures reward-related decision-making. On each of 100 trials, participants select from one of four cards presented on a computer screen. After the selection, feedback is provided. Participants are told that they have won points and, possibly, that they have lost points. Over the course of 100 trials, participants must use this feedback to determine which of the four decks are advantageous (yielding net gains) or disadvantageous (yielding net losses). There are two of each. Outcome measures include the total number of advantageous minus disadvantageous choices across all 100 trials (min = 0; max = 100) as well as for each of five blocks of 20 trials (min score on each block = 0; max = 20). High scores indicate better performance, and the slope of scores across the five blocks indicates rate of learning. Scores will be examined as a function of cannabis use.

The Face-Name Learning Task will be administered while neural activity is measured. During the task, participants will be presented with ten faces, each of which will be paired with a name. They are asked to memorize the face-name pairings. After all 10 pairs are presented, there is a short delay after which each face is presented alone without the name. Participants are asked to silently recall the name that was associated with the face. Neural activation throughout the brain is measured during the encoding (memorization) phase as well as the recall phase to determine which neural networks are active during these cognitive processes. Activation patterns are then analyzed and contrasted between individuals.

The Verbal Paired Associates Learning Task will be administered while neural activity is measured. During the task, participants will be presented with ten word pairs. They are asked to memorize the pairings. After all 10 pairs are presented, there is a short delay after which each word is presented alone without its pair. Participants are asked to silently recall the word that was associated with the presented word. Neural activation throughout the brain is measured during the encoding (memorization) phase as well as the recall phase to determine which neural networks are active during these cognitive processes. Activation patterns are then analyzed and contrasted between individuals.

Participants will complete a resting state MRI scan to yield brainwide measures of neural activity at rest. These neural signals form patterns that can be analyzed to differentiate patterns of activation within and between distinct functional networks. These activations will be associated with other behaviors measured in the study, including cannabis use. For this project, activations within the brain's executive control, salience, and reward networks are of maximal interest and will be quantified

Participants will complete structural MRI scans to yield measures of neural structure (gray and white matter volumes and cortical thickness). Images will be acquired for the entire brain and processed to yield cortical thickness (mm), gray matter (volume mm) and white matter (volume mm) for 138 cortical parcels (regions) and 40 subcortical regions.

To assess frontostriatal structure and function, FreeSurfer's segmentation of striatal nuclei (dorsal striatum/caudate; ventral striatum/nucleus accumbens) will be registered to EPI scans to generate seed regions for analyses of frontostriatal structural (diffusion) and functional (fMRI) connectivity. Connections between the dorsal and ventral striatum and discrete regions of the frontal cortex will be quantified and analyzed in relation to performance on the Go No-Go inhibitory control task and as a function of cannabis use over time.

Brain MRI T1 and T2 scans will be processed using FreeSurfer, yielding brain-wide cortical parcellations (available across several standard atlases) and subcortical segmentation, which in turn can be employed as ROIs for quantification of diffusion and functional scans following structural-to-EPI registrations. To assess hippocampal structure and function, FreeSurfer's segmentation of hippocampal subfields (based on the high- resolution T2-weighted hippocampal anatomical scan) will be registered to EPI scans to generate seed regions for analyses of frontohippocampal structural (diffusion) and functional (fMRI) connectivity. Anterior-to-posterior (head to tail) hippocampal gradients in structural and functional connectivity will be analyzed with regard to performance on tests of verbal and Face-Name learning as a function of cannabis exposure.

Participants will complete an 8-item questionnaire that asked about problems associated with their use of medical cannabis. Each question is rated on a five-point scale (0-4) where high scores indicate increasing frequencies of use or more problematic patterns of use. Scores are summed across the 8 questions to yield a total score, ranging from 0 to 40. Scores of 8 or more indicate hazardous cannabis use, while scores of 12 or more indicate a possible cannabis use disorder.

Participants will provide blood samples at the study baseline and four months post-baseline for the measurement of blood cannabinoid levels.

The SCID-V Substance Use Module is a semi-structured interview that queries the use of substances of abuse (alcohol, cannabis, stimulants, sedatives, opioids, hypnotics) and the extent to which 11 symptoms of substance use disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders V, are present for each substance currently and in the past. For each substance, answers to the 11 symptom questions are scored on a three-point scale (0 = absent; 2 = present at subthreshhold level; 3 = present). The full endorsement of two or more symptoms (scores of 3) for each substance class indicates the presence of a substance use disorder (SUD). Three outcome measures that will be analyzed include (1) presence/absence of a SUD for each class of substance, (2) total symptom scores (number of symptoms positively endorsed with ratings of 3) and (3) total symptom scores (summed scores on the 1-3 scale across 11 items for each substance class; min score = 11; max score = 33).

Participants will complete daily diaries across a four-month period to indicate prescription and non-prescription medications that they are ingesting and in what doses. Average daily doses of each medication type, including medical cannabis products, will be quantified and used as outcome measures in data analyses. Minimum possible values = 0; maximum = unspecified.

Participant alcohol use will be measured over time using the AUDIT, a 10-item screening tool developed by the World Health Organization (WHO) to assess alcohol consumption, drinking behaviors, and alcohol-related problems. Participants rate each item on a five point scale (0 to 4), and scores are summed across all 10 items to yield an index of problematic alcohol use (min score = 0; max score = 40). A score of 8 or more is considered to indicate hazardous or harmful alcohol use.

Participants will complete the Brief Pain Inventory to assess their current pain levels and pain-related quality of life. This self report questionnaire asks patients to rate (a) four pain items (worst pain in 24 hours; average pain; least pain in 24 hours; pain right now) and (b) Extent to which pain interferes with general activity, mood, walking ability, sleep, normal work, relations with other people, and enjoyment of life. Each item is rated on a 10-point scale with 1 reflecting low/less pain scores and 10 reflecting high/high pain/high interference with life scores. In addition to scores on individual items, three scores are derived, one that sums responses to the four pain items (max score = 40) and one that sums responses to the interference items (max score = 70) and a total score (sum of all items; max score = 120). High scores reflect worse pain-related impairment.

The BDI is a 21-item self report questionnaire that assesses symptoms of clinical depression and their severity, each rated on a four point scale (0 = symptom is absent; 3 = full presence of the symptom). The questions assess mood and motivation, cognitive symptoms, suicidality, and vegetative symptoms (sleep; libido; eating/weight). Scores are summed across all 21 items to yield a depression severity score (range from 0 to 63). Scores above 21 indicate moderate to severe depression.

The UPPS-P is a 59-item self-report questionnaire that measures five facets of impulsivity (sensation seeking (12 items; scores range from 12 to 48); positive urgency (14 items; scores range from 14 to 56 ); negative urgency (12 items; scores range from 12 to 48); lack of premeditation (11 items; scores range from 11 to 44); lack of perseverance (10 items; scores range from 10 to 40)). Each question is endorsed on a four point scale (1 = strongly agree; 4 = strongly disagree), and the five metrics are derived after implementing reverse-scoring on some items. These five facets of impulsivity will be examined before versus after use of medical cannabis.