Table 3.

Study characteristics and results.

Study	Population	Intervention	Cannabis use	Outcome	Results
Wallace et al. (39) Randomized, double-blind, placebo-controlled crossover study	Painful Diabetic Neuropathy 16 participants	Placebo, 1, 4, and 7% THC vaporized 4 inhalations using the Foltin Puff Procedure in one single dosing session (equaling 0, 4, 16, or 28 mg THC)	No use of cannabis in past 30 days prior to study tested by urine drug screen	Trail Making Test Paced Auditory Serial Attention Test Testing at 5-min, 30-min and every 30- min for 3 h. Final measurement at 240-min.	Decline in neurocognitive performance with THC exposure which was dose dependent and improved with time. No difference in any groups at 240-min post-inhalation (4-h). Trails: 7% THC group took longer compared to placebo on Trails B at 120-min. No difference between 1 and 4% THC groups and placebo Paced Auditory Serial Addition Test: 7% THC and 4% THC groups had worse performance than placebo at 15-min post-THC dose. There was no difference in performance between 1, 4, or 7% THC groups compared to placebo at the following 60-, 120-, or 240-min testing.
Wilsey et al. (40) Double-blind, placebo-controlled, crossover study	Central and Peripheral Neuropathic Pain 38 participants	Placebo vs. 3.5% THC vs. 7% THC smoked 2 inhalations at 60-min, 3 inhalations at 120-min, and 4 inhalations at 180-min for a total of 9 cumulative inhalations (total estimate: 19 mg THC low dose, 34 mg THC high dose)	All had previous cannabis exposure No cannabis 30 days prior to study	Digit Symbol Test Hopkins Verbal Learning Test and Delayed Learning Grooved Pegboard Dominant and Non-Dominant tests Testing completed at baseline, 60-mins (after 2 puffs), 120-min (after 3 puffs), 180-mins (after 4 puffs), 240-min (after 1-h recovery).	Modest decline in cognitive performance with THC use, most significant in the 7% THC group. 76% of participants had cognitive impairment at baseline. Digit Symbol Test: no significant dose-effect differences Hopkins: 7% THC group had worse performed than the 3.5% THC group which performed worse than placebo. Poor performance even in placebo group Dominant-hand Pegboard: 7% THC group performed worse than placebo. No difference in performance between the 3.5% THC group and placebo. Non-dominant hand pegboard: Both THC groups had decreased performance compared to placebo. 2-h after the last inhalation session, both THC groups had significant improvement compared to their previous scores
Corey-Bloom et al. (41) Randomized placebo-controlled trial	Multiple Sclerosis Spasticity 37 participants	Placebo vs. 4% THC smoked 4 inhalations of 4% THC smoked in one dosing session (~16 mg THC)	Cannabis naïve or negative toxicological screen for THC at study initiation	Timed walk score Paced Auditory Serial Addition Test Baseline and 45-min post-treatment	Timed walk: no difference Paced Auditory Serial Addition Test: 4% THC group had worse performance compared to placebo at 45-min. There was no neurocognitive testing beyond 45-min.
Notcutt et al. (42) Prospective, randomized, double-blind, placebo-controlled crossover study	Chronic mostly neuropathic pain 34 participants	Sublingual Spray 2.5 mg THC vs. 2.5 mg CBD vs. 2.5 mg THC and 2.5 mg CBD One spray every 15–30 min and individually stopped further dosing after response was achieved Total intake: 2–8 sprays over a 4-h period (~5–20 mg THC)	Excluded if significant past or current recreational cannabis use, okay if medical cannabis use	Trail Making Tests A & B Adult Memory and Information Processing Battery Baseline and 3-h post-dose	Equivocal results, requiring a more detailed analysis than the study planned. Testing often improved after the initiation of cannabis-based medicine.
Wilsey et al. (43) Crossover, randomized, placebo-controlled human laboratory experiment	Patients with refractory neuropathic pain who have disease or injury to their spinal cord 48 participants	Placebo vs. 2.9% vs. 6.7% THC vaporized 4 puffs using the Foltin Puff Procedure at 60-min with a second dosing session at 240-min of 4–8 puffs (flexible dosing schedule: the participant chooses their second dose between 4–8 puffs)	17/42 participants used cannabis regularly Some were cannabis naïve or ex-users	Wechsler Adult Intelligence Scale Digit Symbol Test Trail Making Test Grooved Pegboard Test Paced Auditory Serial Addition Test Hopkins Verbal Learning Test Revised with 20-min delay Neurocognitive testing every hour (with variations to prevent learning)	Measurement of neurocognitive performance proved technically challenging due to the various disabilities in the population studied. THC showed dose-dependent neurocognitive impairment with resolution 2 h after inhalation of THC. Dominant-hand Pegboard: no significant dose-effect differences Non-Dominant Hand Pegboard: 6.7% THC group performed worse compared to placebo 1-h after the 2nd THC dosing session. Resolved 1-h later Digit Symbol Test: no significant dose-effect differences, with all groups improving scores over time, consistent with practice effects Trail Making Test-A: 2.9% THC group took longer than the 6.7% THC group on the Trails A at 420 min, immediately after the 2nd THC dosing interval Hopkins: no difference in test scores between the 2.9% THC group and placebo. 6.7% THC group had less true-positive and more false-positive responses compared to placebo. Resolved 2-h after the 2nd dosing session Paced Auditory Serial Addition Test: no significant differences between THC groups and placebo at any timepoint. 6.7% THC group performed better than the 2.9% THC group at 420 min, 3-h after the 2nd dosing interval
Wilsey et al. (44) Randomized double-blind placebo controlled cross-over trial	Central or peripheral neuropathic pain (Refractory) 39 participants	Placebo vs. 1.29%, vs. 3.53% THC vaporized 4 puffs at using the Foltin Puff Procedure at 60-mins with a second dosing session at 180-min of 4–8 more puffs (flexible dosing schedule: the participant chooses their second dose between 4 and 8 puffs)	All had previous cannabis exposure No cannabis 30 days prior to study	Wechsler Adult Intelligence Scale Digit Symbol Test Hopkins Verbal Learning Test Revised Grooved Pegboard Test Baseline, 60-, 120-, 180-, 240-, and 300-min after administration of THC	THC produced a short duration of neurocognitive impairment. No difference in performance between THC and placebo 2-h after the last dosing session Digit Symbol Test: 1.29 and 3.53% THC groups had worse performance at 60-min, (after 1st inhalation) and 180-min, (after the 2nd inhalation) compared to placebo. No difference in either THC group and placebo at 120- and 240-min (1-h after each dose) Dominant Hand Pegboard: 1.29% THC group had worse performance than the 3.53% THC and the placebo group at 60-min (after 1st inhalation) and 240-min, (60-min after 2nd inhalation) which resolved 60-min later Non-dominant Hand Pegboard: 1.29% THC and 3.53% THC groups had decreased performance at 120-min (60-min after 1st inhalation) and 180-min (after 2nd inhalation) which resolved 60-min later Hopkins: performance following higher THC doses was worse than for lower doses of THC, which in turn, were worse than placebo. There was recovery of these differences 2-h after the last THC inhalation session.
Olla et al. (45) Observational Clinical Trial	Medical Cannabis Patients 22 participants	One gram 20% THC in vapes, cannabis cigarettes (joints) and dabs for 10 min One dosing session with 10 min of THC intake	Regular cannabis use ≥6 month 3.2 g/day cannabis average)	Brief Neurocognitive Battery: Animal Fluency, Boston Naming Test-15, Coding, Digit Span, Stroop Color Naming/Word Reading/Interference, Trails Making Test A/B Baseline, 30 min and 2.5–3 h after intake Included Performance Validity Testing	There was no psychometric evidence for a decline in performance on cognitive testing following THC ingestion and some participants had improved performance after THC ingestion compared to the normative sample. Performance Validity Test: More failures in the THC group, which were the most affected parameters of the suppressing effects of THC on cognitive functioning.