Systematic Review of the Neurocognitive Effects of Cannabis Use in Older Adults

Aging
Sexton et al. (2019) [23]	N=2,905 users; Older users (n=507): (50–80), 52.3%	Cross-sectional survey	Recreational and medical Herbal cannabis (mixed THC and CBD), 91.3% inhaled	Yes/no survey of “undesirable” acute cognitive effects	↑ Older users reported fewer cognitive difficulties than younger users (p<0.001). However, this may be explained by medical use of cannabis, which was more common in older adults and associated with fewer subjective cognitive difficulties.
Kolla et al. (2016) [24]	N=5,080: 54.4 ± 16.5 (18–97); 53.4%	Cross-sectional survey (population-based sample)	Likely recreational (N/R) Herbal cannabis	Adult ADHD Self-Report Version 1.1 Screener	↓ effects for hyperactivity (OR=1.083) and impulsivity (OR=1.076) in men, and inattention (OR=1.129) in women
Auer et al. (2016) [25]	N=3,499 at Year 25: Nonusers (n=533): 49.7 ± 3.9, 39.4% Ever users (n=2,852): 50.2 ± 3.6, 37.5% Current users (n=392)	Longitudinal cohort Cognitive testing completed once at Year 25.	N/R (likely recreational) Herbal cannabis (marijuana)	1. Rey AVLT 2. DSST 3. Stroop-Interference (n=3,364 in cognitive analyses)	1. ↓ verbal memory with current use and cumulative lifetime use. Every 5 years of use associated with 0.13 SD decrease in score 2. ↓ processing speed with current use, but not with cumulative use 3. ≈ executive functioning with current use or cumulative use
McKetin et al. (2016) [26]	N=1,897 at baseline: Nonusers (n=4,986): 42.6 ± 1.5, 43% < weekly users (n=225): 42.3 ± 1.5, 58% ≥ weekly users (n=106): 42.7 ± 1.4, 70%	Longitudinal cohort 4 and 8-year follow-up (n=1,653 at Year 8; mean age = 50)	N/R (likely recreational) Herbal cannabis (marijuana/hash)	1. CVLT 2. SDMT 3. Digit Backwards 4. Simple and choice reaction time tasks	1. ↓ immediate memory for ≥ weekly users (−0.55 SD) 2. ≈ processing speed 3. ≈ working memory 4. ≈ reaction time No within-subject effects. Cannabis use was not associated with accelerated cognitive decline.
Burggren et al. (2018) [27]	N=50: Former heavy users (n=24): 65.4 ± 7.2, 67.0% Nonusers (n=26): 67.7 ± 7.1, 54.0%	Cross-sectional	Recreational Herbal cannabis (marijuana)	1. WTAR 2. MMSE 3. SRT, WMS-II Logical Memory, Verbal Paired Associates, RCFT 4. TMT-A, Stroop-Word Reading, DSST 5. TMT-B, FAS, Animals, Stroop-Interference	1. ↓ premorbid IQ 2. ≈ global cognition 3. ≈ immediate and delayed memory (d’s = −0.29 and −0.30) 4. ≈ processing speed (d =−0.36) 5. ≈ executive function (d =−0.07) Former heavy users < controls on all cognitive domains, but p’s > .05.
Thayer et al. (2019) [28]	N=54; Users (n=28): 66.8 ± 5.3, 64% Nonusers (n=28): 69.8 ± 5.7, 39%	Cross-sectional	Recreational Herbal cannabis (smoked and edibles)	NIH Toolbox Cognition Battery (n=38; 28 users and 10 non-users)	≈ global cognition. Users performed >0.5 SD below nonusers on working memory subtest, but this was non-significant after FDR correction (p=.05).
Ahmed et al. (2014) [29]	N=11; 72.1 ± 5.0, 55.0%	RCT (crossover; placebo-controlled) 8 weeks	Medical Oral THC (Namisol) 3.0mg, 5.0mg, and 6.5mg	Test for Attentional Performance – Alertness subtest	≈ attention (p=.18); Effect size and raw data N/R
Dementia
Ahmad et al. (2014) [30]	N=18; AD (n=11): 71.8 ± 6.8, 27.3% Healthy (n=7): 68.0 ± 6.5, 42.9%	Cross-sectional	Endocannabinoids CB1 receptor availability via [18F]MK-9470 PET brain imaging	1. MMSE 2. AVLT	1. ≈ global cognition not associated with CB1 receptor availability 2. ≈ immediate and delayed memory not significantly associated with CB1 receptor availability (r2’s=.46 and .32, p’s>.05)
Altamura et al. (2015) [31]	N=48; AD (n=37): 77.3 ± 6.4, 37.0% Healthy (n=11): 75.0 ± 3.6, 40.6%	Cross-sectional	Endocannabinoids AEA, 2-AG, PEA, and OEA in plasma	1. Rey AVLT 2. Corsi’s test 3. Figure copy 4. Raven’s Progressive Matrices 5. Semantic fluency (n=37 AD)	1. ↑ correlation between immediate memory and higher 2-AG (r=.334, p=.05) 2. ↑ correlation between attention and 2-AG (r=.423, p=.018) 3. ↓ correlation between constructional praxis and PEA (r=−.389, p=.019) 4. N/R 5. N/R Other results (e.g., AEA and OEA) were N/R.
Shelef et al. (2016) [32]	N=10 with AD: 73.2 ± 8.6, 60.0%	Single-group cohort; Open-label trial	Medical Cannabis oil (THC extract 1.65% potency) 2.5mg 2x/day titrated	MMSE	≈ global cognition; MMSE scores were stable from baseline (M=10.3) to Week 4 (M= 11.0) of treatment
van den Elsen et al. (2015) [33]	N=12 with AD, vascular, or mixed (selected from n=22 in RCT): 76.4 ± 5.3, 68%.	Single-group cohort; Open-label extension	Medical Oral THC (Namisol) mean 3.0mg/day; titrated	1. MMSE (n=5 due to attrition [58.3%]) 2. Delirium Observation Scale	1. ≈ global cognition over the 6-month duration of the extension study (p=.96); no comparison to baseline. 2. N/R
Herrmann et al. (2019) [34]	N=38 with AD: 87 ± 10, 77%	RCT (crossover; placebo-controlled) 14 weeks	Medical Synthetic oral THC (Nabilone) 1–2mg/day	1. Standardized MMSE 2. SIB (n=25 with MMSE≤15)	1. ↑ global cognition (b=1.1, 95% CI [0.1, 2.0], p=.026) 2. ↓ global cognition in the subgroup with severe dementia (b=−4.6, 95% CI [−7.3, −1.8], p=.003)
van den Elsen et al. (2015) [35]	N=50 with AD, vascular, or mixed; THC (n=24): 79 ± 8; 45.8% Placebo (n=26): 78 ± 7, 53.8%	RCT (parallel groups; placebo-controlled) 3 weeks	Medical Oral THC (Namisol) 1.5mg 3x/day	1. WMS-R Paired Associate Learning (n=18)	1. ≈ episodic memory; THC and placebo groups showed similar decline from baseline (p=1.0).
Parkinson’s Disease (PD)
Balash et al. (2017) [36]	N=47: 64.2 ± 10.8, 85.1% 100% users	Single-group retrospective survey	Medical Herbal cannabis (mixed THC and CBD; 81% smoked) mean 0.9g/day	1. mCGI – Memory (n=40) 2. mCGI – Attention (n=42)	1. ≈ self-reported memory (r2 = 0.04, p>0.05) 2. ↑ self-reported attention (r2 = 0.11, p=.01)
Kindred et al. (2017) [37]	N=454i; Users (n=36.6%): 60 ± 9.2, 60.6% Nonusers (n=66.3%): 61.7 ± 9.5, 56.3%	Cross-sectional survey	Medical and recreational Herbal cannabis (smoked and edibles)	Guy’s Neurological Disability Scale	↑ self-reported memory; Current users reported fewer problems with memory (F=4.717, p=.030).
Chagas et al. (2014) [38]	N=21; CBD 75 (n=7): 65.9 ± 10.6, 71% CBD 300 (n=7): 63.4 ± 6.5; 71% Placebo (n=7): 67.3 ± 7.2, 71%	RCTii (parallel groups; placebo-controlled) 6 weeks	Medical CBD capsules 75mg or 300mg/day	PDQ-39 – Cognition scale	≈ self-reported cognitive functioning; No differences between placebo, 75mg, and 300mg (p=.332)
Multiple Sclerosis (MS)
Kindred et al. (2018) [39]	N=16; Users (n=8): 49.6 ± 15.0, 25% Nonusers (n=8): 50.8 ± 13.2, 25%	Cross-sectional	Medical Herbal cannabis (mixed THC and CBD; smoked and edibles)	PASAT, as part of the MSFC	↓ working memory (p=.02) after an 8-hour abstinence period PASAT scores did not correlate with regional standardized uptake values from [18F]-FDG-PET.
Castelli et al. (2019) [40]	N=22; Continuers (n=11): 49.4 ± 7.4, 45.5% Quitters (n=11iii): 50.1 ± 9.3, 36.4%	Longitudinal cohort 0, 1, 3, and 12-month follow-ups	Medical THC/CBD oral spray (nabiximols) median 6 puffs	Stroop Color-Word Test under single and dual-task conditions	↓ executive functioning in the dual-task condition (time × group η2=0.14) but ≈ in single-task condition (η2=0.06)
Ball et al. (2015) [41]	N=493; THC (n=329): 52.3 ± 7.6, 40.4% Placebo (n=164): 51.8 ± 8.2, 41.5%	RCT (parallel groups; placebo-controlled) 3 years	Medical Synthetic oral THC (dronabinol) median 4 capsules/day, titrated	PASAT, as part of the MSFC	≈ working memory; mean annual change equivalent between groups (z-score diff. = −0.01, 95% CI [−0.01, 0.09], p=.92)
Human Immunodeficiency Virus (HIV)
Schouten et al. (2016) [42]	N=103: median 54.0 [49–62], 93% 16% used daily to monthly	Cross-sectional	Likely recreational (N/R) Herbal cannabis (marijuana)	Neuropsychological test battery of fluency, attention, processing speed, memory, motor, and executive functions	↓ global cognition; Daily to monthly cannabis use was associated with increased risk of cognitive impairment (OR=27.76 [4.61, 167.18], p<0.001).
De Francesco et al. (2019) [43]	N=1253; Older HIV+ (n=637): 56 [53–62], 88.5%; 14.3% users Younger HIV+ (n=340): 43 [37–47], 80.9% HIV− (n=276): 58 [53–63], 65.2%	Cross-sectional	Recreational Herbal cannabis (marijuana and hashish)	CogState computerized test battery	↓ global cognition associated with use of hashish after adjusting for confounding variables (median z-score difference between users and non-users = −0.29, 95% CI [−0.49, −0.09], p=.005) ≈ association with marijuana (median z-score difference = 0.04, 95% CI [0.06, 0.14], p=.43)
Saloner et al. (2019) [44]	N=734: 55.1 ± 4.0, 84.2%; 31.6% with lifetime cannabis use disorder	Cross-sectional	Likely recreational (N/R) Herbal cannabis (marijuana)	Neuropsychological test battery using Super Ager criteria based on global performance that is comparable to 25-year-olds	↑ global cognition; Lifetime cannabis use disorder (in addition to younger age, higher verbal IQ, absence of diabetes, and fewer depression symptoms) increased the likelihood of being classified as a Super Ager vs. Cognitively Impaired (OR=0.46, 95% CI [0.28, 0.75], p=.002).
Okafor et al. (2019) [45]	N=788 HIV+ men; Users (n=290): 41.6 ± 10.0, 100% Nonusers (n=498): 44.6 ± 9.7, 100%	Longitudinal cohort Up to 17 years	Likely recreational (N/R) Herbal cannabis (marijuana)	1. TMT-A and SDMT 2. TMT-B	1. ↓ processing speed; current daily use associated with 0.41%–0.70% annual decline (f2<0.002); Non-significant effect of cumulative use 2. ≈ cognitive flexibility for current and cumulative use
Pain
Zaki et al. (2017) [46]	N=164 with cancer: 54.9 (70.7% age 50+), 56.1%	Single-group survey with 4-month follow-upiv	Medical N/R (supplied by a single provider)	Adaptive survey designed by the cannabis supplier (n=24 who perceived concentration as relevant)	≈ self-reported concentration
Bar-Sela et al. (2019) [47]	N=34 with advanced cancer; Users (n=17): 63 (35–85), 31% Nonusers (n=17): 63 (40–85), 59%	Longitudinal cohort 3-month follow-up	Medical Herbal cannabis (mixed products; smoked, inhaled, or oil)	1. MoCA 2. DSST	1. ≈ global cognition; 35% cases vs. 18% controls had clinically significant decline (i.e., ≥0.5 SD) 2. ≈ processing speed
Wallace et al. (2015) [48]	N=16 with diabetic neuropathy: 56.9 ± 8.2, 56.0%	RCT (crossover; placebo-controlled) 8 weeks	Medical Vaporized THC: low (1%), medium (4%), or high (7%) doses	1. PASAT 2. TMT-B 3. TMT-A	1. ↓ working memory at medium (d=−1.03) and high doses (d=−1.14) 2. ↓ executive functioning at high dose only (d=−1.15) 3. ≈ processing speed

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