Dementia

Very weak to low evidence quality suggests that cannabinoids may have little or no clinically meaningful effect on cognition or BPSD; sedation was more frequent under nabilone.

Cochrane SR of k=4 RCTs (n=126) on cannabinoids in dementia; predominantly Alzheimer's dementia, individual cases of vascular/mixed dementia. Three studies with low risk of bias. Review assesses efficacy and safety of cannabinoids in dementia treatment (abstract incompletely cut off — quantitative outcomes not in available text).

Positive treatment effects reported for some cannabis products for pain, nausea, appetite and sleep in cancer patients as well as appetite and agitation in dementia patients, however very low to low evidence quality across all included studies.

Systematic review on medical cannabis in the palliative setting; k=52 studies (20 RCTs, 32 non-randomised), n=4.786 participants (cancer n=4.491, dementia n=43, AIDS n=235, spasticity n=16, NORSE n=1). For dementia: positive treatment effects (p<0,05) for appetite and agitation. Evidence quality 'very low' or 'low' for all studies. Meta-analysis not feasible due to heterogeneity of cannabis products and outcomes. High-quality evidence needed for clinical recommendations.

THC- and CBD-based medications were associated with symptom improvements in several mental disorders, but not with remission; adverse effects occurred, severe adverse effects only in isolated cases.

Umbrella review on medical cannabinoids in psychiatric disorders; k=18 studies (4 SRs across 11 RCTs + 14 standalone RCTs), n=1.629 participants. Diagnoses include dementia, cannabis dependence, psychoses, PTSD, anorexia, ADHD, Tourette, among others. THC- and CBD-based medications as adjuvant showed improvements in individual symptoms, but no remission. Severe adverse effects only in isolated cases. Heterogeneous outcomes, no meta-analysis possible; narrative synthesis applied.

Cannabinoids significantly reduced agitation (SMD -0,52), but not overall neuropsychiatric symptoms; the effect on agitation lost significance after exclusion of high risk-of-bias studies; increased risk of sedation.

Systematic review + meta-analysis of k=10 RCTs (n=328) on cannabinoids for neuropsychiatric symptoms of dementia; 8 studies assessed total NPS, 9 examined agitation. Cochrane RoB-2 tool applied, random-effects model, I² heterogeneity analysis, subgroup analyses by cognitive impairment and BMI performed. Risk ratios for adverse effects calculated.

No efficacy for dyskinesia, dyspnea and chemotherapy-induced nausea; possible benefit for anorexia and behavioural symptoms in dementia; more frequent side effects (sedation) under cannabinoid treatment.

Systematic review on medical cannabinoids in older persons (≥65 years); k=5 RCTs with separate data on older persons (n=267, age 47-78 years). Interventions: oral THC (k=3) or THC+CBD (k=2). Two studies showed possible benefit of THC for anorexia and behavioural symptoms in dementia. No efficacy for dyskinesia, dyspnea or chemotherapy-induced nausea. Adverse events (mainly sedation) more frequent under cannabinoid treatment vs. control.

Cannabinoids showed no significant effect on agitation overall (P = 0,10), with considerable heterogeneity present; increased sedation was observed.

Meta-analysis of k=6 double-blind, placebo-controlled trials (n=251) on cannabinoids for agitation/aggression in Alzheimer's dementia; no overall effect on agitation (SMD=-0.69, p=0.10), significant heterogeneity (I²=86%). Trend toward larger effect of synthetic cannabinoids vs. THC (χ²=3.05, p=0.08). Stronger effect with greater cognitive impairment (B=0.27, p=0.03). Sedation significantly more frequent than placebo (RR=1.73, p=0.04).

Cannabinoids led to significant improvements in neuropsychiatric symptoms of dementia as measured by several instruments (Cohen Mansfield Agitation Inventory, Neuropsychiatric Inventory, nocturnal actigraphy) and were well tolerated.

Systematic review + meta-analysis of cannabinoids for neuropsychiatric symptoms (NPS) in dementia; k=9 studies (n=205, 44% female, 78±7 years, 85% Alzheimer's). Cannabinoids led to significant improvements on the Cohen-Mansfield Agitation Inventory (SMD=-0,80; 95% CI -1,45 to -0,16), Neuropsychiatric Inventory (SMD=-0,61; CI -1,07 to -0,15) and nocturnal actigraphy (SMD=-1,05; CI -1,56 to -0,54). Completion rate 93% (193/205), no serious treatment-related adverse events. Efficacy was associated with baseline dementia severity and dose.

Positive signals for several indications, but no confirmed evidence of efficacy due to methodologically weak studies.

Systematic review of k=24 RCTs on cannabis/cannabinoids in psychiatric, neurodegenerative and movement disorders; positive findings identified for agitation in Alzheimer's dementia and dementia; definitive statements on efficacy limited by methodological quality issues of the included studies (Cochrane risk-of-bias assessment).

Observational studies showed promising results, but the highest-quality RCT found no significant improvement; safety profile favourable with mainly mild adverse effects.

Systematic review on cannabinoids for neuropsychiatric symptoms of dementia; k=12 studies (50% RCTs), interventions: dronabinol (33%), nabilone (25%), THC (42%). Dronabinol (3 studies) and THC (1 study) showed significant improvements in neuropsychiatric scores. Most common adverse event: sedation. The highest-quality RCT showed no significant improvement. 8 studies with high risk of bias.

Nabilone showed significant improvement in agitation, THC showed no significant differences to placebo; low to very low evidence quality; no studies on cognitive symptoms available.

Systematic review (PRISMA-compliant) on cannabinoids in dementia; k=5 RCTs identified (4 databases: Medline, Embase, Cochrane, PsychINFO). Dronabinol 5 mg/day improved weight in anorexia. THC 1.5-4.5 mg/day showed no significant differences to placebo for agitation (2 studies). Nabilone 1-2 mg/day achieved significant agitation reduction (1 study). Evidence quality low to very low due to small sample sizes and methodological limitations. No RCTs on cognitive symptoms available.

Meta-analysis shows overall no significant differences in ECS components between controls and AD patients; however, subgroup analyses reveal significantly lower CB1R expression in AD (especially in Western blot studies and frontal cortex) and significantly higher 2-AG levels in HPLC studies.

Meta-analysis on endocannabinoid system alterations in Alzheimer's dementia; subgroup analysis showed significantly lower CB1R expression in AD vs. controls (Western blot: SMD=-0.88, p<0.01; frontal cortex: SMD=-1.09, p<0.01). HPLC studies showed significantly higher 2-AG levels in AD (SMD=0.46, p=0.02). Network meta-analysis: 2-AG and MAGL with the largest increase, CB1R with the largest decrease relative to controls.

Systematic review identified mixed findings on ECS alterations in Alzheimer's disease without a clear characteristic profile.

Systematic review on endocannabinoid system alterations in Alzheimer's dementia and MCI in human studies (k=22: neuroimaging, serum/CSF biomarkers, post-mortem); examined CB1R, CB2R, AEA, 2-AG, MAGL, FAAH, TRPV1. Mixed findings for most ECS components; no uniform profile of ECS alterations characteristic for AD identifiable. Included studies small, methodologically heterogeneous, often without control for AD pathology progression.

Medical cannabinoids show preliminary indications of benefit for neuropsychiatric symptoms in moderate to severe dementia, particularly for agitation, aggressive behaviour, sleep disturbances and sexual disinhibition, however further controlled studies are required.

Systematic review of medical cannabinoids for neuropsychiatric symptoms of dementia; evidence for reduction of agitation, aggression and sleep disturbances, heterogeneous study landscape with predominantly small RCTs and observational studies.

No clear conclusion drawn on the efficacy of psychoactive cannabinoids for psychiatric manifestations in Alzheimer's dementia; multiple sources of bias and methodological deficiencies in the analysed studies.

Systematic review according to PRISMA-2009 of k=6 RCTs (n=422 patient-treatments, including crossover duplicates) on psychoactive cannabinoids for neuropsychiatric symptoms of Alzheimer's dementia. No clear conclusions on efficacy for agitation/aggression; methodological limitations identified due to polypharmacy and crossover designs.

Due to insufficient data, neither benefit nor lack of benefit of cannabinoids in dementia can be demonstrated.

Cochrane SR (2009) on cannabinoids in dementia; k=1 RCT met inclusion criteria, data not extractable (insufficient quantitative presentation). Conclusion: No evidence of efficacy for cannabinoids for behavioural symptoms of dementia or other dementia symptoms. Negative evidence from the Cochrane process.

Dronabinol reduced agitation in Alzheimer's dementia significantly more than placebo on the Pittsburgh Agitation Scale (primary endpoint, p = 0.015), but was not significant on the NPI-C A/A (p = 0.094).

THC-AD trial: 3-week RCT (n=75) of dronabinol (THC, target dose 10 mg/day) vs. placebo for agitation in Alzheimer's dementia (IPA criteria, NPI-C A/A ≥4). 84% completion rate. Co-primary outcomes: Pittsburgh Agitation Scale (PAS) showed significant reduction (fitted difference -0.74/week, SE 0.3, p=0.015, effect size d=0.53); NPI-C A/A reduction -1.26 (SE 0.67, p not significant in abstract snippet). Clinically relevant reduction in agitation. Diverse cohort (9% Black, 11% Hispanic), severe cognitive impairment.

Avidekel oil reduced agitation significantly more than placebo: 60% vs. 30% achieved a ≥4-point reduction in the Cohen-Mansfield Agitation Inventory Score (p=0.03), with good safety.

RCT (n=60, mean age 79,4 years, 60% women) on CBD-rich oil (30% CBD/1% THC) vs. placebo for behavioral disturbances in dementia over 16 weeks. Primary endpoint (CMAI reduction ≥4 points): 60,0% (24/40) under active treatment vs. 30,0% (6/20) under placebo (χ²=4,80, p=0,03). CMAI reduction ≥8 points: 50% vs. 15% (χ²=6,42, p=0,011). ANOVA showed significantly greater improvement at week 14 and 16 (F=3,18, p=0,02). Good tolerability, no significant differences in adverse events.

Low-dose THC (4,5 mg daily) showed no significant benefit for dementia-associated neuropsychiatric symptoms after 21 days, but was well tolerated.

RCT n=50 dementia patients with neuropsychiatric symptoms (NPS), THC 4,5 mg/day vs. placebo over 21 days. No significant difference in NPI reduction (mean difference 3,2; 95% CI -3,6 to 10,0), Cohen-Mansfield Agitation Inventory (4,6; 95% CI -3,0 to 12,2), quality of life (-0,5; 95% CI -2,6 to 1,6) or ADL (0,6; 95% CI -0,8 to 1,9). THC well tolerated, no effects on vital signs or episodic memory. Class I evidence: low-dose THC does not significantly reduce NPS in dementia.

Nabilone showed significant improvement in agitation (CMAI) and neuropsychiatric symptoms, but worsening in one cognition test (SIB) and increased sedation.

n=39 Alzheimer's patients (moderate to severe, sMMSE=6.5±6.8) with agitation, randomized crossover study nabilone (1–2 mg) vs. placebo over 6 weeks each. Significant reduction in CMAI (b=-4.0, 95% CI -6.5 to -1.5, p=0.003), NPI-NH total (b=-4.6, p=0.004), caregiver distress (b=-1.7, p=0.041); sMMSE improvement (b=1.1, p=0.026), however SIB worsening in completers (b=-4.6, p=0.003). Sedation more frequent under nabilone (45% vs. 16%, p=0.02).

THC did not significantly reduce the Neuropsychiatric Inventory score compared to placebo.

n=22 dementia patients with neuropsychiatric symptoms (15 men, age 76.4±5.3 years), repeated crossover RCT over 6 blocks of 2 weeks each. Oral THC 0.75 mg or 1.5 mg 2×daily vs. placebo. Primary endpoint NPI score: no reduction with THC (blocks 1-3: 1.8, 97.5% CI -2.1 to 5.8; blocks 4-6: -2.8, 97.5% CI -7.4 to 1.8). THC well tolerated, completion rate 91% (20/22), no treatment-related serious adverse events.

Nabilone is associated with TNF-α reduction and consecutive agitation decrease, however no significant effects are shown for the oxidative stress marker 4-HNE.

RCT substudy (n=38 Alzheimer's patients with agitation, 14 weeks cross-over, nabilone vs. placebo); OS marker 4-HNE associated with agitation severity (F=6,41, p=0,016); in the nabilone phase: lower baseline TNF-α predictive of agitation decrease (b=1,14, p=0,045), TNF-α decrease correlates with agitation decrease (b=1,12, p=0,006); indication of anti-inflammatory mechanism of action.

Nabiximols showed good tolerability and feasibility, however the recruitment target was not fully reached and efficacy on agitation remains unclear.

STAND feasibility RCT (n=29) of nabiximols (1:1 THC:CBD) vs. placebo for agitation in Alzheimer's dementia over 4 weeks in UK care homes. Primary goal was feasibility (≥75% follow-up, ≥80% adherence, Cohen's d ≥0,3 on CMAI). Follow-up rate 100%, adherence 100%, no study dropouts, no adverse reactions. Well tolerated and feasible; supports a larger efficacy study.

Mini-Mental State Exam total score was significantly higher in the cannabis group than in the placebo group.

Phase 2 RCT (26 weeks) with THC-CBD extract (0.35 mg THC + 0.245 mg CBD daily) vs. placebo in Alzheimer's patients (60–80 years). MMSE total score significantly higher in the cannabis group (p<0.05, mixed-model analysis); no significant differences in secondary outcomes or adverse event rate.

THC increased body sway while standing with eyes closed and increased step length while walking, but no increased risk of falls was observed and it was well tolerated.

n=18 outpatients with dementia (M=77 years), randomized crossover study on oral THC 1,5 mg 2×daily vs. placebo over 3 days. THC significantly increased body sway with eyes closed (roll angle +0,32° [±0,6], p=0,05; pitch angle +1,04° [±1,5], p=0,009; pitch velocity +1,96°/s [±3,3], p=0,02). When walking: step length +4,3 cm [±5,4] (p=0,005), trunk sway +1,18° [±1,6] (p=0,005). No falls, well-tolerated side effect profile.

THC showed low pharmacodynamic effects with minimal adverse events; some significant parameters (VAS internal perception, heart rate, body sway with eyes closed, blood pressure) were dose-dependent, but overall the effects were small.

n=10 dementia patients (age 77,3±5,6 years), randomised crossover trial of oral THC (weeks 1-6: 0,75 mg; weeks 7-12: 1,5 mg) 2×daily over 3 days vs. placebo. Only 6 of 98 adverse events THC-associated. After 0,75 mg: VAS internal perception +0,025 units (95% CI 0,010-0,040), heart rate +2 beats/min (95% CI 0,4-3,8). After 1,5 mg: body sway (eyes closed) +0,59°/s (95% CI 0,13-1,06). THC rapidly absorbed, dose-linear pharmacokinetics with large interindividual variability (CV% up to 140%). Cmax after 0,75 mg: 0,41 ng/mL (0,18-0,90); after 1,5 mg: 1,01 ng/mL (0,53-1,92). Tmax 1-2 hours. Minor pharmacodynamic effects and side effects.

Open-label pilot study (n=6) on dronabinol 2,5 mg/day over 2 weeks for nocturnal agitation in severe dementia (5 Alzheimer's, 1 vascular dementia). Reduction in nocturnal motor activity (p=0,028). Improvement in NPI total score (p=0,027) as well as in subscores for agitation, aberrant motor behavior and nighttime behavior (p<0,05). No side effects observed.

Placebo-controlled crossover study with 15 Alzheimer's patients (11 periods fully completed) who refused food. Under dronabinol, body weight increased more than under placebo, and the severity of disturbed behavior decreased (effect persisted in patients treated first with dronabinol during the placebo phase). More frequent side effects under dronabinol: euphoria, somnolence, fatigue, without treatment discontinuation. Very small case number, only exploratory indication.

MCO add-on therapy significantly reduced NPI and CGI scores in Alzheimer's patients within 4 weeks.

n=10 Alzheimer's patients, open-label pilot add-on study with medical cannabis oil (MCO/THC). CGI severity from 6,5 to 5,7 (p<0,01), NPI score from 44,4 to 12,8 (p<0,01). Significant improvement in NPI domains delusions, agitation, irritability, apathy, sleep and caregiver distress.

Dronabinol was associated with significant reduction in agitation as well as improvement in global function, sleep and food intake in patients with severe dementia.

n=40 inpatients with severe dementia; dronabinol add-on therapy showed significant improvements in all domains of the Pittsburgh Agitation Scale, in the CGI score, in sleep duration and in meal consumption; 26 adverse events, no treatment discontinuation due to adverse drug reactions.

THC/CBD (1:2) improved neuropsychiatric symptoms and agitation in severe dementia over the long term without relevant safety issues.

Prospective observational study (n=19, mean age 81,4 years, 17 women) on THC/CBD (1:2) in severe dementia over up to 13 months in long-term care. Average dose 12,4 mg THC/24,8 mg CBD daily. No treatment-related problems, limited adverse drug reactions. Clinical scores showed marked, time-stable improvement; deprescription of other medications; facilitated care. Pharmacokinetics showed the expected slight reduction in CYP1A2 and CYP2C19 activity.

THC/CBD medication led after 2 months to a 40% reduction in neuropsychiatric symptoms and agitation as well as a 50% reduction in rigidity in severely demented patients.

n=10 female patients with severe dementia and behavioural problems, THC/CBD oil (final 9.0 mg THC/18.0 mg CBD daily after 2 months). Neuropsychiatric Inventory and Cohen-Mansfield Agitation Inventory Score as well as behavioural VAS decreased by 40%, rigidity by 50%. Half of the patients reduced/discontinued other psychotropic medications. No treatment discontinuations due to side effects.

CBD-rich oil led to a reduction in the NPI-Q severity score of >30% in 94,9% of patients after 3 months (p<0,001), with improvements sustained up to 24 months.

Treatment of neuropsychiatric symptoms in Alzheimer's dementia with a compounded cannabis formulation; clinical observational data on behavioral improvements, limited methodological rigor.

In an 85-year-old patient with dementia with Lewy bodies, THC tincture led to rapid improvement of agitation after multiple antipsychotics had failed.

Case report n=1: 85-year-old man with Lewy body dementia and treatment-refractory aggression (multiple antipsychotic regimens failed). After starting THC tincture, rapid behavioral improvement, successful discharge home. THC as an alternative to antipsychotics for persistent dementia-associated agitation. Limited evidence from a single case.

n=1 case report: 75-year-old patient with mild Alzheimer's dementia, cannabis extract in microdoses over 22 months. Clinical evaluation with MMSE and ADAS-Cog. Report describes improvement of memory and brain functions without major side effects.

Narrative review reports promising preclinical effects (reduction of amyloid plaques, stimulation of neurogenesis) and clinical benefits for dementia symptoms, but also points to contradictory findings and uncertainties regarding dosage and timing.

Narrative review on cannabinoids in Alzheimer's dementia. Preclinical evidence shows reduction of amyloid plaques and stimulation of hippocampal neurogenesis in AD rodent models. Clinical studies report improvements in dementia-associated symptoms. Review emphasizes the need to identify correct therapeutic dosage and treatment timing.

Six studies showed significant improvements in agitation and aggression under synthetic cannabinoids, however with considerable methodological limitations.

Narrative review: k=6 studies (case reports, case series, controlled trials) on synthetic cannabinoids (dronabinol, nabilone) for agitation/aggression in Alzheimer's dementia; all 6 studies showed significant improvements; limitations: small sample sizes, short study duration, partly lacking placebo control.

Narrative overview of active substances in clinical development for behavioral and psychological symptoms of dementia (BPSD). Highlights cannabinoids alongside dextromethorphan/quinidine, lumateperone and others as a promising class with positive results and good tolerability. Calls for large, adequately powered studies with validated BPSD outcome measures.

Synthetic cannabinoids are well tolerated but show no significant effect on neuropsychiatric dementia symptoms in RCTs; case reports suggest possible adjuvant benefit.

Narrative review on the safety and efficacy of cannabinoids for behavioural and neuropsychiatric symptoms of dementia; 2 RCTs with synthetic THC showed good tolerability, but no significant therapeutic effect on NPI scores; case reports and open-label studies suggest possible benefit as adjunctive therapy for agitation.

Cannabinoids appear to be well tolerated and potentially effective for agitation and sleep in dementia patients, but the evidence remains limited due to small sample sizes and heterogeneous populations.

Narrative review; k=8 studies/reports (7 studies + 1 case report) on cannabinoids for neuropsychiatric symptoms (NPS), pain, and weight loss in dementia; 5 of 7 studies reported decreased agitation or improved sleep under cannabinoids; 1 crossover study showed positive weight effect; 1 chart review showed increased food intake without weight effect. Overall picture: well tolerated, possibly effective for NPS/agitation; further controlled studies necessary.

Older studies with low-dose oral synthetic THC showed no positive results, more recent studies with THC/CBD-based oral medication at higher doses show promising results and are feasible and safe.

Narrative review on cannabinoids for behavioral symptoms of dementia; summary presentation of the evidence base with focus on agitation, aggression and apathy, no systematic meta-analysis.