Table 1 Study characteristics (n = 25)

Ahmed et al. 2015

12-week crossover RCT (n = 10)

Adults with dementia with significant neuropsychiatric symptoms

Dronabinol; 1.5–3 mg vs. placebo, p.o.

98 mild AEs were reported during the study period. Thirteen reported AEs were possibly related to study drugs (dronabinol or placebo). No SAEs related to THC were reported.

22

Balash et al. 2017

Retrospective cohort study (n = 47)

Adults with PD

MC; 0.2–2.25 g/day, mostly smoked (84%)

MC improved PD symptoms in the majority (82.2%), while two (4.4%) reported no difference and six (13.3%) reported a worsening of symptoms. 59.6% reported AEs: confusion (17%), anxiety (17%), hallucinations (17%), short-term amnesia (6.5%), psychosis (2.1%), cough (34.9%), dyspnea (4.7%), dizziness (12.8%), and unsteadiness (15.6%).

12

Bruce et al. 2018

Retrospective cohort study (n = 30)

Patients receiving medicinal cannabis for a qualifying health condition

MC; 60% smoked cannabis flowers

MC was most frequently (60% of participants) reported as an alternative to prescription medications. Minor AEs were reported with MC compared to prescription medications.

10

Carroll et al. 2004

10-week crossover RCT (n = 19, ages 18–78)

19 PD patients with levodopa-induced motor symptoms (dyskinesia)

THC; 0.25 mg/kg and 0.125 mg/kg CBD vs placebo, p.o.

UPDRS dyskinesia scores worsened (p = 0.09), and mild AEs were reported in both groups. All AEs improved by dose reduction, and there were no SAEs. 37 mild AEs reported total: 18 physical, with dry mouth most common (n = 4), and 20 psychological, with drowsy/lethargic most common (n = 9).

20

Chagas et al. 2014a

6-week RCT (n = 21)

Adults with idiopathic PD with motor symptoms (dyskinesia)

CBD; capsules; 75–300 mg (n = 14) vs. placebo (n = 7)

No difference (p = 0.544) in mean UPDRS score variations between the three treatment groups. No AEs were observed in any of the groups through UKU or verbal reports. No difference (p = 0.855) between groups in BDNF levels, measured complementary to subjective AE reports.

20

Chagas et al. 2014b

6-week case series (n = 4)

Patients with PD in RCT (Chagas et al. 2014a) that also fulfilled criteria of: a) complete clinical assessment for RBD and b) at least two episodes of complex sleep-related behaviors per week.

CBD; capsules 75 mg/day (n = 3), 300 mg/day (n = 1)

Prompt, substantial, and persistent reduction in the frequency of RBD-related events in all four cases.

AEs were not reported.

9

Consroe et al. 1991

15-week crossover RCT (n = 18)

Adults with HD not taking antipsychotics with motor symptoms (chorea)

CBD; 10 mg/kg vs. placebo, p.o., b.i.d.

Treatment response favored CBD with a lower median M and Q chorea severity score (11.5) than placebo (13.7, p = 0.71). No difference between CBD and placebo for cannabis side-effect inventory. Three male patients withdraw after completing 5, 6, and 10 weeks of the study for reasons unrelated to the trial.

20

Curtis et al. 2009

15-week crossover RCT (n = 44)

Adults with HD with motor symptoms (chorea)

Nabilone; 1–2 mg vs. placebo, p.o., b.i.d.

No difference in UHDRS total motor score between treatment groups. There were three SAEs, seven withdrawals from the study (two due to SAEs).

22

Herrmann et al. 2019

14-week RCT (n = 39)

Adults with dementia and NPS

Nabilone; 1–2 mg vs. placebo, p.o.

Nabilone reduced agitation. However, it increased the risk of sedation and worsened cognition.

27

Lopez-Sendon Moreno et al. 2016

12-week crossover RCT (n = 25)

Adults with HD

Dronabinol; 2.7 mg THC/2.5 mg CBD per spray, 12 sprays per day

No differences in motor, cognitive, or functional outcomes against placebo, or in symptomatic effects.

24

Lotan et al. 2014

1-day prospective cohort study (n = 22)

Adults with PD

MC; smoked 0.5 g per day for 2 months

UPDRS total motor score improved (p < 0.001) from baseline (33.1 ± 13.8) to 30 min after (23.2 ± 10.5) cannabis consumption. One patient had hypoglycemia that resolved after oral glucose intake, and one patient complained of dizziness. AEs included sleepiness, palpitations, and bad taste.

17

Mahlberg and Walther 2007

2-week RCT (n = 24)

Adults with AD and NPS

Dronabinol; 2.5 mg vs. melatonin 3 mg, p.o.

The nocturnal activity was significantly reduced (p = 0.001) in the dronabinol group. No AEs were observed.

13

Mesnage et al. 2004

9-day RCT (n = 25)

Adults with PD and motor fluctuations and levodopa-induced dyskinesia

SR 141716; 20 mg; SR 48692 180 mg; SR 142801; 200 mg vs. placebo, p.o.

No significant differences in the delay before turning “on” between groups. No AEs were observed. One patient did not complete the study due to unexpected nausea (SR 48692), symptoms disappeared within 24 h.

14

Shelef et al. 2016

4-week RCT (n = 11)

Adults with AD and BPSD

Dronabinol; 5–15 mg vs. placebo, p.o., b.i.d.

MMSE showed modest trend (p = 0.08) of change from baseline (10.3) to 4 weeks (11.0). There were three AEs reported, including confusion at 10.0 mg dose, a fall and resulting pelvic fracture, and dysphagia, who withdrew from the study.

16

Shohet et al. 2017

40-week prospective cohort study (n = 20)

Adults with PD

Cannabis; smoked (n = 18) or vaporized (n = 2)

Decrease (p < 0.0001) in UPDRS motor function score from before (38.1 ± 18) to 30 min after (30.4 ± 15.6) cannabis consumption. No AEs were observed.

11

Sieradzan et al. 2001

2-week crossover RCT (n = 9)

Adults with PD and stable levodopa-induced dyskinesia

Nabilone; 0.03 mg/kg vs. placebo, p.o.

Nabilone reduced (p < 0.05) median total dyskinesia score (17, range 11 to 25) over placebo (22, range 16 to 26). All patients experienced a postural fall in systolic blood pressure, but no difference between groups. AEs included sedation, dizziness, hyperacusis, partial disorientation, and visual hallucinations. Two patients withdrew after nabilone from vertigo and symptomatic postural hypotension.

19

van den Elsen et al. 2015a

3-week RCT (n = 50)

Adults with AD, vascular, or mixed dement and clinically relevant NPS (NPI ≥ 10)

Dronabinol; 4.5 mg (n = 24) vs. placebo (n = 26), p.o., t.i.d.

NPI was reduced in both treatment groups after 14 (p = 0.002) and 21 days (p = 0.003). There was no difference (NPI change score = 3.2 [− 3.6 to 10.0]) between groups at 21 days. There was no difference in AEs between groups (16 vs. 14). Three patients withdrew: pneumonia, nausea, and withdrew consent.

27

van den Elsen et al. 2015b

14-week crossover RCT (n = 22)

Adults with AD, vascular, or mixed dement and clinically relevant NPS (NPI ≥ 10)

Dronabinol; 1.5–3 mg (n = 22) vs. placebo (n = 22), p.o., b.i.d.

No difference in effect on NPI between dronabinol and placebo. There were 184 AEs, distributed between dronabinol (94) and placebo (93) treatments. Four SAEs occurred in three patients, all requiring a prolongation of hospitalization. None of the SAEs were judged to be related to the study drug. Two patients withdrew, one due to the occurrence of malignancy and extensive use of psychotropic rescue medication.

25

van den Elsen et al. 2017

8-week crossover RCT (n = 18)

Adults with AD, vascular, or mixed dementia and clinically relevant NPS (NPI ≥ 10)

Dronabinol; 1.5 mg (n = 18) vs. placebo (n = 18), p.o., b.i.d.

Static balance as assessed by body sway (roll angle) was similar with eyes opened (p = 0.10), but significantly higher (0.32 ± 0.6°/s, p = 0.05) after dronabinol versus placebo administration.

24

Venderova et al. 2004

Retrospective cohort study (n = 630)

Adults with PD

Whole cannabis; smoked

45.9% (n = 39) described mild or substantial alleviation of PD symptoms in general. There were no AEs reported.

8

Volicer et al. 1997

12-week crossover RCT (n = 15)

Adults with AD and food refusal

Dronabinol; 2.5 mg vs. placebo, p.o., b.i.d.

Bodyweight increased (p = 0.006) over the 12-week study period regardless of the order of treatment. However, the treatment effect was more significant (p < 0.017) when participants received dronabinol during the first (7.0 ± 1.5 lbs) versus second (2.3 ± 1.7 lbs) period, compared to placebo during the first (4.6 ± 1.3 lbs) versus second (1.7 ± 2.3 lbs). One patient withdrew from a seizure and two from infections, and one died of a heart attack.

18

Walther et al. 2006

2-week RCT (n = 6)

Adults with dementia and nighttime agitation

Dronabinol; 2.5 mg vs. placebo, p.o.

Actigraphy nocturnal motor activity during the last 5-nights of treatment. Dronabinol reduced (p = 0.028) nocturnal motor activity from baseline (24.29) to 14 days (3.76). No AEs were observed.

17

Walther et al. 2011

4-week crossover RCT (n = 2)

Two patients with AD or mixed dementia with agitation

Dronabinol; 2.5 mg vs. placebo, p.o.

No severe AEs or deterioration occurred during the trial.

16

Woodward et al. 2014

Retrospective cohort study (n = 40)

Inpatients with dementia and NPS

Dronabinol; variable dose

Dronabinol decreased agitation and improve global ratings of function, sleep duration, and proportion of meals consumed, but caused mild AE.

20

Zuardi et al. 2009

4-week RCT (n = 6)

Adults with PD and treatment-resistant psychosis

CBD; flexible dose, starting at 150 mg vs. placebo, p.o.

Reduced BPRS scores (18.5 to 5.5, p < 0.001) in BPRS total scores from baseline (median 18.5) to 4 weeks (5.5) with CBD treatment. No AEs were observed.

17