Parkinson Disease

Medical cannabis shows efficacy for MS spasticity (oral cannabis extract), probable efficacy for pain, but probable ineffectiveness for tremor and unclear evidence for epilepsy and other neurological diseases.

Systematic review by the American Academy of Neurology on medical cannabis in neurological diseases; k=34 studies (8 Class I). For Parkinson's: Oral cannabis extract (OCE) probably ineffective for treating levodopa-induced dyskinesias. Oral cannabinoids of unclear efficacy for non-chorea-related Huntington's symptoms, Tourette syndrome, cervical dystonia, and epilepsy. Risk of serious psychopathological adverse effects ~1%.

No compelling evidence of cannabis benefit in Parkinson's disease, but potential benefits identified for tremor, anxiety, pain, sleep quality and quality of life.

Systematic review and meta-analysis on cannabis in Parkinson's disease; k=23 studies (5 RCTs + 18 non-randomised studies). No convincing evidence for a general cannabis recommendation in PD, but potential benefits identified for tremor, anxiety, pain, sleep quality and quality of life. Call for further well-designed RCTs in these specific areas.

Safinamide showed the greatest pain reductions (SMD = -4.83), followed by cannabinoids, opioid, multidisciplinary care and other therapies; safinamide is recommended as an important adjuvant to standard medication.

Systematic review and meta-analysis across k=25 RCTs on pain therapy in Parkinson's disease. Greatest pain reduction with safinamide (SMD=-4.83, 95% CI [-5.07 to -4.59], p<0.0001), followed by cannabinoids and opioids. Moderate evidence quality (GRADE).

Positive effects on motor and non-motor symptoms in uncontrolled studies were not confirmed by a few small RCTs; only individual RCTs showed effects on levodopa-induced dyskinesias, anxiety and tremor.

Systematic review on medical cannabinoids in Parkinson's; k=14 studies (5 RCTs + 9 uncontrolled studies). Positive effects on motor (5 studies) and non-motor symptoms (4 studies) from uncontrolled studies were NOT confirmed in the few, small RCTs. Only 1 RCT showed reduction of levodopa-induced dyskinesias, 1 RCT reduction of anxiety and tremor amplitude in an anxiogenic situation; 3 RCTs without effect on motor/non-motor symptoms. Conclusion: insufficient evidence for cannabis use in PD.

Cannabis, CBD and nabilone consistently improved motor symptoms more than placebo; all treatments improved various non-motor symptoms with mostly mild side effects.

Systematic review on cannabinoids in Parkinson's disease; k=13 clinical studies included. Cannabis, CBD and nabilone consistently improved motor symptoms more than placebo. Non-motor symptoms: cannabis improved pain intensity, CBD reduced psychiatric symptoms in a dose-dependent manner. Side effects mostly mild, rare with CBD (except at very high doses).

Randomised studies show no efficacy of cannabinoids for motor symptoms of Parkinson's disease.

Systematic review on cannabis in Parkinson's disease; k=7 randomised studies identified. Results do NOT support efficacy of cannabinoids for motor symptoms of Parkinson's disease. Conclusion: currently insufficient data for cannabinoid use in PD patients.

Cannabinoids probably do not reduce the symptoms of Parkinson's disease or dyskinesia and are probably associated with common adverse effects.

Umbrella review across k=6 systematic reviews (8 studies in total, of which 4 RCTs) on cannabinoids in Parkinson's disease. Meta-analysis according to GRADE: cannabinoids probably do NOT reduce Parkinson's symptoms or dyskinesias and are probably associated with common adverse effects.

CBD/THC showed no significant benefit over placebo on motor MDS-UPDRS (difference -1,80, p=0,379); placebo was possibly superior for sleep and cognition, with more adverse effects in the CBD/THC group.

RCT n=61 (CBD/THC n=31, placebo n=30), 2 weeks titration to final dose 191,8±48,9 mg CBD + 6,4±1,6 mg THC daily. Primary endpoint motor MDS-UPDRS: reduction -4,57 (95% CI -8,11 to -1,03; p=0,013) in CBD/THC group vs. -2,77 (-4,92 to -0,61; p=0,014) in placebo; group difference not significant: -1,80 (-5,88 to 2,27; p=0,379). No benefit, possibly worsened cognition and sleep; strong placebo effect. Adverse effects mild, more frequent in CBD/THC group.

Nabilone showed no significant worsening of NMS symptoms (MDS-UPDRS-I: 1.00 vs. placebo: 2.63, p=0.030 for difference), but the placebo group improved more strongly; positive trends reported for anxiety and sleep problems.

Phase II RCT, n=47 Parkinson's patients with stable motor function but troublesome non-motor symptoms (NMS, MDS-UPDRS-I ≥4). Open-label nabilone titration (0,25–1 mg 2×/d), then randomisation of responders to nabilone vs. placebo (n=19). Primary endpoint MDS-UPDRS-I after 4 weeks: placebo group worsened by 2,63 points (95% CI 1,53–3,74, p=0,002), nabilone group by only 1,00 points (95% CI −0,16–2,16, p=0,280); difference 1,63 points (95% CI 0,09–3,18, p=0,030, effect size 0,66). Positive effects mainly on anxiety and nocturnal sleep problems. 77% AEs in the titration phase (mostly transient), no serious AEs.

The CBD/THC group showed worse performance in Animal Verbal Fluency and reported cognitive adverse events at least twice as often as the placebo group.

n=58 (CBD/THC n=29, placebo n=29), randomized, double-blind phase IIb study of high-dose CBD (100 mg) + low-dose THC (3,3 mg) in Parkinson's disease over an average of 16,3 days. Primary outcome: cognitive safety. CBD/THC group showed worse performance in the Animal Verbal Fluency Test vs. placebo (adjusted for age/education, p<0,05); cognitive adverse events at least twice as frequent as under placebo.

CBD improved naming scores on the MoCA, but showed no differences in the primary outcome (delayed recall) and no benefit for motor, cognitive, or affective symptoms.

n=51 Parkinson's patients (CBD n=27 vs. placebo n=24), sublingual CBD 26 mg/day (+ 1,2 mg/day THC) over 12 weeks. Primary endpoint (MoCA delayed recall) no group differences. CBD group improved MoCA naming score (mean difference: 0,37, 95% CI: 0,01–0,73). No differences in motor, cognitive, or affective symptoms; increased alkaline phosphatase in the CBD group, no serious adverse events.

CBD showed no difference to placebo in the primary endpoints (frequency of nights with RBD, CGI-I, CGI-S); only temporary improvement in sleep satisfaction in weeks 4-8 at the 300mg dose.

n=33 Parkinson's patients with REM sleep behavior disorder (RBD), randomized 1:1 to CBD (75–300 mg) vs. placebo over 14 weeks. Primary outcomes (frequency of RBD nights, CGI-I, CGI-S): no difference CBD vs. placebo. Secondary outcome: significant improvement in sleep satisfaction with 300 mg CBD vs. placebo at week 4–8 (p=0,049 and p=0,038 respectively).

Acute CBD administration (300 mg) reduced anxiety-induced symptoms and tremor amplitude in Parkinson's patients in a stressful situation.

n=24 Parkinson's patients, randomized crossover study on acute CBD administration (300 mg) vs. placebo in the Simulated Public Speaking Test (SPST). CBD significantly reduced experimentally induced anxiety (VAMS anxiety factor, p<0,05) and decreased tremor frequency (accelerometer, p<0,05).

CBD showed no difference from placebo in reducing RLS/WED severity in patients with Parkinson's and RBD.

Post-hoc analysis of a phase II/III RCT (n=18) of CBD (75-300 mg) vs. placebo in Parkinson's patients with RBD and restless legs syndrome; CBD showed no difference from placebo for the IRLSSG severity score after 14 weeks of follow-up.

Oral cannabis extract did not improve dyskinesia or parkinsonism compared with placebo.

n=17 Parkinson's patients (completers out of 19 randomised) with levodopa-induced dyskinesia, oral cannabis extract vs. placebo, 4 weeks per phase; no treatment effect on UPDRS dyskinesia score (items 32–34) or secondary endpoints (Rush Scale, Bain Scale, PDQ-39). No pro- or antiparkinsonian effect; well tolerated.

Nabilone significantly reduces levodopa-induced dyskinesia in Parkinson's patients versus placebo.

n=7 Parkinson's patients with levodopa-induced dyskinesia, nabilone (cannabinoid receptor agonist) vs. placebo (randomised, double-blind, crossover); nabilone significantly reduced levodopa-induced dyskinesia (p<0.05 implied).

CBD significantly improved motor and non-motor Parkinson's symptoms, but caused frequent side effects and relevant liver enzyme elevations at high dose.

Open-label study (n=13 PD patients); CBD (Epidiolex, 5–25 mg/kg/day, 10–15 days); MDS-UPDRS total improved by 17,8% (p=0,012) and motor score by 24,7% (p=0,004); liver transaminases elevated in 38,5% of participants (20–25 mg/kg/day); discontinuation rate 23% due to intolerability.

CBD 300 mg/day improved quality of life (PDQ-39) versus placebo, with no effect on motor function or neuroprotection markers.

n=21 Parkinson's patients without dementia, CBD 75 mg/d vs. CBD 300 mg/d vs. placebo (7 per group); no statistically significant difference in UPDRS motor scores; quality of life (PDQ-39 total score) significantly better in the CBD 300 mg group vs. placebo (p=0.05).

Open pilot study (n=6 Parkinson patients with psychosis present for at least 3 months): Cannabidiol (CBD, flexible oral dose starting from 150 mg/day over 4 weeks in addition to standard therapy) significantly lowered psychotic symptoms (Brief Psychiatric Rating Scale, Parkinson Psychosis Questionnaire), did not worsen motor function and reduced UPDRS total scores; no side effects observed. Very weak evidence: tiny sample, uncontrolled, open-label design, only preliminary data.

Subjective symptom improvements were reported by a relevant proportion of cannabis-using Parkinson's patients, with inhaled THC having a stronger effect on motor symptoms than oral CBD.

n=1.348 Parkinson's patients (1.123 nationwide + 225 local), 8,4% reported cannabis use. >40% of cannabis users reported reduction of pain and muscle cramps; >20% improvement of rigor/akinesia, freezing, tremor, depression and anxiety. Inhaled THC reduced akinesia/rigor more frequently than oral CBD (50,0% vs. 35,4%, p<0.05).

Medical cannabis showed improvements in various Parkinson's symptoms, in particular falls (r=0,89), pain relief (r=0,73), depression (r=0,64), tremor (r=0,64), muscle stiffness (r=0,62) and sleep (r=0,60), but caused significant side effects (confusion and hallucinations) leading to discontinuation in 10,6% of patients.

n=47 non-demented Parkinson's patients (mean disease duration 10,8±8,3 years, median H&Y stage III), retrospective telephone survey after ≥3 months of cannabis treatment (mean duration 19,1±17,0 months). Effect size (r) for improvements: falls r=0,89, pain reduction r=0,73, depression r=0,64, tremor r=0,64, muscle stiffness r=0,62, sleep r=0,60. Most common side effects: cough (34,9% among smokers), confusion and hallucinations (17% each), 10,6% treatment discontinuation due to side effects.

Significant improvement in motor symptoms (tremor, rigidity, bradykinesia) as well as sleep and pain scores after cannabis consumption, no substantial side effects observed.

n=22 Parkinson's patients, open-label observational study. UPDRS motor score improved significantly from 33,1±13,8 to 23,2±10,5 after cannabis consumption (t=5,9; p<0,001). Significant improvements in tremor (p<0,001), rigidity (p=0,004) and bradykinesia (p<0,001). Additionally significant improvement of sleep and pain scores. No significant side effects observed.

Cannabis led to significant improvements in motor symptoms (UPDRS), pain indices (PRI, VAS) and changes in pain thresholds after 30 minutes and after long-term use.

n=20 Parkinson's patients with cannabis license, evaluated before, 30 min after and after long-term cannabis consumption. Significant decrease in motor UPDRS score (38,1±18 to 30,4±15,6, p<0,0001), Pain Rating Index (27±13,5 to 9,7±11, p=0,001) and VAS (6,4±2,8 to 3,6±3,1, p=0,0005). Cold pain threshold decreased significantly in the more affected extremity (19,5±5,2 to 15,6±8,7°C, p=0,02). After long-term exposure (median 14 weeks) significant decrease in heat pain threshold (43,6±3,5 to 40,9±3,3°C, p=0,05).

Case report n=1, 77-year-old man with advanced Parkinson's disease (22 years since diagnosis) and gastrostomy. After treatment with Cannabis sativa oil: improvement in walking ability, pasty food orally possible without aspiration, significant improvement in non-motor symptoms (more active, more communicative, less depressed).

Anonymous questionnaire survey of n=339 Parkinson's patients: 25% reported cannabis use; of these, 45,9% described a subjective improvement of motor symptoms. No control arm; purely reported patient perspective.

CBD reduced RBD event frequency promptly and substantially in all 4 Parkinson's patients.

Case series (n=4) with Parkinson's patients with REM sleep behaviour disorder (RBD): CBD treatment led to a prompt and substantial reduction in the frequency of RBD-related events without side effects in all 4 patients.