Cannabis-Based Oil Fails to Improve Pain or Nonmotor Symptoms in Parkinson Disease Study

A recent phase 2 randomized, double-blind, placebo-controlled trial published in Movement Disorders reported that an oral cannabis-based oil containing cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) did not significantly reduce pain or other nonmotor symptoms (NMS) in patients with Parkinson disease (PD) compared with placebo over 9 weeks.¹ The findings represent the first phase 2 placebo-controlled trial to specifically evaluate cannabinoids for PD-related chronic pain as a primary end point, and challenge the analgesic promise suggested by earlier observational and open-label work.

Study Overview

Lead author Gabriel T. Kubota, MD, PhD, a neurologist at the University of São Paulo Hospital in Brazil, and colleagues conducted a parallel-group, double-blind, phase 2 trial at the hospital's outpatient clinics and the surrounding community. Adults aged 25 years or older who met Movement Disorder Society diagnostic criteria for PD and reported PD-related chronic pain, defined as persisting or recurring pain for 3 or more months per the PD-Pain Classification System (PD-PCS), were eligible for enrollment. Patients with severe psychiatric disorders, prior cannabis use, high risk for substance use disorder, or liver disease were excluded. Of 140 individuals screened, 101 were randomized 1:1 to receive either the cannabis-based oil or a matched placebo, and 87 completed the full study protocol.

Participants underwent a 3-week titration phase, beginning at 2 drops twice daily (CBD 10.97 mg/day; THC 0.24 mg/day), with dose escalation guided by tolerability to a final maintenance dose of CBD 43.88 mg/day and THC 0.96 mg/day administered across a subsequent 6-week phase. The formulation was extracted from Cannabis sativa L. and contained CBD at 96 mg/mL and THC at 2.1 mg/mL. The primary outcome was between-group difference in PD-PCS score at the final visit (day 63).

Key Findings

No significant difference in PD-PCS scores was observed between the CBD/THC and placebo groups at the final assessment (P = 0.757), and the study was halted early after a pre-planned interim futility analysis indicated results were below the threshold to justify continuation. Effect sizes at day 21 and day 63 were small and not clinically meaningful (0.20 and 0.09, respectively). Secondary pain end points were similarly null. Total Brief Pain Inventory scores did not differ significantly between groups (P = .776), nor did the proportion of participants achieving a 30% or greater reduction in pain intensity.

Across the broader NMS battery, including the MDS-Non-Motor Rating Scale, the Scale for Outcomes in Parkinson Disease-Autonomic Dysfunction, the Hospital Anxiety and Depression Scale, and the Montreal Cognitive Assessment, no significant between-group differences emerged at the final visit. Motor outcomes assessed with MDS-Unified Parkinson's Disease Rating Scale Part III, the New Freezing of Gait Questionnaire, and the Timed Up-and-Go scale were also unchanged.

READ MORE: Bezisterim Shows Improvements in Motor, Nonmotor Symptoms in Phase 2 SUNRISE-PD Trial

The cannabis formulation was generally safe and well-tolerated. Both groups experienced mild adverse events (AEs); irritability occurred more frequently in the CBD/THC group (P = .005). Two serious AEs, 1 case each of Guillain-Barré syndrome and cryptococcal meningitis, were deemed unrelated to treatment. Severity of Dependence Scale scores did not differ between groups.

Clinical Context

Pain affects an estimated 40% to 85% of patients with PD and is among the most disabling and undertreated NMS in the disease.² Current pharmacologic options for PD-related pain are limited; neither duloxetine nor oxycodone-naloxone has demonstrated convincing benefit in controlled trials.¹ Against this backdrop, cannabinoids have attracted growing clinical interest, supported by preclinical analgesic data, web-based patient surveys, open-label observational studies, and a phase Ib safety trial establishing tolerability of cannabis oil in PD.³ However, no prior phase 2 or 3 randomized trial had tested a cannabinoid formulation for PD-related pain as the primary end point.

Interpretation

The negative findings may be partially attributable to the low THC dose employed. At 0.96 mg/day, the THC concentration was substantially lower than formulations associated with analgesic benefit in other pain conditions, including a phase 3 trial of Cannabis sativa extract for chronic low back pain that used 32.5 mg THC. and lower than doses studied in prior PD cannabinoid trials.¹ The authors also noted a pronounced placebo response: more than one-third of placebo recipients reported meaningful pain reduction, which may have diminished the ability to detect a treatment signal. Notably, no cognitive safety signal emerged in the active treatment group, which contrasts with trends observed in prior trials using higher THC concentrations.

Limitations

The study's 9-week follow-up period limits conclusions about long-term safety and efficacy. Plasma cannabinoid concentrations were not measured, and participants received no standardized instructions on meal timing relative to dosing, an important variable given that bioavailability of both CBD and THC increases with high-fat food intake. More patients in the CBD/THC group underwent deep brain stimulation than in the placebo group (22% vs 12%), which, though not statistically significant (P = .213), could have introduced symptomatic confounding. The trial was conducted at a single academic center in Brazil, limiting generalizability.

Future Research

The authors called for future trials using larger samples and higher CBD and THC concentrations before cannabinoids are dismissed as a therapeutic class for PD-related pain. Standardized pharmacokinetic monitoring, meal-timing protocols, and longer follow-up periods should be incorporated into next-phase designs to better characterize the dose-response relationship and long-term safety profile.

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REFERENCES
1. Kubota GT, Parmera JB, Deltreggia M, et al. Cannabis-based oil for pain and other non-motor symptoms in Parkinson's disease: a randomized controlled trial. Mov Disord. 2026. doi:10.1002/mds.70449
2. de Andrade DC, Mylius V, Perez-Lloret S, et al. Pain in Parkinson disease: mechanistic substrates, main classification systems, and how to make sense out of them. Pain. 2023;164(11):2425–2434.
3. di Luca DG, Gilmour GS, Fearon C, et al. A phase Ib, double blind, randomized study of cannabis oil for pain in Parkinson's disease. Mov Disord Clin Pract. 2023;10(7):1114–1119.
4. Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson's disease — an evidence-based medicine review. Mov Disord. 2019;34(2):180–198.
5. Liu Y, Bainbridge J, Sillau S, et al. Short-term cannabidiol with Δ-9-tetrahydrocannabinol in Parkinson's disease: a randomized trial. Mov Disord. 2024;39(5):863–875.