Short-term cannabidiol with delta-9-tetrahydrocannabinol in Parkinson disease: a randomized trial

Abstract

Background:

Cannabis use is frequent in Parkinson disease (PD), despite inadequate evidence of benefits and risks.

Objective.

To study short-term efficacy and tolerability of relatively high cannabidiol (CBD)/low delta-9-tetrahydrocannabinol (THC) to provide preliminary data for a longer trial.

Methods:

Persons with PD with ≥20 on motor Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) who had negative cannabis testing took cannabis extract (National Institute of Drug Abuse) oral sesame oil solution for 2 weeks, increasing to final dose of 2.5mg/kg/day. Primary outcome was change in motor MDS-UPDRS from baseline to final dose.

Results.

Participants were randomized to CBD/THC (n=31) or placebo (n=30). Mean final dose (CBD/THC group) was 191.8 ±48.9mg CBD and 6.4 ±1.6mg THC daily. Motor MDS-UPDRS was reduced by 4.57 (95% CI, −8.11 to −1.03; p=0.013) in CBD/THC group, and 2.77 (−4.92 to −0.61; p=0.014) in placebo; the difference between groups was non-significant: −1.80 (−5.88 to 2.27; p=0.379). Several assessments had a strong placebo response. Sleep, cognition, and activities of daily living showed a treatment effect, favoring placebo. Overall adverse events were mild and reported more in CBD/THC than placebo group. On 2.5mg/kg/day CBD plasma level was 54.0 ± 33.8 ng/mL; THC 1.06 ± 0.91 ng/mL.

Conclusions:

The brief duration and strong placebo response limits interpretation of effects, but there was no benefit, perhaps worsened cognition and sleep, and many mild adverse events. Longer duration high quality trials that monitor cannabinoid concentrations are essential and would require improved availability of research cannabinoid products in the U.S.

Introduction

Parkinson disease (PD) is a common, debilitating disorder with insufficient treatment. Since cannabis is increasingly available in the U.S., with recreational use legal in 24 states and Washington DC, and in numerous countries, many persons with PD self-medicate.^{1, 2} This is despite expense and inadequate data regarding its benefits and risks in PD.^{3, 4} Information is lacking because there are many forms of cannabis, and cannabis research is difficult, at least in the U.S., because of governmental restrictions on regulated products.

Research is needed to define what cannabinoids and doses are useful in PD. Delta-9-tetrahydrocannabinol (THC) induces a “high,” psychosis, cognitive dysfunction, and anxiety⁵, while, cannabidiol (CBD), has been reported to have benefits in PD.^{1, 6–9} Therefore, CBD is likely to be safer than THC, but combining it with some THC has merit, since many persons with PD take both and there are reports of greater benefit from THC than CBD in PD.^{1, 10}

Based on literature and our experience, we sought an oral formulation with the following combination: greater cannabidiol (CBD)^{1, 6–9} than delta-9-tetrahydrocannabinol (THC),⁵ with between 150 and 1000mg CBD^{6–8, 11, 12} and <10mg THC daily. Since there was limited availability of a feasible compound and no matching placebo given federal U.S. restrictions, we designed a short-term trial, with the aim to provide feasibility and safety data for a longer trial. We hypothesized 100mg CBD with low dose THC orally twice daily for two weeks would lead to improved PD motor and some non-motor symptoms, with minimal adverse effects.

Methods

This phase 2, randomized, double-blind, parallel-group, placebo-controlled, single-site study was funded by the Colorado Department of Public Health and Environment. The funder had no influence on study design or interpretation of results. ClinicalTrials.gov ID is NCT0358213.

Participants

All participants provided written informed consent. The study was approved by the Colorado Multiple Institutional Review Board #IORG0000433 and the FDA, IND 138195, and the principal investigator, M.A.L., held a DEA Schedule 1 license. An independent data and safety monitoring board provided oversight. Candidates were recruited from the University of Colorado Movement Disorders Center, a tertiary-care academic referral center, and from the local community. Eligibility required idiopathic PD¹³ with a score of ≥20 on the motor, Part III, of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)¹⁴. Since we sought to study effects of the study drug on persons with PD receiving usual medical care, if participants were on anti-PD medication, this score was required when the medications were working optimally, i.e., best ON state. Participants agreed not to drive while on study drug. Major exclusion criteria included a positive blood test at screening or urine test at baseline for cannabinoids, history of drug or alcohol dependence, and taking specified potentially hepatotoxic medications. Prior studies found doses of >1500mg/day were associated with liver enzyme changes^{8, 12} and hepatitis.⁸

Study Design and Procedures

Eligible candidates were randomized 1:1 to study drug or placebo, by a computer-generated randomization schedule. The randomization model stratified participants by age (45–60 vs. 61–85) and Modified Hoehn & Yahr¹⁵ (1–2.5 vs. 3–5) into blocks of four, with two per block being assigned to each treatment group. Study visits included a screening visit, a baseline visit within four weeks, an initial and final dose visit, and a safety follow-up visit two weeks later. Participants were called after four days on the final dose to check for tolerability, and after three and seven days of stopping the study drug to check for signs of withdrawal. To monitor compliance, tolerability and efficacy, participants filled out a daily home diary, recording the date, time and dose of study drug, as well as adverse and beneficial events. Participants were allowed to take a reduced dose as needed for tolerability.

The statistician, S.S., and the PharmD team were the only unblinded study staff. The statistician generated the random allocation sequence and notified the lead PharmD, J.B., via encrypted email, of the allocation assignment. The appropriate study drug was prepared by the PharmD team within a few days of the baseline visit. Despite best efforts, e.g., strawberry extract being added to the active and placebo products to mask taste, the placebo was slightly different in appearance and odor, so procedures were developed to optimize preservation of the blind. First, the design of the study was changed from crossover to parallel and participants were discouraged from conversing. Second, the study drug for each participant was prepared into a brown opaque bottle that was placed into a plastic Ziplock bag and then into a “masking envelope”, a thick brown postage envelope with plastic bubble wrap lining to obscure odor. The envelope was kept in a double locked cabinet until dispensed by the unblinded PharmD team or a blinded physician assistant, the only study personnel to see or smell the study drug. The singular role of the physician assistant in the study was dispensing the study drug at the baseline visit. Third, the study drug was administered in a closed, vented room that removes the odor of cannabis within four minutes. Blinded study staff did not enter for at least 10 minutes. Further, the study drug was transported by the participant to their home and to clinic in the masking envelope.

Cannabinoid and metabolite concentrations were measured in plasma samples collected during the screening or baseline visit, the initial and final dose assessment visits (three hours after dose administration) and the safety follow-up visit, by iC42 Clinical Research and Development.¹⁶

Intervention

The study drug, supplied by National Institute of Drug Abuse as a frozen extract, was formulated to a 100mg/mL CBD and 3.3mg/mL THC sesame oil solution by our PharmD team. Placebo was compounded with USP-grade sesame oil, food coloring, and strawberry extract. ElSohly Laboratories, Inc. performed stability, potency, and microbial analyses.

Participants took 1.25mg/kg/day each morning (approximately 1 mL) for 4 ±1 days and then twice daily for 14 ±4 days. To test short-term use, the duration of time on study drug was at least the minimum time needed for CBD to be at steady state concentration. Half-life of oral CBD is 2 days,^{17, 18} and THC approximately 4 hours.¹⁷ To facilitate interpretation of effects, cannabinoid plasma levels were documented at the final dose visit.

Outcome Measures

The primary aim was to evaluate the efficacy of the study drug on motor symptoms in PD, by comparing the change in scores of the motor, Part III, MDS-UPDRS¹⁴ from baseline to final dose visit between the CBD/THC and placebo groups. PD medications were kept constant throughout the study, and MDS-UPDRS score was measured in best ON state. Secondary aims were to examine the effect of CBD/THC on other motor and on non-motor PD-related symptoms (Supplementary data, Table S1) and its safety and tolerability. Since rest tremor is variably present, it was measured repeatedly in clinic and at home using an Objective Tremor MATLAB GUI test: accelerometry measured presence, amplitude, and duration while the contralateral hand performed open/close, pronation/supination and finger tapping (MDS-UPDRS items 3.4–6). Comprehensive neuropsychological testing was conducted at baseline and 1½ hours after final dose, and results reported recently.^{19, 20}

Secondary outcome measures for safety and tolerability included adverse events, safety related blood tests (liver function tests, routine hematology and chemistries), vital signs (including orthostatic blood pressures) and electrocardiograms. Adverse events were collected at each participant contact and from daily home diaries. To evaluate a possible soporific effect of the study drug, the Stanford Sleepiness Scale was administered before and three hours after the first dose of study drug. Signs of hepatotoxicity were assessed at each visit and phone call, and liver function tests were monitored throughout the study. Another outcome addressing tolerability was comparison between groups of the number of participants that discontinued study drug due to intolerance.

Exploratory analyses adjusting for gender, age, and disease duration were done to examine whether these covariates affected treatment outcomes. Both additive and time interacting covariates were considered. Since cannabinoid levels within the treated group were widely variable, an exploratory correlation analysis was performed between cannabinoid levels and pre-specified outcomes.

Sample Size Calculation

Using preliminary data⁸ we estimated a standard deviation for the motor MDS-UPDRS change scores of 6.72 and anticipated a mean change of at least magnitude 5.75 (standardized effect size = 0.856), 25% of baseline.⁸ A two independent samples T-test, testing for a between treatment difference in the MDS-UPDRS change scores, at two-sided alpha = 0.05, would require a total sample size of 60 for 90% power. We planned to recruit 75 participants to guard against 20% drop out. Since other outcomes are either descriptive and/or exploratory, and sample size is limited, adjustment for multiple testing adjustments were not planned across different outcome variables.

Statistical Analysis

Summary statistics of baseline values were presented and tested for differences between groups, using T-tests for continuous or scale variables, and chi-square/Fisher’s exact association test for categorical variables. The null hypothesis for the primary outcome, comparison of the change in motor, Part III, MDS-UPDRS scores from baseline to the final dose visit between groups, was that there would be no treatment effect. Longitudinal regression models were fit for the assigned treatment x visit means. Linear combinations of estimated means were constructed to estimate and test change from baseline within treatment group, and to compare between treatment groups. The between group differences in change from baseline within treatment groups was the treatment effect. T and F tests were applied to single and multiple linear combinations respectively. Expected values, 95% confidence intervals, and p values were calculated and presented. Scatter plots with a fitted regression line, and Spearman correlations were run to assess the relationship between change in cannabinoid plasma levels and change in outcomes for the final dosage in the CBD group. Two-sided univariate alpha was set to 0.05 unless otherwise stated. Cohen’s d was used for the effect size calculation. Assessment results were considered clinically relevant if the p value was ≤0.05 and i) the difference was greater than the minimal clinical important difference (when one is defined), or ii) the effect size was at least moderate, ≥0.5.

Results

Participant Characteristics

Between 9/5/2018 and 1/4/2022, 233 participants were screened by phone, 172 were excluded (primarily due to driving restrictions and difficulties during the time of COVID), 73 signed consent and 61 were randomized: 31 to CBD/THC and 30 to placebo (Figure 1). Six participants were using cannabis regularly (four topically, two by mouth; four in CBD/THC group, two in placebo) and stopped 30 days prior to the baseline visit. Table 1 shows that baseline participant characteristics were similar between groups for most variables, although the study drug group trended toward longer disease duration (p = 0.071) and higher total MDS-UPDRS (p = 0.076).

Figure 1. Flow of Study Participants.

Abbreviations: MDS-UPDRS, International Parkinson and Movement Disorder Society Unified Parkinson’s Disease Rating Scale; CBD, cannabidiol; THC, delta-9-tetrahydrocannabinol; AEs, adverse events

^aIncludes 13 that had a screening visit.

^b7 Were in or preferred another clinical trial, 5 lived outside Colorado, 1 did not have Parkinson disease, and 1 was too young.

^c17 Declined due to long distance travel and 6 due to schedule conflicts.

^d12 Were not responsive after phone screening, 3 had health concerns, and 2 had legal conflicts

^eNo participants were lost to follow-up.

Table 1.

Baseline Demographic and Parkinson Disease Characteristics and Study Drug Measures

	CBD/THC (n = 31)	Placebo (n = 30)	P-value
Age, mean (SD), y	70.4 (6.2)	68.6 (7.6)	0.3148
Male gender, No. (%)	18 (58.1)	23 (76.7)	0.1218
Years since Parkinson disease diagnosis, mean (SD)	7.0 (6.8)	4.5 (3.9)	0.0761
Modified Hoehn & Yahr, mean (SD)a	2.47 (0.69)	2.30 (0.48)	0.2749*
Motor (part III) MDS-UPDRS, mean (SD)b	34.5 (9.1)	30.9 (9.0)	0.1240*
Total MDS-UPDRS, mean (SD)b	56.7 (17.9)	48.8 (15.5)	0.0710*
LEDD, mean (SD), mg/dayc	417.9 (440.3)	427.5 (292.8)	0.9212
Montreal Cognitive Assessment, mean (SD)d	26.9 (3.6)	27.1 (2.2)	0.7971*
Married, No. (%)	25 (80.6)	23 (76.7)	0.7044
Retired, No. (%)	25 (80.6)	24 (80.0)	0.9495
Education, ≥college educated, No. (%)	23 (74.2)	27 (90.0)	0.1084
Income, >$75,000, No. (%)	17 (54.8)	18 (60.0)	0.6936
Ethnicity, not Hispanic or Latino, No. (%)	30 (96.8)	29 (96.7)	1.0000
Race, white, No. (%)	31 (100.0)	28 (93.3)	0.2377
Body weight, mean (SD), kg,	79.0 (16.2)	82.1 (12.4)	0.4064
Time on study drug, mean (SD), days	15.8 (4.9)	16.8 (4.5)	0.4108
Final study drug dose, mean (SD), mg/kg/day	2.24 (0.5)	2.5 (0.0)g
CBD Final dose, mean (SD), mg/day	182.3 (59.2)	200.0 (0.0)g
THC final dose, mean (SD), mg/day	6.1 (2.0)	6.6 (0.0)g

Abbreviations: MDS-UPDRS = Movement Disorder Society Unified Parkinson Disease Rating Scale; LEDD = levodopa-equivalent daily dosage; MoCA = Montreal Cognitive Assessment; CBD = cannabidiol: THC = delta-9-tetrahydrocannabinol.

^aModified Hoehn & Yahr is a Parkinson disease staging system, 8 levels from 0 (normal) to 5 (bedridden unless aided).

^bThe Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument with four parts that comprises clinician and patient reported outcomes focused on motor and non-motor symptoms. Motor (part III) scores range 0 – 132; total score ranges 0 – 260.

^cLEDD = immediate release levodopa × 1 + controlled release levodopa × 0.75 + pramipexole × 100 + ropinirole × 20 + rotigotine × 30 + selegiline × 10.

^dThe Montreal Cognitive Assessment is a rapid screening tool assessing cognition; scores range 0 to 30, with higher scores indicating better function.

^eOne unknown, 8 declined to provide.

^fOne not reported.

^gThese parameters are perceived for the placebo group, since they did not receive cannabinoids.

^*p value is from model results.

Primary Outcome

There was no significant difference between the change in motor, Part III, MDS-UPDRS scores of the CBD/THC compared to placebo group from baseline to final dose visit (p = 0.379) (Table 2). Interestingly, while there was no treatment effect, both groups had statistically significant improvements, but only the CBD group passed the defined threshold for a minimally clinically important difference i.e., −3.25,²¹ decreasing by a mean (CI) of 4.57 (−8.11 to −1.03) at the final dose visit (p=0.013).

Table 2.

Primary and Secondary Outcomes (Intention-to-Treat Analysis)

Assessments & Groupsa	Baseline Mean (SD)	Final Doseb Mean (SD)	Change Mean (95% CI)	P-valuec	Standardized effect sized	Treatment difference Mean (95% CI)	P-value	Standardized effect size
Primary outcome
MDS-UPDRS, motor (part III) e
CBD/THC	34.55 (9.15)	29.98 (11.89)	−4.57 (−8.11 to −1.03)	0.013	0.48	−1.80 (−5.88 to 2.27)	0.379	−0.23
Placebo	30.93 (8.98)	28.16 (9.12)	−2.77 (−4.92 to −0.61)	0.014	0.48
Secondary outcomes
Total MDS-UPDRS
CBD/THC	56.68 (17.94)	50.40 (17.72)	−6.28 (−11.53 to −1.03)	0.021	0.44	0.95 (−5.17 to 7.07)	0.756	0.08
Placebo	48.80 (15.51)	41.56 (14.74)	−7.23 (−10.58 to −3.89)	<0.001	−0.81
Rest Tremor Sub-score f
CBD/THC	4.84 (4.41)	3.68 (3.72)	−1.16 (−2.04 to −0.28)	0.012	0.49	−1.06 (−2.14 to 0.02)	0.055	−0.50
Placebo	3.30 (3.16)	3.20 (2.90)	−0.10 (−0.76 to 0.56)	0.760	−0.06
Postural & Kinetic Tremor Sub-score f
CBD/THC	2.19 (1.86)	1.76 (2.02)	−0.43 (−0.93 to 0.07)	0.088	0.32	0.24 (−0.43 to 0.90)	0.479	0.18
Placebo	1.90 (1.83)	1.23 (1.94)	−0.67 (−1.13 to −0.20)	0.007	0.53
Total Tremor Sub-score f
CBD/THC	8.48 (5.97)	6.68 (5.55)	−1.80 (−2.81 to −0.80)	0.001	0.66	−0.94 (−2.33 to 0.45)	0.183	−0.35
Placebo	6.30 (4.20)	5.43 (3.88)	−0.87 (−1.87 to 0.13)	0.087	0.32
Neuro-QOL - Emotional & Behavioral Dyscontrol short form T-scores
CBD/THC	43.40 (7.45)	39.41 (7.32)	−3.99 (−6.32 to −1.65)	0.002	−0.63	0.286 (−3.09 to 3.66)	0.866	0.04
Placebo	42.64 (7.81)	38.37 (7.34)	−6.80 (−3.42 to −1.75)	0.002	−0.63
Neuro-QOL - Anxiety short Form T-scores
CBD/THC	45.69 (7.07)	43.59 (5.77)	−2.10 (−3.61 to −0.59)	0.008	−0.52	1.35 (−0.65 to 3.36)	0.182	0.35
Placebo	47.20 (7.48)	43.75 (7.64)	−3.45 (−4.83 to −2.07)	<0.0001	−0.93
PROMIS - Pain Intensity 3a short form
CBD/THC	5.55 (2.76)	4.63 (2.06)	−0.92 (−1.49 to −0.36)	0.002	−0.60	−0.26 (−1.05 to 0.53)	0.513	−0.17
Placebo	5.33 (2.13)	4.67 (1.99)	−0.66 (−1.24 to −0.08)	0.027	−0.43
PROMIS - Pain Interference 4a short form
CBD/THC	7.00 (3.71)	6.49 (2.65)	−0.51 (−1.28 to 0.27)	0.190	−0.24	0.38 (−0.59 to 1.36)	0.434	0.20
Placebo	6.50 (3.00)	5.61 (2.66)	−0.89 (−1.52 to −0.27)	0.007	−0.54
Insomnia Severity Index
CBD/THC	7.13 (4.80)	5.43 (3.62)	−1.70 (−2.82 to −0.58)	0.004	−0.56	−0.06 (−1.60 to 1.47)	0.933	−0.02
Placebo	7.27 (5.46)	5.63 (4.59)	−1.63 (−2.75 to −0.54)	0.005	−0.56
Pittsburgh Sleep Quality Index
CBD/THC	5.58 (3.65)	4.76 (2.68)	−0.82 (−1.77 to 0.12)	0.086	−0.32	0.68 (−0.46 to 1.82)	0.238	0.31
Placebo	6.20 (3.30)	4.70 (2.72)	−1.50 (−2.17 to −0.08)	< 0.0001	−0.83
Non-Motor Symptoms Scale for PD
CBD/THC	36.61 (24.36)	30.75 (26.40)	−5.87 (−11.63 to −0.10)	0.046	0.38	−0.83 (−7.68 to 6.02)	0.809	−0.06
Placebo	27.33 (19.70)	22.30 (19.10)	−5.03 (−8.96 to −1.10)	0.014	0.48
Non-Motor Symptoms Scale for PD, Sleep Domain
CBD/THC	5.42 (5.56)	4.35 (5.27)	−1.07 (−2.87 to 0.7)	0.235	−0.22	0.53 (−1.61 to 2.67)	0.622	0.13
Placebo	5.47 (6.03)	3.87 (5.23)	−1.60 (−2.83 to −0.37)	0.013	−0.48
Non-Motor Symptoms Scale for PD, Mood Domain
CBD/THC	2.16 (3.98)	1.26 (2.80)	−0.90 (−1.78 to −0.03)	0.043	−0.38	1.20 (−0.30 to 2.70)	0.115	0.41
Placebo	2.73 (3.59)	0.63 (1.33)	−2.10 (−3.35 to −0.85)	0.002	−0.62
Non-Motor Symptoms Scale for PD, Sex Domain g
CBD/THC	3.68 (6.24)	1.69 (5.96)	−1.99 (−3.82 to −0.16)	0.034	−0.40	−2.17 (−4.43 to 0.12)	0.063	−0.49
Placebo	1.30 (2.42)	1.47 (3.47)	0.17 (−1.26 to 1.59)	0.813	0.04
Non-Motor Symptoms Scale for PD, Cognitive Domain
CBD/THC	3.26 (5.39)	3.84 (5.38)	0.58 (−0.39 to 1.54)	0.230	0.22	1.61 (0.40 to 2.82)	0.010	0.69
Placebo	2.50 (3.49)	1.47 (2.65)	−1.03 (−1.80 to −0.27)	0.010	0.50
Parkinson’s Disease Questionnaire 39
CBD/THC	25.45 (24.74)	20.65 (19.31)	−4.80 (−10.02 to 0.41)	0.070	−0.34	−0.32 (−6.86 to 6.22)	0.922	−0.03
Placebo	19.26 (17.93)	14.78 (15.96)	−4.48 (−8.63 to −0.33)	0.035	−0.40
Neuropsychiatric Inventory, Distress 12
CBD/THC	1.50 (3.22)	1.37 (3.25)	−0.13 (−0.52 to 0.25)	0.481	−0.13	0.97 (0.07 to 1.86)	0.036	0.56
Placebo	2.40 (2.76)	1.30 (2.41)	−1.10 (−1.92 to −0.28)	0.011	0.50
Modified Schwab & England ADL score e
CBD/THC	86.13 (9.65)	86.65 (10.00)	0.52 (−1.25 to 2.29)	0.555	0.11	−3.15 (−6.15 to −0.15)	0.040	−0.54
Placebo	88.00 (9.54)	91.67 (7.11)	3.67 (1.17 to 6.17)	0.005	0.55

^aCBD/THC, n = 31; Placebo, n = 30. For all assessments, other than the Schwab & England, higher scores are worse. Assessments are referenced in Supplement data, Table S1.

^bThis assessment score is from the Final Dose visit: the dose the participant was able to tolerate and was taking at the Final Dose Visit; mostly this was 2.5mg/kg/day.

^cStatistically significant p values, ≤0.5, are in bold, analyzed by the longitudinal regression model, applying a two-sided T-test to a linear combination of model parameters.

^dCohen’s d.

^eThese are the only assessments that have a defined minimal clinical important difference, which is 3.25 for motor MDS-UPDRS, from Horvath et al., Parkinsonism Relat Disord. 2015 Dec;21(12):1421–6, and 10 for the Modified Schwab & England ADL score, from Shulman et al., Arch Neurol 2010 Jan;67(1):64–70.

^fRest tremor sub-score consists of MDS-UPDRS items 3.17 and 3.18; Postural & Kinetic Tremor is items 3.15 and 3.16; Total Tremor sub-score is items 2.10 and 3.15 – 3.18.

^gBaseline difference between groups, p=0.0553; adjusting for time interacting LEDD made a difference in treatment effect: −2.23 (−4.37 to −0.08) p value = 0.0419).

Abbreviations: CI, confidence interval; MDS-UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; CBD, cannabidiol; THC, delta-9-tetrahydrocannabinol; PROMIS, Patient-Reported Outcomes Measurement Information System; Neuro-QOL, a brief measure of health-related quality of life for clinical research in neurology; ADL, Activities of Daily Living.

Secondary Outcomes

Several assessments demonstrated a difference between groups (Table 2). The placebo group Neuropsychiatric Inventory Distress 12²² scores improved, but the CBD/THC group did not. This was mainly due to disparate responses on the sleep question, suggesting CBD/THC group caregivers were more distressed about the participants’ sleep than those of the placebo group. CBD/THC group scores for the cognition domain of the Non-motor Symptoms Scale for PD ²³ worsened while placebo group scores improved, mainly due to responses to question 16 on concentration, suggesting CBD/THC caregivers noted more difficulties than those of the placebo group. The Modified Schwab & England Activities of Daily Living Scale score²⁴ in the CBD/THC group was unchanged while the placebo group improved.

There was no treatment effect in the total MDS-UPDRS, but there were statistically significant improvements in scores of both groups. There is no defined minimally clinically important difference for the total MDS-UPDRS, but effects sizes were moderate to large, supporting clinical relevance. The CBD/THC group had statistically significant improvements in rest tremor and total tremor MDS-UPDRS sub-scores, while the placebo group did not (but did have an improvement in postural and kinetic sub-scores). However, again, there was no treatment effect in these and all other motor sub-scores. Further, there was no treatment effect on rest tremor on the in-home Objective Tremor MATLAB GUI measure. Regarding dyskinesia,²⁵ there was a trend toward improvement in the placebo group and worsening in the CBD/THC group, with no treatment effect.

Many non-motor assessment results had a similar pattern to that of the motor tests, with clinically relevant results within one or both groups, but no difference between groups, indicating no treatment effect. These findings include assessments on emotional dyscontrol,²⁶ anxiety,²⁶ pain,²⁷ sleep,^{28, 29} and the mood domain of the Non-motor Symptoms Scale for PD.²³ There was no difference in any outcomes in the restless legs syndrome assessment,³⁰ however, when only symptomatic persons were included in the analysis, i.e., total score ≥5, there were again improvements in both groups but no treatment effect. Of note, in all the aforementioned non-motor assessments, except the sexual function domain of the Non-motor Symptoms Scale for PD,²³ the placebo group had clinically relevant responses.

The other assessments, i.e., fatigue,³¹ Stanford Sleepiness Scale,³² REM behavior disorder,³³ clinical global impression,³⁴ EQ-5D-5L,³⁵ NPI²² scores other than Distress 12, and bladder function,³⁶ showed no differences in outcomes, within or between groups. Very few participants had obsessive-compulsive symptoms,³⁷ so this was not analyzed.

Exploratory outcomes

Including co-variants of gender, age, and disease duration did not result in a change in the statistical significance of outcomes treatment effects. Cannabinoid concentrations in the CBD/THC group were widely variable (Figure 2) and correlated with some outcome scores (Supplementary data, Table S2). Surprisingly, higher cannabinoid levels correlated with less improvement in several assessments, including pain, depression, overall perception of sleep, restless legs syndrome, anxiety, and tremor amplitude. More in line with expectations, higher cannabinoid levels correlated with improvement in bladder function.

Figure 2. Plasma cannabinoid levels.

Three hours after the CBD/THC study drug administration plasma concentrations of CBD (A) in participants on 1.25mg/kg/day, n=23, was mean (SD) 37.1 (26.7), range 5.7 – 109.4 ng/mL and on 2.5mg/kg/day, n=20, was 54.0 (33.8), range 10.1 – 124.0 ng/mL. Plasma concentrations of THC (B) in participants on 1.25 mg/kg/day, n = 23, was 0.61 (0.53), range 0.20 – 2.20 ng/mL and on 2.5 mg/kg/day was 1.06 (0.91), range 0.20 – 3.86 ng/mL.

Abbreviations: CBD = cannabidiol; THC = delta-9-tetrahydrocannabinol

Safety and Tolerability

Adverse events were assessed in all participants that took at least one dose of study drug (Table 3). Twice as many treatment emergent adverse events were reported by the CBD/THC group; most were mild and occurred with the initial rather than the final dose. For example, dizziness, the most common adverse effect in the CBD/THC group, was rated as mild for 88.9% of the reports, and was reported 80.6% of the time at doses less than 2.5mg/kg/day. Cognitive adverse effects were reported more frequently by the CBD/THC group. Pneumonia was the only serious adverse event during the study and occurred in one participant 10 days after they completed study drug treatment. There were no effects on orthostatic blood pressure, heart rate or temperature, comparing before the first study medication dose to the final dose, and comparing before a dose to one and three hours afterwards. There were also no notable changes in blood laboratory studies, including liver tests. Thirteen participants, all in the CBD/THC group, did not reach the per protocol dose, including seven for the 1.25mg/kg/day visit and six for the 2.5mg/kg/day visit, due to intolerance. Only one participant (in the CBD/THC group) dropped out of the study, due to adverse events after the first dose.

Table 3.

Treatment Emergent Adverse Events Per Group

	CBD/THC (n = 31)	Placebo (n = 30)
Treatment Emergent Adverse Events Per Group
Number of AEs reported	275	135
Number of AEs per participant (SD)	8.9 (9.2)	4.5 (4.2)
Number of AEs per severity (% of the total AEs in the group)
Mild	236 (85.8%)	126 (93.3%)
Moderate	32 (11.6%)	6 (4.4%)
Severe	7 (2.6%)	2 (2.2%)
Number of AEs per dosage (% of the total AEs in the group)
<1.25mg/kg/daya	70 (25.5%) (n = 13)	13 (9.3%) (n = 10)
1.25 – <2.5mg/kg/dayb	138 (50.2%) (n = 31)	56 (41.5%) (n = 30)
2.5mg/kg/day	67 (24.4%) (n = 22)	66 (48.9%) (n = 30)
Number of Participants with at Least One Occurrence of a Type of Adverse Event
Adverse Eventc	Frequency n (%)	Frequency n (%)
Any	26 (83.9)	25 (83.3)
Dizziness	18 (58.1)	6 (20.0)
Feeling of relaxation	13 (41.9)	7 (23.3)
Fatigue	10 (32.3)	6 (20.0)
Decreased concentration	10 (32.3)	4 (13.3)
Headache	9 (29.0)	10 (33.3)
Somnolence	8 (25.8)	8 (26.7)
Feeling abnormal	8 (25.8)	2 (6.7)
Feeling drunk	7 (22.6)	2 (6.7)
Nausea	6 (19.4)	3 (10.0)
Confusion	5 (16.1)	1 (3.3)
Thinking abnormal	5 (16.1)	0
Disorientation	4 (12.9)	0
Dry mouth	4 (12.9)	1 (3.3)
Fall	4 (12.9)	3 (10.0)
Increased concentration	4 (12.9)	1 (3.3)
Weakness	4 (12.9)	1 (3.3)
Agitation	3 (9.7)	1 (3.3)
Elevated mood	3 (9.7)	3 (10.0)
Diarrhea	2 (6.5)	4 (13.3)
Anorexia	2 (6.5)	3 (10.0)
Anxiety	2 (6.5)	3 (10.0)
Insomnia	2 (6.5)	3 (10.0)
Abdominal pain	1 (3.2)	3 (10.0)
Sleep disturbance	1 (3.2)	2 (6.7)
Weight loss	1 (3.2)	2 (6.7)
Cold	0	2 (6.7)
Cough	0	2 (6.7)
Depression	0	2 (6.7)

AEs = adverse events

^aThis is the number of AEs reported from participants when they could not tolerate increasing to the 1.25mg/kg/day dose.

^bThis is the number of AEs reported from participants on 1.25mg/kg/day (n= 31 in CBD/THC group and n = 30 in placebo group) and from those that did not tolerate increasing fully from 1.25 to 2.5mg/kg/day (n= 5 in CBD/THC group and n = 0 in placebo group). These latter participants were on doses between 1.25 and 2.5mg/kg/day.

^cThis is the number of participants who experienced the AE at least once, not a count of AEs, as repeated specific AEs on the same participant are counted only once here. Types of AEs that made up at 5% of reported AEs in either group are listed.

Participant compliance with study drug was good, judged by the cannabinoid plasma levels (Figure 2) and drug accountability measures.

Sensitivity analysis

A per-protocol analysis was performed, excluding participant data from one participant that dropped out, and from four others that involved important protocol deviations. Results were similar to the presented intention-to-treat analysis.

Discussion

This study found that short term use of a specific oral cannabis formulation and dosage did not improve PD symptoms more than placebo. In fact, the extensive testing performed in this study found no clear evidence of benefit, and several tests, as well as reports of adverse effects, suggested a trend in worsening of some non-motor symptoms, especially cognitive dysfunction and perhaps sleep difficulty. We recently reported that analysis of a global statistical test of neuropsychological exams in this study showed a small detrimental effect in cognition.^{19, 20} A recent, elegant systematic review³ of randomized controlled trials of cannabis use in PD reports eight;^{6, 7, 9, 38–42} all were performed outside the U.S., and each used different cannabis-based formulations. There was no benefit in motor signs, except one study⁶ that found reduced tremor amplitude, and others,^38–40 using various cannabinoid formulations, reported conflicting effects on levodopa-induced dyskinesia. Some formulations improved anxiety^{6, 41} sleep⁴¹, and quality of life.⁷ Our study is unique from these studies, in that while CBD dosage is similar as in prior trials, it includes low dose THC, and because it reports plasma concentrations of both cannabinoids. Even with the addition of THC, we found no benefits in motor and non-motor symptoms, even for pain, sleep, depression, or anxiety. In fact, higher cannabinoid levels correlated with less reduction of some non-motor symptoms, including pain. This was unexpected since cannabinoids are thought to reduce pain, but this effect is likely due more to THC than CBD.^{43, 44} In our study the THC plasma levels were quite low, and our population had relatively low pain scores at baseline.

The participants in this study displayed a marked placebo response. This study was held at an established PD research center and run by experienced PD researchers, so routine efforts were taken to minimize placebo response. However, placebo response is common in PD, with up to 50% of research participants showing improvement in motor symptoms while on placebo treatment.^45–47 It is mediated by the release of endogenous dopamine within the ventral striatum^48–50 and can be tuned by the expectation of therapeutic benefit and prior learning strategies.⁵⁰ Placebo response may have been enhanced in this study by the excitement of taking a novel, previously illegal drug. The placebo remains an integral part of rigorous scientific research, and this study again illustrates its importance. For future study design in cannabis trials, some strategies could be employed to mitigate the placebo response, such as focusing on neutralizing subject expectations, improving the ability of subjects to accurately report symptom severity,⁵¹ and incorporating a placebo run-in period.⁵²

Our study drug was relatively well tolerated, but with many, mostly mild, adverse effects. Prior literature reports that cannabinoid medications are generally well tolerated³ although CBD needs further study.⁵³ Our previous trial⁸ in PD found that 20–25mg/kg/day was associated with cholestatic liver enzyme changes, and one person had frank hepatitis, but no notable liver enzyme changes occurred at the 2.5mg/kg/day dose used in the current trial. Literature suggests THC¹ and nabilone, a synthetic THC analog, at higher doses were associated with more adverse events^{38, 40, 41} than generally are reported with CBD. Cardiovascular adverse effects of cannabis, including tachycardia and supine hypertension and/or postural hypotension⁵⁴ have been reported, but did not occur in the present study, which, again, may be due to our low THC plasma concentrations. Factors likely to contribute to intolerability include advanced age, taking numerous medications, and drug interactions, especially those related to CYP2C19 and CYP3A4 with CBD and CYP2C9 with THC.

Only one prior randomized controlled study in PD³⁸ presented plasma cannabinoid levels: on approximately 11mg of oral THC daily the level was widely variable, ranging from 0.25 – 5.4ng/mL. We also found wide variability, likely because oral absorption is erratic. Even though plasma levels are variable, without plasma levels it is hard to know whether participants absorbed study drug at levels adequate to have a CNS effect. It is reasonable to surmise that plasma levels have some correlation with CNS effect.

This study has multiple strengths and limitations. The major limitation is that study drug was taken for a short period and placebo effect, likely in both groups, limits interpretation of results to the short duration studied. Another limitation of this study is the same as for all cannabinoid research: these results can only be generalized to persons taking a similar cannabinoid product, orally, for a similar (short) duration. Strengths include that our results can be generalized to much of the PD population – since the study drug was composed of cannabinoids frequently taken in PD, and since there were minimal exclusion criteria, i.e., the study population was heterogenous. Also, the route of administration, i.e., oral, is applicable for PD. Vaping and smoking are less safe and more technically difficult. Additional strengths include that the dose of each cannabinoid, as a combination, adds to the current literature to guide future research, and the presentation of cannabinoid plasma levels associated with our study drug is an important starting data point for future studies, to allow consideration of plasma levels, not just cannabinoid dose, when interpreting results.

Based on current literature and our findings, we posit the following. Pure CBD is not likely to improve bradykinesia or rigidity, and its effect on tremor needs further study. Troublesome non-motor symptoms that especially have potential to respond to CBD or CBD/THC include anxiety and sleep (but studies on sleep should include polysomnograms), and to low dose THC or THC analogs include pain, depression, and apathy. Thus, study of low dose CBD, e.g., 10–75mg/day or twice daily, high dose CBD, e.g., 250–500mg/day or twice daily (carefully monitoring liver function), both with and without low dose THC, e.g., 1–5mg/day or twice daily are indicated. The oral route is most feasible and monitoring cannabinoid plasma levels is essential. Since we found that participants and their caregivers’ responses were sometimes discordant, future trials could include subjective outcomes that incorporate caregiver input. Rigorous, smartly designed randomized clinical trials that are double-blind (ensuring that placebo is adequately matched to study drug to preserve the blind) and controlled (at least 3 months in duration to overcome placebo effect) are needed.

Conclusion

While interpretation of efficacy of daily oral CBD 200mg with THC 6.6mg is limited by brief duration on study drug and strong placebo response, there was no benefit, a suggestion of worsened cognition and sleep, and many mild adverse events. Longer duration high quality trials are essential. However, in the U.S., this would require improved availability of feasible research cannabinoid products.

Data Availability Statement

Anonymized data not published within this article will be made available by request from qualified investigators who provide a valid research question, for 20 months after the trial is electronically published. Key elements of the protocol, data analysis plan and main study results are available at clinicaltrials.gov, NCT03582137.