Double-Blind, Randomized, Placebo-Controlled, Crossover Study of Oral Cannabidiol and Tetrahydrocannabinol for Essential Tremor

Abstract

Background: Essential tremor (ET) is characterized by often disabling action tremors. No pharmacological agent has been developed specifically for symptomatic treatment. Anecdotal reports describe tremor improvement with cannabis, but no evidence exists to support these claims. We conducted a phase Ib/II double-blind, placebo-controlled, crossover pilot trial in participants with ET to investigate tolerability, safety, and efficacy of Tilray TN-CT120 LM, an oral pharmaceutical-grade formulation containing tetrahydrocannabinol (THC) 5 mg and cannabidiol (CBD) 100 mg. Our objectives were to determine if short-term THC/CBD exposure improved tremor amplitude and was tolerated.

Methods: Participants with ET were randomized (1:1) to receive either TN-CT120 LM or placebo. Dose titration, driven by tolerability, was attempted every 2-3 days to three capsules daily maximum. Participants remained on the highest tolerated dose for two weeks before returning to complete assessments. After completing the first arm, participants titrated off the agent, underwent a three-week washout, and then returned for the same procedures with the alternate compound. The primary endpoint was tremor amplitude change from baseline using digital spiral assessment. Secondary endpoints explored safety and tolerability.

Results: Among thirteen participants screened, seven were eligible and enrolled. Five completed all visits; one withdrew following a serious adverse event, and another did not tolerate the lowest dose. Intent-to-treat analyses performed for six participants did not reveal significant effects on primary or secondary endpoints.

Conclusions: This pilot trial did not detect any signals of efficacy of THC/CBD in ET. Although preliminary due to the small sample size, our data do not support anecdotal reports of cannabinoid effectiveness for ET.

Highlights: This double-blind, randomized, placebo-controlled efficacy and tolerability pilot trial did not detect any signals of efficacy of oral cannabidiol and tetrahydrocannabinol in reducing essential tremor amplitude using either digital outcome measures or clinical rating scales. The oral cannabinoids were well-tolerated by most (five out of seven) participants.

Keywords: cannabis, therapeutics; digital outcome measures; essential tremor.

Figure 1

Schema of the study protocol. Each participant underwent a baseline assessment and eight follow-up assessments. Each arm of the study period included a one-week titration period, a two-week treatment period, and a one-week tapering period, with a three-week washout period between the two study arms.

Figure 2

Titration and taper schedule of the study drug. The same titration schedule was used for TN-CT120 LM (each capsule contained THC/CBD 5/100 mg) and identical-appearing placebo capsules. Participants remained on the highest tolerated dose throughout the treatment arm.

Figure 3

CONSORT diagram of randomized, placebo-controlled, crossover trial. Consent was obtained and participants were screened; eligible participants were randomized in a 1:1 ratio to receive either oral THC/CBD 5/100 mg or placebo first.

Figure 4

Tremor amplitude measured by digital spiral drawing over time. The digital spiral drawings were repeated at various time points ranging from time = 0 [pre-dose] to 230 minutes after dose at visits 4 and 8 at the end of the two-week treatment period in the THC/CBD and placebo arms. Error bars indicate 95% confidence intervals.