Results from an open-label clinical trial of dronabinol (THC) given with PEA (palmitoylethanolamide) were recently reported \citep{h2019,biosciences2018}. The study enrolled 17 medication-refractory adults with relatively severe TS (baseline YGTSS total tic score [TTS] of 38.4 ± 8.3), 16 of whom completed the study. There was significant improvement overall in tics, compared to the beginning of the study, with a mean improvement in TTS of 7.6 (95% CI = 2.5-12.8, p=.002), or 21%, and 6 of the 16 responding with a TTS reduction of more than 25%. No serious adverse events were reported, but every participant reported feeling "high" and drowsiness or fatigue. Other possible side effects were common, including difficulty concentrating (81%), ataxia (62%) and nausea (50%). This study marks an important advance, though without a comparison group one cannot conclude that the improvement is due to the treatment itself, as opposed to e.g. expectation effects.

Abide Therapeutics's drug ABX-1431 is now Lundbeck's Lu AG06466 \citep{lundbeck,lundbeck2019}. Results have not yet been posted on ClinicalTrials.gov for the study mentioned above \cite{clinicaltrialsgov2017}, but the 2018 AAN abstract reported that this was a single-dose crossover study with 40 mg ABX-1431 or placebo \citep{schindler2018}. Tics improved significantly more at 8 hours after drug than with placebo (p<.04), with improvements vs. baseline seen at 4 and 8 hours by TTS and by the ATQ, a self-report measure of tic severity. Transient headache, somnolence and fatigue were the most common side effects.

Lundbeck announced that the multisite, European, phase IIa trial of the MAG lipase inhibitor LuAG06466 (previously ABX-1431) completed, but did not meet its primary endpoint of statistically significantly better YGTSS Total Tic Score reduction compared to placebo \cite{as2020}. While disappointing, phase 2 trials are generally not powered for efficacy, and the company points out that the lack of serious adverse events supports further development either for other indications if not for TS.

A few months ago, a report appeared on a survey of people with TS before and 6 months after starting cannabis for tics \citep{36342913}. The mean daily dose was 123 mg (THC) and 50.5mg (CBD). Survey responders reported significant improvements in quality of life, employment status and number of (other) medications. Those with OCD (67%) and anxiety (89%) were especially likely to improve. However, tic improvement was not statistically significant: "motor tics (p=0.375), vocal tics (p>0.999), tics frequency (p=0.062)." "General mood" also did not improve significantly. The results suggest that, while cannabis may help people with tics, it does not primarily improve tics per se.

The biggest news yet on this page comes from the CANNA-TICS study, whose results were published last month \citep{36878177}. The authors performed a randomized, controlled trial of nabiximols in 97 adults with TS or chronic motor or verbal tic disorder. Befitting the study investigators' view of the literature, people were randomized to drug or placebo in a 2:1 ratio. The primary, predefined efficacy endpoint was a tic reduction of at least 25% on the YGTSS total tic score after 13 weeks of treatment, a magnitude of change recognized as clinically meaningful improvement by an expert panel. The study did not show significant improvement by this measure. However, there were some indications of improvement, including a higher response rate (22% vs 9%) in the nabiximols group, a significantly greater reduction in self-reported tic severity on the Adult Tic Questionnaire, a numerically greater improvement of tics on a standardized video rating scale, and trends for improvement in quality of life and in impairment due to tics. There were no serious safety issues, with side effects of similar severity in 95% of those in the active drug group versus 79% of those in the placebo group (p=.03). Patients with ADHD or with worse general health were most likely to improve. Thirteen percent of patients at the site that enrolled over half the participants reported intentional or accidental unblinding on an end-of-study interview. Of course, other participants likely suspected their drug assignment; a forced-choice blindedness assessment is not reported. In sum, a reasonably large RCT showed hints of superiority for nabiximols over placebo, but the study did not meet the pre-specified treatment target.