Smoke gets in your tics

Authorea preprint April 25, 2017 DOI: 10.22541/au.149308896.61629534

Many (though not all) of my patients who have tried marijuana have felt that their tics improved after using it. Such self-treatment is not rare (poster P94 here), and other doctors report similar results (see for example poster P6 here). Pharmacological benefits from cannabis products are plausible, since cannabinoid receptors in the brain's basal ganglia are well positioned to affect movement (Kluger et al., 2015).

Of course, in addition to any real benefit from marijuana, there could be expectation effects, or one could simply care less about tics when high. Random allocation clinical trials with blind rating of benefit (RCTs) are essential to demonstrating whether marijuana has any true benefit for tics. Müller-Vahl and colleagues carried out two RCTs about 15 years ago in Tourette syndrome (TS) using THC (tetrahydrocannabinol), the main intoxicating ingredient in cannabis (Müller-Vahl et al., 2002; Müller-Vahl et al., 2003). Both trials showed benefit, but the trials were relatively small. Two to 3 years ago, the Tourette Association of America funded two pilot studies in this field, but results have not yet been reported. One trial, at Yale, was to study the FAAH (fatty acid amide hydrolase) inhibitor PF-04457845 in TS (Ahn et al., 2011), but the trial was placed on clinical hold pending results from a different trial. Investigators at Toronto Western Hospital were funded for a trial in TS of medical cannabis products with varying concentrations of THC and cannabidiol. Cannabidiol is being studied in several brain disorders, including epilepsy, with hopes that it may provide benefit without the psychological side effects of THC.

Not surprisingly, the paucity of data has led to different viewpoints. Müller-Vahl has argued that THC may be appropriate in some TS patients (Müller-Vahl, 2013), whereas an American Academy of Neurology review and a Cochrane-style review in JAMA concluded that the evidence was insufficient to recommend THC for tic disorders (Koppel et al., 2014; Whiting et al., 2015). The clinical utility of cannabinoids in TS was one of two clinical controversies debated at the 2015 First World Congress on Tourette Syndrome and Tic Disorders (Mathews et al., 2016).

In this setting, several recent announcements demonstrate hope for answering whether, for cannabinoids in TS, "where there's smoke, there's fire." At the beginning of 2017, an Israeli company announced enrollment of the first subject in a phase IIa clinical trial of THX-TS01. Notably, this study is enrolling in the USA. THX-TS01 is a combination product, containing both THC and palmitoylethanolamide (PEA), another "endocannabinoid-like" compound. Based on some preclinical studies, the company hopes the combination may prove more effective than either ingredient alone.

In mid-April, 2017, the first patient was enrolled in a Phase 1b study of the monoacylglycerol lipase (MGLL) inhibitor ABX-1431. Inhibition of MGLL in mice increases the concentration of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol (2AG) in brain, with consequent activation of cannabinoid CB1 receptors (Savinainen 2012).

Müller-Vahl and her colleagues are about to start a much more definitive RCT of cannabinoids in TS. This multicenter study aims to enroll almost 100 subjects in a study of nabiximols, a combination product containing THC and cannabidiol in nearly a 1:1 ratio. This product is available by prescription in some European countries for spasticity in multiple sclerosis.

At this time, there is insufficient evidence of anti-tic efficacy to recommend any of the products discussed above for treatment of tics. This is especially true given medical, practical and legal drawbacks to marijuana smoking (Svrakic et al., 2012) and substantial recent changes in the pharmacology of cannabis and related products available on the street (Cascini et al., 2012; Ford et al., 2017; Monte et al., 2017). On the other hand, there is good reason to expect that some of these products—perhaps cannabidiol or the small molecule modifiers of endocannabinoid metabolism—may prove to be safe and effective, and the appropriate studies are finally underway. An update on this topic likely will look very different in a few years.

Addendum 26 April 2017: A nice review of cannabinoid safety appeared recently in Lancet Psychiatry (Englund et al., 2017).

Addendum 03 May 2017: Abi-Jaoude and c