Should we consider using cannabis for the treatment of tics in adolescents with Tourette syndrome? If so, under what circumstances? What are the harms, and how do these compare with the harms of other interventions? These questions warrant urgent and in-depth exploration – the use of cannabis for Tourette syndrome, until recently largely limited to adult patients, is now being pursued for adolescents, with the recent publication of two feasibility trials from the same group of clinical researchers. ^{Reference Eapen, Lin, Taylor, Chan, Chay and Cranswick1,Reference Efron, Taylor, Chan, Payne, Prakash and Lee2}

Tourette syndrome is a developmental neuropsychiatric condition characterised by tics and multiple comorbidities, in particular obsessive–compulsive disorder and attention-deficit hyperactivity disorder. ^{Reference Robertson, Eapen, Singer, Martino, Scharf and Paschou3} Tics are often mild to moderate, in which case the main intervention would be psychoeducation, support and reassurance. ^{Reference Andrén, Jakubovski, Murphy, Woitecki, Tarnok and Zimmerman-Brenner4,Reference Murphy, Lewin, Storch and Stock5} This is especially salient in children and adolescents given the known natural history of tics, which typically start around age 6 years, peak in severity around age 10–12 years and thereafter steadily improve for the large majority. ^{Reference Robertson, Eapen, Singer, Martino, Scharf and Paschou3}

When tics are problematic, whether from significant social difficulties, interference in function or physical pain, then targeted intervention is warranted – the first-line treatment for tics is behavioural therapy, whether based on habit reversal training or exposure and response prevention. ^{Reference Pringsheim, Okun, Müller-Vahl, Martino, Jankovic and Cavanna6} When necessary, pharmacological interventions can also be considered – the medications with the most evidence for tics are the alpha-2 agonists clonidine and guanfacine, and also antipsychotics, specifically haloperidol, pimozide, risperidone and aripiprazole.

When the mainstay interventions fail, other treatment options with lower-level evidence can be considered. Among these, medical cannabis has been emerging as a promising treatment. In addition to several observational studies, ^{Reference Szejko, Saramak, Lombroso and Müller-Vahl7} there have been multiple, although mostly small, randomised controlled trials. ^{Reference Abi-Jaoude, Bhikram, Parveen, Levenbach, Lafreniere-Roula and Sandor8–Reference Müller-Vahl, Pisarenko, Szejko, Haas, Fremer and Jakubovski12} The overall body of the literature points to a benefit from tetrahydrocannabinol (THC) for reducing tics in Tourette syndrome. ^{Reference Szejko, Saramak, Lombroso and Müller-Vahl7–Reference Mosley, Webb, Suraev, Hingston, Turnbull and Foster9} At the same time, it is evident that THC causes a noteworthy degree of harm, including high rates of adverse psychomotor effects and, less commonly but more seriously, psychotic symptoms. ^{Reference Szejko, Saramak, Lombroso and Müller-Vahl7,Reference Abi-Jaoude, Bhikram, Parveen, Levenbach, Lafreniere-Roula and Sandor8} A claim commonly made is that cannabidiol (CBD) can mitigate the adverse effects of THC; however, there is no consistent evidence to support such a claim. ^{Reference Hindley, Beck, Borgan, Ginestet, McCutcheon and Kleinloog13} In addition, it is fairly clear at this point that the evidence does not support any benefit from CBD for tics. ^{Reference Abi-Jaoude, Bhikram, Parveen, Levenbach, Lafreniere-Roula and Sandor8,Reference Mosley, Webb, Suraev, Hingston, Turnbull and Foster9,Reference Müller-Vahl, Pisarenko, Szejko, Haas, Fremer and Jakubovski12}

Until very recently, there has barely been any published literature in the paediatric population, which was limited to a few case reports. ^{Reference Szejko, Saramak, Lombroso and Müller-Vahl7,Reference Woerner, Szejko, Fremer, Schmitt and Müller Vahl14} This is despite the fact that most patients presenting with Tourette syndrome are children and adolescents. The hesitation to use and study cannabis in paediatric patients is understandable and probably for several reasons, not the least of which is that the association between regular cannabis use and psychosis is especially a concern for adolescents. ^{Reference Bechtold, Hipwell, Lewis, Loeber and Pardini15,Reference McDonald, Kurdyak, Rehm, Roerecke and Bondy16} A recent meta-analysis found that, while rates of cannabis-associated psychotic symptoms were highest in the context of recreational use, such symptoms also occurred in medical cannabis samples, at a rate of 1–2%. ^{Reference Schoeler, Baldwin, Martin, Barkhuizen and Pingault17} Furthermore, younger age was identified as a risk factor for cannabis-associated psychotic symptoms. ^{Reference Schoeler, Baldwin, Martin, Barkhuizen and Pingault17} Nevertheless, there are situations in which young patients with severe tics have not benefited from mainstay interventions, leading some clinicians to consider, or even pursue, cannabis for these patients. Given this, and promising evidence from the emerging adult literature, studies evaluating cannabis in young patients with Tourette syndrome are justified, even called for.

We now have two published trials – an open-label, single-arm trial ^{Reference Eapen, Lin, Taylor, Chan, Chay and Cranswick1} and a double-blind, placebo-controlled, crossover trial ^{Reference Efron, Taylor, Chan, Payne, Prakash and Lee2} – that have been conducted in adolescent patients aged 12–18 years, both intended to evaluate the feasibility, acceptability and signal of efficacy of cannabis for tics in Tourette syndrome. Both studies used cannabis oil containing THC (10 mg/ml) and CBD (15 mg/ml) in a 2:3 ratio, with THC doses of 5–10 mg daily for participants <50 kg in weight, and 10–20 mg daily for those 50 kg or more. The dosing was administered once daily by default and, in the case of tolerability concerns, it was divided into two daily doses.

In the open-label study, 10 adolescents, mean age 14.4 years (range 12–18) and who had severe tics were recruited. ^{Reference Eapen, Lin, Taylor, Chan, Chay and Cranswick1} According to the authors, this demonstrated the feasibility of recruitment. One participant dropped out, but otherwise study procedures were deemed acceptable based on 100% study visit attendance rate and completion of questionnaires. In terms of adverse effects, 40% of participants experienced tiredness and drowsiness, 30% experienced dry mouth, 22% reported blurred vision, increased appetite and decreased motivation and 11% reported various other harms, including unsteadiness, restlessness, shaky hands, confusion and disorientation. In terms of signal of efficacy, there were improvements in tic symptoms and related quality of life from baseline to day 85 of treatment, bearing in mind that this was an open-label, uncontrolled study.

The placebo-controlled crossover study, described as a phase I/II pilot trial, also recruited 10 adolescents, mean age 14.8 years (range 12–18) with moderate to severe Tourette syndrome. ^{Reference Efron, Taylor, Chan, Payne, Prakash and Lee2} Three participants dropped out and medication adherence was 64%, with otherwise good protocol adherence and overall acceptability ratings by parents. The single most common adverse effect was dizziness, occurring in 67% of participants. In terms of efficacy signal, there were very small numerical improvements in tic scores after 10 weeks of treatment; the investigators did not carry out inferential statistics given the small study size. On the Clinical Global Impression-Improvement scale, three participants were rated as much improved on cannabis compared with one on placebo; on the other hand, one participant was rated as much worse on cannabis compared with none on placebo.

These first trials of cannabis for adolescents with Tourette syndrome suggest the feasibility of pursuing further such studies in this population. It is worth questioning, however, whether recruitment for these studies was overly successful, with each recruiting ten adolescents within approximately one and a half years. In our fairly large centre we have only a small handful of adolescents with Tourette syndrome on cannabinoids. This is because the vast majority do reasonably well with one or more of our mainstay interventions, including behavioural therapy, an alpha-2 agonist and antipsychotic medication. In contrast, in neither of these studies did the inclusion criteria include a requirement for potential participants to have failed, or at least to have been offered, standard evidence-based treatments. ^{Reference Eapen, Lin, Taylor, Chan, Chay and Cranswick1,Reference Efron, Taylor, Chan, Payne, Prakash and Lee2} This raises the prospect of putting adolescents – as young as 12 – on daily cannabis before providing them with behavioural therapy, widely recognised as the first-line treatment for tics. This is of significant concern given our knowledge regarding the age-related risks of chronic cannabis use among youth. ^{Reference Bechtold, Hipwell, Lewis, Loeber and Pardini15,Reference McDonald, Kurdyak, Rehm, Roerecke and Bondy16} While both these studies reported no serious adverse effects, in neither case are we provided with details and, crucially, little can be said about safety given the very small sample sizes and limited study durations. For example, could we reassure families about the risk of psychosis with daily cannabis use based on these studies?

Granted, we cannot claim that our evidence-based pharmacological treatments are benign. ^{Reference Pringsheim, Okun, Müller-Vahl, Martino, Jankovic and Cavanna6} The serious harms of antipsychotics are well known, and a particular parent or adolescent may very well prefer to forgo being subjected to the risks from these agents and opt instead for a trial with cannabis. However, such a decision would need to be explicitly considered and deliberated among all those involved, including clinicians and researchers. Importantly, behavioural therapy eliminates the need for such dilemmas and must be offered as first-line treatment to all patients requiring targeted intervention for tics. ^{Reference Andrén, Jakubovski, Murphy, Woitecki, Tarnok and Zimmerman-Brenner4,Reference Pringsheim, Okun, Müller-Vahl, Martino, Jankovic and Cavanna6} While access is often a challenge, resources to address this should be prioritised over more invasive or less established interventions.

Investigating cannabis as an option for tics in adolescents with Tourette syndrome is an important pursuit, and the authors of these two studies should be commended for their foray into this field. The imperative of such research is underlined by the increasing use of medical cannabis in the paediatric population across the world, including in Canada, the USA, Germany and the UK. ^{Reference Schlag, Baldwin, Barnes, Bazire, Coathup and Curran18} At the same time, we should proceed gingerly, keeping sight of clinical and research ethical principles to ensure that, as we pursue ways to alleviate problematic tics, we prioritise the safety and well-being of youth with Tourette syndrome.