**2. Possible role of the endocannabinoid system in Tourette syndrome**

involve only one group of muscles in a brief jerk-like movement, with examples such as eye blinking, head jerking or shoulder shrugging. Complex motor tics, on the contrary, involve multiple groups of muscles or resemble purposeful movements. Examples of complex motor tics are as follows: touching people or objects, echopraxia (mirroring another person's actions) or copropraxia (involuntary performing of obscene gestures). Simple vocal tics are short vocalizations, for example throat clearing, sniffing or grunting. Complex vocal tics involve the involuntary production of words or entire sentences, for example echolalia (repeating another person's words), palilalia (repeating one's own words) and coprolalia (involuntary pronunciation of obscene words). Although coprolalia is often associated with TS, it is only present in approximately 10% of patients [2]. The majority of patients report a premonitory urge that proceeds the tics. This is often described as an "uncomfortable" physical sensation located in a particular body part or as a more generalized feeling [3]. Most (adult) patients are

In almost 90% of TS patients, tics are accompanied by other co-occurring psychiatric disorders such as attention deficit/hyperactivity disorder (ADHD), obsessive–compulsive disorder

Tics typically first emerge between 5 and 7 years of age and increase in severity until they reach a peak in early adolescence (most often at the age of 10–12 years). After this worst-ever period, tics—in most cases—decrease until a mild to minimal degree of severity is reached in early adulthood [5]. At the same time, TS is characterized by spontaneous fluctuations and waxing and waning over time. The occurrence of tics is influenced by various environmental factors. While the majority of patients experience fewer tics when relaxing or concentrating (e.g. when practicing sports, playing musical instruments or computer games), tics often

To date, no single cause of TS was identified; instead, several lines of evidence suggested that TS is caused by an interplay between genetic [6] and environmental factors [7]. For example, there is clear evidence that prenatal and perinatal complications including low birth weight and maternal smoking during pregnancy [8, 9] may represent such epigenetic factors. In contrast, the influence of infections [7] and immunological factors [10] is still unclear. As for the pathophysiology of TS, most studies suggest a major involvement of the dopaminergic system [11–17]; however, several other neurotransmitter systems might play a role including the serotonergic [12, 18], histaminergic [19], glutamatergic [20], GABAergic [21], cholinergic [22], and noradrenergic systems [23]. Furthermore, it is believed that disturbances of cortico-

striato-thalamo-cortical (CSTC) pathways play a role in the generation of tics [24].

Both European [25–27] as well as Canadian [28] treatment guidelines for TS recommend application of behavioral psychotherapy techniques (either habit reversal training or exposure and response prevention training), pharmacotherapy and, in otherwise treatment resistant very severely affected patients, surgical intervention using deep brain stimulation. Like in the case

(OCD), self-injurious behaviors (SIB), anxiety disorders and depression [4].

able to control their tics for a short period of time.

120 Recent Advances in Cannabinoid Research

**1.2. Course and causes of Tourette syndrome**

increase with stress, tiredness and infections.

**1.3. Treatment of Tourette syndrome**

The main function of the central endocannabinoid system (ECS) is inhibitory modulation of other neurotransmitter systems. Among other brain regions, cannabinoid type 1 receptors (CB1) are expressed with high density in the basal ganglia [29] indicating a paramount role of the ECS in the control of movements. In TS, there is substantial evidence for an involvement of the dopaminergic system. However, until today it is unclear, whether these alterations represent the primary cause of the disease or are related to secondary or compensatory changes. In addition to the dopaminergic hypothesis in TS, changes in several other transmitter systems have been suggested including the glutamatergic, GABAergic, serotonergic, noradrenergic and histaminergic systems. Since the ECS is a highly important modulatory system in the brain that influences and controls all important neurotransmitter systems, it can be speculated that TS might be caused by a dysfunction in the ECS system. This hypothesis is in line with studies reporting about an involvement of several different neurotransmitter systems in TS. In addition, alterations within the ECS would explain the complex clinical presentation of TS including both hyperkinetic movements with tics and a large variety of psychiatric manifestations.

Noteworthy, there is a strong interaction between the dopaminergic and the ECS [29, 30], particularly in basal ganglia regions including the striatum [31] and the globus pallidus [32]. Since there is substantial evidence for an involvement of the dopaminergic system in the pathobiology of TS, it, therefore, can also be speculated that CBM may inhibit dopaminergic activity in brain areas associated with motor control resulting in a reduction of hyperkinetic movements such as tics [33]. However, one might also speculate that the modulation of other neurotransmitter systems including glutamate and GABA might result in a reduction of tics.

Until today, only one neuroimaging study has been performed using single photon emission computed tomography (SPECT) and [123I]AM281 to investigate the ECS in patients with TS [34]. In this study, it could be demonstrated that CB1 receptor binding is reduced after treatment with THC. Since in this study, no control group has been included, no statement is possible, whether CB1 receptor binding is changed in patients with TS. So far, genetic analyses failed to demonstrate any genetic variations in the cannabinoid receptor gene (CNR1) in TS [35].

*3.2.1. Case studies using tetrahydrocannabinol*

and visual abilities improved after THC administration.

Moreover, coexisting psychiatric conditions improved.

*3.2.2. Case studies using nabiximols*

reported.

absence of AEs.

amisulpride.

In 1999, Müller-Vahl et al. [40] published the first case of a 25-year old patient with TS treated with oral tetrahydrocannabinol (THC). This patient suffered from a complex TS and a number of additional psychiatric disorders such as ADHD, obsessive–compulsive behavior (OCB), SIB, anxiety disorder, and impulsivity. According to the patient's report, self-medication with smoked cannabis (2–3 g/day) caused a clinically relevant improvement of all these symptoms. Therefore, the patient was prospectively treated once with a single dose of 10 mg THC. This resulted in a significant reduction of tics of about 80% as well as an improvement in attention, impulse control, OCB, and premonitory urges. In addition, neuropsychological tests showed improvements in signal detection, sustained attention, and reaction time in the

Possible Role of the Endocannabinoid System in Tourette Syndrome

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The same group described another case of a 24-year old female, who had an improvement of tics and premonitory urges after combined therapy of THC and the antipsychotic amisulpride [41]. The patient did far better on this combination than on monotherapy with either THC or

In addition, in 2011, Brunnauer et al. [42] reported the case of a 42-year-old male with TS, who suffered from multiple motor and vocal tics as well as OCB. Treatment with 15 mg THC resulted in a 75% tic reduction. As this patient was a professional driver, his driving abilities were assessed by professional computerized tests. Interestingly, the patient's concentration

Finally, Jakubovski and Müller-Vahl [43] reported about a 16-year old patient with vocal tics resembling stuttering-like phenomena accompanied by multiple simple and complex vocal tics as well as simple motor tics. Apart from tics, he was also experiencing further psychiatric problems including rage attacks, sleeping problems, tic-related anxiety and shame about speaking in public, depressed mood, and OCB (e.g., ordering of pencils, not just right feeling, and rumination) resulting in difficulties concentrating. Due to treatment resistance and intolerable AEs after established therapeutic interventions, it was decided to implement treatment with vaporized THC (up to a maximum dose of 22.4–33.6 mg THC/day). This leads to an improvement of his tics including complex vocal tics resulting in improved speech fluency.

The first case report about effective treatment with nabiximols in a patient with TS was published by Trainor et al. [44] in 2016. This 26-year-old male suffered from treatment-resistant TS with severe motor and vocal tics, OCD, SIB, and depression. Administration of 4 puffs nabiximols (=10.8 mg of THC and 10 mg cannabidiol (CBD)) resulted in a 85% reduction of motor and 90% reduction of vocal tics after 4 weeks of treatment measured via the Rush Video Tape Rating Scale [45] and a 35% tic improvement according to the YGTSS-TTS. No AEs were
