**3. Cannabis-based medicine in patients with Tourette syndrome**

#### **3.1. Retrospective reports on self-medication**

A substantial number of patients with TS report using cannabis illegally in order to improve their tics or comorbid psychiatric disorders. While doing so, most of these patients rely on their own judgment and self-medicate without a proper consultation with their treating physician. Such an observation was first described in two small case series published in 1988 and 1993 [36]. Sandyk et al. [37] described three male patients, who benefitted both in terms of tics and comorbid psychiatric symptoms after smoking 0.5–2 marijuana cigarettes per day. Hemming et al. [36] reported a case of a 36-year-old man, who smoked a marijuana cigarette every day and claimed to be symptom-free for 1 year. More recently, Müller-Vahl et al. [38] conducted a retrospective survey about self-medication with cannabis in 64 patients with TS seen at a specialized Tourette outpatient clinic in Germany. Seventeen patients indicated to use marijuana illegally as self-treatment for their symptoms, and 14 of them reported beneficial effects not only on tics, but also on different comorbidities. Interestingly, none of the patients reported clinically relevant adverse events (AEs) or a deterioration of tics after the use of marijuana. This effect was not influenced by concomitant use of antipsychotics or selective serotonin reuptake inhibitors (SSRIs).

Finally, Abi-Jaoude et al. [39] in Canada reported results from a retrospective analysis investigating efficacy and safety of smoked cannabis in 19 adults with TS. Patients experienced an average improvement of their tic severity measured with the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) of approximately 60%. Altogether, 18 out of 19 patients experienced an improvement of their TS symptoms. All patients included in this study had used cannabis for self-medication for more than 1 year. Most often reported AEs were a feeling of "being high", decreased concentration, increased anxiety, increased appetite, sedation, irritability, dry mouth, and dry eyes. However, no serious adverse events (SAEs) were reported.

#### **3.2. Prospective case studies using different cannabis-based medicines**

To date, there is a small number of prospective case studies available providing increasing evidence that CBM might be effective and well tolerated in adults with TS. Interestingly, in these case reports, different CBMs have been used. While most of these studies report about beneficial effects in adults, only very recently, first promising case reports in minors have been published.

#### *3.2.1. Case studies using tetrahydrocannabinol*

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

A substantial number of patients with TS report using cannabis illegally in order to improve their tics or comorbid psychiatric disorders. While doing so, most of these patients rely on their own judgment and self-medicate without a proper consultation with their treating physician. Such an observation was first described in two small case series published in 1988 and 1993 [36]. Sandyk et al. [37] described three male patients, who benefitted both in terms of tics and comorbid psychiatric symptoms after smoking 0.5–2 marijuana cigarettes per day. Hemming et al. [36] reported a case of a 36-year-old man, who smoked a marijuana cigarette every day and claimed to be symptom-free for 1 year. More recently, Müller-Vahl et al. [38] conducted a retrospective survey about self-medication with cannabis in 64 patients with TS seen at a specialized Tourette outpatient clinic in Germany. Seventeen patients indicated to use marijuana illegally as self-treatment for their symptoms, and 14 of them reported beneficial effects not only on tics, but also on different comorbidities. Interestingly, none of the patients reported clinically relevant adverse events (AEs) or a deterioration of tics after the use of marijuana. This effect was not influenced by concomitant use of antipsychotics or selec-

Finally, Abi-Jaoude et al. [39] in Canada reported results from a retrospective analysis investigating efficacy and safety of smoked cannabis in 19 adults with TS. Patients experienced an average improvement of their tic severity measured with the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) of approximately 60%. Altogether, 18 out of 19 patients experienced an improvement of their TS symptoms. All patients included in this study had used cannabis for self-medication for more than 1 year. Most often reported AEs were a feeling of "being high", decreased concentration, increased anxiety, increased appetite, sedation, irritability, dry mouth, and dry eyes. However, no serious adverse events (SAEs) were

To date, there is a small number of prospective case studies available providing increasing evidence that CBM might be effective and well tolerated in adults with TS. Interestingly, in these case reports, different CBMs have been used. While most of these studies report about beneficial effects in adults, only very recently, first promising case reports in minors have

**3.2. Prospective case studies using different cannabis-based medicines**

demonstrate any genetic variations in the cannabinoid receptor gene (CNR1) in TS [35].

**3. Cannabis-based medicine in patients with Tourette syndrome**

**3.1. Retrospective reports on self-medication**

122 Recent Advances in Cannabinoid Research

tive serotonin reuptake inhibitors (SSRIs).

reported.

been published.

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 absence of AEs.

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 amisulpride.

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 and visual abilities improved after THC administration.

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. Moreover, coexisting psychiatric conditions improved.

#### *3.2.2. Case studies using nabiximols*

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 reported.

Another single case study using nabiximols was reported by Kanaan et al. [46]. This was a 22-year-old male with complex and severe treatment resistant TS. Nabiximols (up-titrated to 9 puffs/day = 24.3 mg THC and 22.5 mg CBD) resulted in a reduction of tics measured with YGTSS-TTS, Tourette's Syndrome Symptom List (TSSL), and Rush Video Tape Rating Scale, premonitory urges, and a general improvement of quality of life without causing clinically relevant AEs.

significant insomnia. Therefore, the boy's parents—both of whom were medical doctors decided to medicate their son with 0.02 g vaporized cannabis (Bedrocan® variety containing 22% THC and 1% CBD, corresponding to a dose equivalent of 4.4 mg THC). This resulted according to their reports—in a tremendous symptom improvement. Because of a further tic increase, the family presented at our Tourette outpatient clinic. Since the family reported about an ongoing effect while using cannabis with a relevant tic decrease, we decided to implement a combined treatment with vaporized medicinal cannabis (up to 0.1 g cannabis per day, varieties Bedrocan® and Amnesia Haze®, corresponding to 22 mg THC/day) plus oral THC drops (up to 12.5 mg/day). This combined therapy resulted not only in a marked tic

Possible Role of the Endocannabinoid System in Tourette Syndrome

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125

Thus, currently, the database for treatment of minors with TS using CBM is very limited. However, from available preliminary results, it is suggested that CBM is effective and well tolerated even in this age group. At present time, no long-term follow-up data are available, and therefore, no statement is possible about positive and possible negative long-term effects, in particular with respect to detrimental effects on the developing brain. From observational oncological studies in children, however, it is also suggested that controlled application of CBM is safe and well tolerated. It is unknown, whether in children with TS the risk for psychosis is increased after treatment with CBM comparable to the increased risk in healthy children after excessive recreational cannabis use. Assuming a dysfunction in the ECS in TS, it can also be speculated that CBM may have beneficial effects on the course

Up to this date, only two small controlled studies have been conducted in adult patients with TS using CBM. Both of them were performed by Müller-Vahl's group. Dr. Müller-Vahl is an internationally renowned expert in the field of TS and tic disorders. She introduced CBM in the treatment of TS, conducted the first randomized controlled trials in this group of patients in the early 2000s, and since then dedicated a large part of her research endeavors in this area. In both controlled studies, efficacy and safety of pure THC have been investigated. The first one, published in 2002 by Müller-Vahl et al. [48], was a randomized double-blind placebocontrolled cross-over single-dose trial using 5.0, 7.5 or 10 mg of THC. The trial included 12 adult TS patients with a mean age of 34 ± 13 years. Tic severity was assessed both via a self-rating (TSSL) and different examiner-rating scales (Shapiro Tourette's syndrome Severity Scale (STSSS) and YGTSS). The Tourette's syndrome Global Impression Scale (TS-CGI) was used to assess global disease severity. To assess changes in psychiatric comorbidities (including OCB, ADHD, and anxiety), the self-assessment of the TSSL was used. According to TSSL, there was a significant improvement of tics and OCB compared to placebo. According to examiner rating scales for the assessment of tic severity, there was an improvement in the subscore "complex motor tics" and a trend toward a reduction in the subscores "motor tics," "simple motor tics" and "vocal tics." The following AEs were recorded: headache, nausea, dizziness, tiredness, cheerfulness, dry mouth, anxiety, sensitivity to noise and light, ataxia and poor concentration, but no SAEs were reported. Plasma levels of the THC metabolite 11-hydroxy-

delta-tetrahydrocannabinol correlated with tic reduction as assessed by TSSL.

reduction, but also an improvement of premonitory urges without any AEs.

of the disease.

*3.2.5. Controlled trials using tetrahydrocannabinol*

#### *3.2.3. Case studies using medicinal cannabis*

Recently, Jakubovski and Müller-Vahl published a case report of a patient with TS treated with medicinal cannabis [43]. He suffered from a rare form of TS: a severe, impairing and treatment resistant vocal blocking and stuttering-like vocal tics as well as palilalia. These symptoms significantly impaired social contacts and daily living. The 19-year old patient received medicinal cannabis at a dose of 0.1 g cannabis once daily. After 8 months of followup, the symptoms improved significantly, especially speech fluency, but also other tics. After cannabis inhalation, beneficial effects lasted for about one and a half hour. Although the acute effect resolved thereafter, he experienced an overall positive effect during most time of the day. Only at the beginning of the treatment, he experienced a "high sensation" that resolved later on.

#### *3.2.4. Treatment of minors with Tourette syndrome using cannabis-based medicines*

Until today, only three single case studies are available reporting about treatment of minors with TS using CBM. The first report was published by Hasan et al. [47] in 2010. They described a 15-year old adolescent with severe and treatment resistant TS and comorbid ADHD. In this boy, augmentation of preexisting medication with risperidone (1 mg), aripiprazole (10 mg), and methylphenidate (15 mg) with oral THC (gradually up-titrated to 15 mg/day during 9 weeks) resulted in a significant tic reduction (global score of the YGTSS (range, 0–100) decreased from 97 to 54) and improved quality of life. The only AE observed was mild and transient euphoria.

The first ever case report of a child with TS treated with CBM was published only recently by Szejko et al. [48]. This 7-year-old boy suffered from severe tics and comorbid ADHD, which prevented him to attend school and finally resulted in social isolation, depression, and suicidal ideation. As all previous therapies including behavioral interventions and various medications (including risperidone, aripiprazole, tiapride, methylphenidate, and guanfacine) turned out to be unsuccessful, THC was proposed as a therapy of last choice. THC (in combination with risperidone (2 mg/day) and guanfacine (2 mg/day)) were gradually up-titrated to a maximal dose of 29.4 mg/day. Follow-up for more than 4 months demonstrated not only a clinically relevant improvement of tics, but also of accompanying psychiatric symptoms resulting in overall improved quality of life and social performance. Despite the relatively high dose of THC, no AEs were reported.

Furthermore, there is another single case report available describing beneficial effects of a combined treatment with vaporized medicinal cannabis and oral THC in a 12-year-old boy with TS (unpublished data, under revision). The boy complained of severe motor tics causing significant insomnia. Therefore, the boy's parents—both of whom were medical doctors decided to medicate their son with 0.02 g vaporized cannabis (Bedrocan® variety containing 22% THC and 1% CBD, corresponding to a dose equivalent of 4.4 mg THC). This resulted according to their reports—in a tremendous symptom improvement. Because of a further tic increase, the family presented at our Tourette outpatient clinic. Since the family reported about an ongoing effect while using cannabis with a relevant tic decrease, we decided to implement a combined treatment with vaporized medicinal cannabis (up to 0.1 g cannabis per day, varieties Bedrocan® and Amnesia Haze®, corresponding to 22 mg THC/day) plus oral THC drops (up to 12.5 mg/day). This combined therapy resulted not only in a marked tic reduction, but also an improvement of premonitory urges without any AEs.

Thus, currently, the database for treatment of minors with TS using CBM is very limited. However, from available preliminary results, it is suggested that CBM is effective and well tolerated even in this age group. At present time, no long-term follow-up data are available, and therefore, no statement is possible about positive and possible negative long-term effects, in particular with respect to detrimental effects on the developing brain. From observational oncological studies in children, however, it is also suggested that controlled application of CBM is safe and well tolerated. It is unknown, whether in children with TS the risk for psychosis is increased after treatment with CBM comparable to the increased risk in healthy children after excessive recreational cannabis use. Assuming a dysfunction in the ECS in TS, it can also be speculated that CBM may have beneficial effects on the course of the disease.

#### *3.2.5. Controlled trials using tetrahydrocannabinol*

Another single case study using nabiximols was reported by Kanaan et al. [46]. This was a 22-year-old male with complex and severe treatment resistant TS. Nabiximols (up-titrated to 9 puffs/day = 24.3 mg THC and 22.5 mg CBD) resulted in a reduction of tics measured with YGTSS-TTS, Tourette's Syndrome Symptom List (TSSL), and Rush Video Tape Rating Scale, premonitory urges, and a general improvement of quality of life without causing clinically

Recently, Jakubovski and Müller-Vahl published a case report of a patient with TS treated with medicinal cannabis [43]. He suffered from a rare form of TS: a severe, impairing and treatment resistant vocal blocking and stuttering-like vocal tics as well as palilalia. These symptoms significantly impaired social contacts and daily living. The 19-year old patient received medicinal cannabis at a dose of 0.1 g cannabis once daily. After 8 months of followup, the symptoms improved significantly, especially speech fluency, but also other tics. After cannabis inhalation, beneficial effects lasted for about one and a half hour. Although the acute effect resolved thereafter, he experienced an overall positive effect during most time of the day. Only at the beginning of the treatment, he experienced a "high sensation" that resolved

Until today, only three single case studies are available reporting about treatment of minors with TS using CBM. The first report was published by Hasan et al. [47] in 2010. They described a 15-year old adolescent with severe and treatment resistant TS and comorbid ADHD. In this boy, augmentation of preexisting medication with risperidone (1 mg), aripiprazole (10 mg), and methylphenidate (15 mg) with oral THC (gradually up-titrated to 15 mg/day during 9 weeks) resulted in a significant tic reduction (global score of the YGTSS (range, 0–100) decreased from 97 to 54) and improved quality of life. The only AE observed was mild and

The first ever case report of a child with TS treated with CBM was published only recently by Szejko et al. [48]. This 7-year-old boy suffered from severe tics and comorbid ADHD, which prevented him to attend school and finally resulted in social isolation, depression, and suicidal ideation. As all previous therapies including behavioral interventions and various medications (including risperidone, aripiprazole, tiapride, methylphenidate, and guanfacine) turned out to be unsuccessful, THC was proposed as a therapy of last choice. THC (in combination with risperidone (2 mg/day) and guanfacine (2 mg/day)) were gradually up-titrated to a maximal dose of 29.4 mg/day. Follow-up for more than 4 months demonstrated not only a clinically relevant improvement of tics, but also of accompanying psychiatric symptoms resulting in overall improved quality of life and social performance. Despite the relatively

Furthermore, there is another single case report available describing beneficial effects of a combined treatment with vaporized medicinal cannabis and oral THC in a 12-year-old boy with TS (unpublished data, under revision). The boy complained of severe motor tics causing

*3.2.4. Treatment of minors with Tourette syndrome using cannabis-based medicines*

relevant AEs.

124 Recent Advances in Cannabinoid Research

later on.

transient euphoria.

high dose of THC, no AEs were reported.

*3.2.3. Case studies using medicinal cannabis*

Up to this date, only two small controlled studies have been conducted in adult patients with TS using CBM. Both of them were performed by Müller-Vahl's group. Dr. Müller-Vahl is an internationally renowned expert in the field of TS and tic disorders. She introduced CBM in the treatment of TS, conducted the first randomized controlled trials in this group of patients in the early 2000s, and since then dedicated a large part of her research endeavors in this area. In both controlled studies, efficacy and safety of pure THC have been investigated. The first one, published in 2002 by Müller-Vahl et al. [48], was a randomized double-blind placebocontrolled cross-over single-dose trial using 5.0, 7.5 or 10 mg of THC. The trial included 12 adult TS patients with a mean age of 34 ± 13 years. Tic severity was assessed both via a self-rating (TSSL) and different examiner-rating scales (Shapiro Tourette's syndrome Severity Scale (STSSS) and YGTSS). The Tourette's syndrome Global Impression Scale (TS-CGI) was used to assess global disease severity. To assess changes in psychiatric comorbidities (including OCB, ADHD, and anxiety), the self-assessment of the TSSL was used. According to TSSL, there was a significant improvement of tics and OCB compared to placebo. According to examiner rating scales for the assessment of tic severity, there was an improvement in the subscore "complex motor tics" and a trend toward a reduction in the subscores "motor tics," "simple motor tics" and "vocal tics." The following AEs were recorded: headache, nausea, dizziness, tiredness, cheerfulness, dry mouth, anxiety, sensitivity to noise and light, ataxia and poor concentration, but no SAEs were reported. Plasma levels of the THC metabolite 11-hydroxydelta-tetrahydrocannabinol correlated with tic reduction as assessed by TSSL.

In 2003, Müller-Vahl et al. published results of a randomized, double-blind, placebo-controlled follow-up trial [49]. In this study, 24 adult patients with TS were treated for a period of 6 weeks with up to 10 mg THC/day. Tic severity was evaluated at six different time points. For tic assessment, both self-rating scales as well as examiner rating scales were used (TSSL, YGTSS, STSSS, and Rush Video-Based Tic Rating Scale) [45]. Nearly all rating scales indicated a significant superiority of the THC arm compared to placebo at visits 3 and 4. The Rush Video-Based Tic Rating Scale also showed a significant difference or trends toward significant group differences at visits 2 and 4 for the items "motor tic intensity" and "motor tic frequency," respectively. Seven patients dropped out of the study, but only one due to AEs (restlessness and anxiety). Five patients in the THC group reported AEs (tiredness, dry mouth, dizziness and fuzziness), while three in the placebo group (tiredness, dizziness, anxiety, depression) in the absence of SAEs.

Although most patients with TS treated with CBM report about an improvement of one or even more psychiatric comorbidities, larger controlled trials are needed to confirm these

Possible Role of the Endocannabinoid System in Tourette Syndrome

http://dx.doi.org/10.5772/intechopen.79895

127

From the available preliminary results, it is suggested that—on average—the AE profile of CBM in the treatment of patients with TS is very similar to that in other groups of patients. In line with data from recent meta-analyses including mixed patients' groups [52], for example, in the retrospective study by Abi-Jaoude et al. [53], a relatively high number of AEs were reported in patients with TS, but most AEs were mild and transient, respectively. Most often reported AEs after use of cannabis in patients with TS were a "feeling of high," decreased concentration, decreased short-term memory, increased anxiety, increased appetite, sedation,

Contrary to these reports from open uncontrolled studies, from preliminary controlled data, it is suggested that the impact of THC on neuropsychological performance in adults with TS may differ as compared to both healthy people and other patient groups. In two controlled studies investigating the effects of THC in patients with TS, additionally, neuropsychological tests were performed. In the first study [54], the influence of a single dose treatment of THC on neuropsychological performance was investigated. However, no negative impact of THC compared to placebo was found on verbal and visual memory, reaction time, intelligence, sustained attention, divided attention, and vigilance. In another study, Müller-Vahl et al. [55] investigated the influence of a 6-week THC treatment as compared to placebo on neuropsychological performance using different neuropsychological tests to assess verbal learning, attention, and memory. Again, THC had no detrimental effects on neuropsychological performance and immediate verbal memory span even improved after treatment with THC.

These results are completely in line with observations in two open uncontrolled single case studies. In 2007, Strohbeck-Kühner et al. [56] published a case of a 28 year-old male with ADHD (without TS), who benefitted from treatment with THC, and, moreover, his fitness to drive improved after treatment. A similar case was reported by Brunnauer et al. [42] some years later. They described an effective treatment with THC in a 42 year-old male. Furthermore, his driving ability (concentration and visual abilities) was better under treatment with THC as compared to the off-medication state. The authors, therefore, suggested that in TS, CBM such as THC may have beneficial effects on psychomotor functions related to driving performance. Thus, from this preliminary data, it is strongly suggested that the influence of CBM on neuropsychological performance in patients

Finally, until today, very little is known about safety of CBM in children and adolescents with TS [47–49]. However, from available preliminary case reports, it is suggested that in this group of patients CBM such as THC is well tolerated or even better tolerated than in adults. This observation is in line with reports in other groups of young patients. For example when using CBM in antineoplastic therapy [30] it has been suggested that CBM—even at high doses—are well toler-

with TS may differ from effects in healthy people and other groups of patients.

*3.2.7. Safety profile and influence on psychomotor functioning in patients with Tourette* 

promising, but preliminary results.

irritability, dry mouth and eyes, and wheezing.

*syndrome*

ated in children.

#### *3.2.6. Efficacy of cannabis-based medicines in the treatment of psychiatric comorbidities in patients with Tourette syndrome*

Up to 90% of patients with TS suffer from psychiatric comorbidities and studies investigating quality of life in these patients clearly demonstrate that most patients are more impaired by ADHD, OCD, and depression, respectively, than their tics. Thus, in the majority of patients with TS, effective treatment of comorbidities is even more important than treatment of tics. Until today, however, there is no treatment strategy known that improves both tics and comorbidities. Therefore, in patients with complex TS combined therapy using different treatment strategies in parallel is inevitable.

Interestingly, from all available case studies and controlled trials, it is suggested that CBM improves not only tics, but also psychiatric symptoms. Therefore, it can be speculated that CBM might be the first treatment strategy that is useful in the treatment of the complete spectrum of symptoms. More specifically, there is preliminary evidence that CBM also improves ADHD [39], OCB/OCD [40] impulsivity [43], depression [50], sleeping problems [51], and anxiety [43].

For example, in the retrospective survey by Abi-Jaoude et al. [39], all patients reported in addition to the tic improvement also an improvement of psychiatric symptoms after treatment with cannabis including sleeping disturbances, anxiety, OCB, impulsivity, irritability and rage attacks. With respect to comorbid ADHD, only one out of 13 patients demonstrated no improvement of ADHD symptoms. This data in patients with TS is in line with preliminary results in patients suffering from pure ADHD (without tics or TS). In 2017, Cooper et al. [52] published results of a randomized placebo-controlled pilot study using nabiximols in patients with ADHD. In this trial, 30 adults with ADHD were included, and cognitive performance was assessed using an objective assessment for inattention, hyperactivity, and impulsivity (Qb-Test). Although for the primary outcome, no significant difference was observed, several secondary outcomes demonstrated superiority of nabiximols compared to placebo with improvements in hyperactivity, impulsivity and inattention, respectively. In the active group, three mild AEs and one SAE (muscular spasms/seizures) were recorded, while in the placebo group, one SAE (cardiovascular problems) occurred.

Although most patients with TS treated with CBM report about an improvement of one or even more psychiatric comorbidities, larger controlled trials are needed to confirm these promising, but preliminary results.

#### *3.2.7. Safety profile and influence on psychomotor functioning in patients with Tourette syndrome*

In 2003, Müller-Vahl et al. published results of a randomized, double-blind, placebo-controlled follow-up trial [49]. In this study, 24 adult patients with TS were treated for a period of 6 weeks with up to 10 mg THC/day. Tic severity was evaluated at six different time points. For tic assessment, both self-rating scales as well as examiner rating scales were used (TSSL, YGTSS, STSSS, and Rush Video-Based Tic Rating Scale) [45]. Nearly all rating scales indicated a significant superiority of the THC arm compared to placebo at visits 3 and 4. The Rush Video-Based Tic Rating Scale also showed a significant difference or trends toward significant group differences at visits 2 and 4 for the items "motor tic intensity" and "motor tic frequency," respectively. Seven patients dropped out of the study, but only one due to AEs (restlessness and anxiety). Five patients in the THC group reported AEs (tiredness, dry mouth, dizziness and fuzziness), while three in the placebo group (tiredness, dizziness, anxiety, depression) in

*3.2.6. Efficacy of cannabis-based medicines in the treatment of psychiatric comorbidities in* 

Up to 90% of patients with TS suffer from psychiatric comorbidities and studies investigating quality of life in these patients clearly demonstrate that most patients are more impaired by ADHD, OCD, and depression, respectively, than their tics. Thus, in the majority of patients with TS, effective treatment of comorbidities is even more important than treatment of tics. Until today, however, there is no treatment strategy known that improves both tics and comorbidities. Therefore, in patients with complex TS combined therapy using different treat-

Interestingly, from all available case studies and controlled trials, it is suggested that CBM improves not only tics, but also psychiatric symptoms. Therefore, it can be speculated that CBM might be the first treatment strategy that is useful in the treatment of the complete spectrum of symptoms. More specifically, there is preliminary evidence that CBM also improves ADHD [39], OCB/OCD [40] impulsivity [43], depression [50], sleeping problems [51], and

For example, in the retrospective survey by Abi-Jaoude et al. [39], all patients reported in addition to the tic improvement also an improvement of psychiatric symptoms after treatment with cannabis including sleeping disturbances, anxiety, OCB, impulsivity, irritability and rage attacks. With respect to comorbid ADHD, only one out of 13 patients demonstrated no improvement of ADHD symptoms. This data in patients with TS is in line with preliminary results in patients suffering from pure ADHD (without tics or TS). In 2017, Cooper et al. [52] published results of a randomized placebo-controlled pilot study using nabiximols in patients with ADHD. In this trial, 30 adults with ADHD were included, and cognitive performance was assessed using an objective assessment for inattention, hyperactivity, and impulsivity (Qb-Test). Although for the primary outcome, no significant difference was observed, several secondary outcomes demonstrated superiority of nabiximols compared to placebo with improvements in hyperactivity, impulsivity and inattention, respectively. In the active group, three mild AEs and one SAE (muscular spasms/seizures) were recorded, while in the placebo

the absence of SAEs.

anxiety [43].

*patients with Tourette syndrome*

126 Recent Advances in Cannabinoid Research

ment strategies in parallel is inevitable.

group, one SAE (cardiovascular problems) occurred.

From the available preliminary results, it is suggested that—on average—the AE profile of CBM in the treatment of patients with TS is very similar to that in other groups of patients. In line with data from recent meta-analyses including mixed patients' groups [52], for example, in the retrospective study by Abi-Jaoude et al. [53], a relatively high number of AEs were reported in patients with TS, but most AEs were mild and transient, respectively. Most often reported AEs after use of cannabis in patients with TS were a "feeling of high," decreased concentration, decreased short-term memory, increased anxiety, increased appetite, sedation, irritability, dry mouth and eyes, and wheezing.

Contrary to these reports from open uncontrolled studies, from preliminary controlled data, it is suggested that the impact of THC on neuropsychological performance in adults with TS may differ as compared to both healthy people and other patient groups. In two controlled studies investigating the effects of THC in patients with TS, additionally, neuropsychological tests were performed. In the first study [54], the influence of a single dose treatment of THC on neuropsychological performance was investigated. However, no negative impact of THC compared to placebo was found on verbal and visual memory, reaction time, intelligence, sustained attention, divided attention, and vigilance. In another study, Müller-Vahl et al. [55] investigated the influence of a 6-week THC treatment as compared to placebo on neuropsychological performance using different neuropsychological tests to assess verbal learning, attention, and memory. Again, THC had no detrimental effects on neuropsychological performance and immediate verbal memory span even improved after treatment with THC.

These results are completely in line with observations in two open uncontrolled single case studies. In 2007, Strohbeck-Kühner et al. [56] published a case of a 28 year-old male with ADHD (without TS), who benefitted from treatment with THC, and, moreover, his fitness to drive improved after treatment. A similar case was reported by Brunnauer et al. [42] some years later. They described an effective treatment with THC in a 42 year-old male. Furthermore, his driving ability (concentration and visual abilities) was better under treatment with THC as compared to the off-medication state. The authors, therefore, suggested that in TS, CBM such as THC may have beneficial effects on psychomotor functions related to driving performance. Thus, from this preliminary data, it is strongly suggested that the influence of CBM on neuropsychological performance in patients with TS may differ from effects in healthy people and other groups of patients.

Finally, until today, very little is known about safety of CBM in children and adolescents with TS [47–49]. However, from available preliminary case reports, it is suggested that in this group of patients CBM such as THC is well tolerated or even better tolerated than in adults. This observation is in line with reports in other groups of young patients. For example when using CBM in antineoplastic therapy [30] it has been suggested that CBM—even at high doses—are well tolerated in children.

#### *3.2.8. Practical clues for the treatment of patients with Tourette syndrome using cannabisbased medicines*

Despite lack of clear evidence, recent European [25] and Canadian treatment guidelines [28] for TS acknowledged available data and recommend CBM in otherwise treatment resistant adult patients with TS. Most experts suggest treatment with CBM, before taking surgical treatment with deep brain stimulation into consideration. Comparable to most other indications, until today it is unclear, which CBM is the most effective and best tolerated in patients with TS. However, from available data, it is suggested that pure CBD is not effective in the treatment of tics. Data obtained from both a retrospective and prospective survey performed at the Tourette outpatient clinic at Hannover Medical School, Germany, provide preliminary evidence that medicinal cannabis might be superior to pure THC and nabiximols (unpublished data). Currently, treatment with CBM in minors with TS should be only taken into consideration in otherwise treatment resistant and severely affected patients.

With respect to the dose, no clear recommendation can be given. In any case, starting dose should be low (corresponding to 2.5 mg THC/day) and up-titration should be slow, for example by 2.5 mg THC every 3–5 days. Maximal dose differs from patient to patient, but usually ranges from 0.1 to 1 g cannabis/day, corresponding to about 2.5–30 mg THC/day. However, in individual patients, maximal doses can be much higher.


**4. Future directions**

**Table 1.** Case studies employing CBM in TS.

**Reference Number** 

Müller-Vahl et al.

Brunnauer et al.

Abi-Jaoude et al.

Jakubovski and Müller-Vahl. 2017

Szejko et al. (submitted to Frontiers in Psychiatry)

2003b

2011

2017

**of patients (sex)**

12 (11 male, 1 female)

Hasan et al. 2010 1 (male) 15 THC (in

19 (16 males, 3 females)

2 (male) 16, 19 THC, medical

1 (male) 12 THC, medical

cannabis

cannabis

with median to high THC content.

Larger well-designed controlled studies are urgently needed to confirm available preliminary results. Further studies should investigate not only the efficacy of CBM in the treatment of tics, but also their potency to improve typical psychiatric comorbidities in TS including ADHD, OCB, depression, anxiety, sleeping disorders, and rage attacks. Finally, the AE profile should be investigated in detail, since from available data, it is suggested that neuropsychological performance may improve—and not deteriorate—after treatment with CBM in this group of patients. So far, it is unknown, which CBM is the most effective and best tolerated in patients with TS. However, based on available reports, patients with TS seem to prefer CBM

**Age Substance Study design Outcome**

double-blind placebo-controlled crossover trial

1 (male) 42 THC Case report Reduction of tics, improvement

structured interview

Tic reduction; improvement of

129

http://dx.doi.org/10.5772/intechopen.79895

quality of life; treatment with methylphenidate was tolerated

of concentration and visual

complex vocal tics resulting in improved speech fluency, co-existing psychiatric conditions

without tic increase

OCB

Possible Role of the Endocannabinoid System in Tourette Syndrome

Case report Tic reduction, improvement of

perception

Case report Improvement of tics including

improved

Case report Reduction of tics, improvement

of quality of life

of comorbid psychiatric conditions (ADHD, depression), improvement of quality of life

of sleeping problems

Reduction of tics

18-66 THC Randomized

combination with aripiprazole and risperidone)

Trainor et al. 2016 1 (male) 26 Nabiximols Case report Reduction of motor and vocal tics

Kanaan et al. 2017 1 (male) 22 Nabiximols Case report Reduction of tics, improvement

Szejko et al. 2018 1 (male) 8 THC Case report Reduction of tics, improvement

18-51 Medical cannabis Case series,

An overview on all available studies investigating efficacy and safety of CBM in TS is given in **Table 1**.


**Table 1.** Case studies employing CBM in TS.

## **4. Future directions**

*3.2.8. Practical clues for the treatment of patients with Tourette syndrome using cannabis-*

consideration in otherwise treatment resistant and severely affected patients.

in individual patients, maximal doses can be much higher.

39

1 (female) 24 THC (in

Despite lack of clear evidence, recent European [25] and Canadian treatment guidelines [28] for TS acknowledged available data and recommend CBM in otherwise treatment resistant adult patients with TS. Most experts suggest treatment with CBM, before taking surgical treatment with deep brain stimulation into consideration. Comparable to most other indications, until today it is unclear, which CBM is the most effective and best tolerated in patients with TS. However, from available data, it is suggested that pure CBD is not effective in the treatment of tics. Data obtained from both a retrospective and prospective survey performed at the Tourette outpatient clinic at Hannover Medical School, Germany, provide preliminary evidence that medicinal cannabis might be superior to pure THC and nabiximols (unpublished data). Currently, treatment with CBM in minors with TS should be only taken into

With respect to the dose, no clear recommendation can be given. In any case, starting dose should be low (corresponding to 2.5 mg THC/day) and up-titration should be slow, for example by 2.5 mg THC every 3–5 days. Maximal dose differs from patient to patient, but usually ranges from 0.1 to 1 g cannabis/day, corresponding to about 2.5–30 mg THC/day. However,

An overview on all available studies investigating efficacy and safety of CBM in TS is given

1 (male) 36 *Cannabis sativa L.* Case report Symptom free

combination with amisulpride)

18-68 THC Randomized

**Age Substance Study design Outcome**

*Cannabis sativa L.* Case report Reduction of tics, premonitory

15-64 Medical cannabis Case series Tic reduction or remission;

1 (male) 25 THC Case report Tic reduction, premonitory

double-blind parallel group placebo-controlled

trial

urges and self-injurious behavior; general relaxation; improvement of attention and hypersexuality

premonitory urges; improvement

urges; improvement of attention, impulse control, and OCB

of OCB and ADHD

Tic reduction; global improvement

Case report Tic reduction, premonitory urges

*based medicines*

128 Recent Advances in Cannabinoid Research

in **Table 1**.

Hemming et al.

Müller-Vahl et al.

Müller-Vahl et al.

Müller-Vahl et al.

Müller-Vahl et al.

1993

1998

1999

2002a

2002b

**Reference Number** 

**of patients (sex)**

64 (55 male, 9 female)

24 (19 male, 5 female)

Sandyk et al. 1988 3 (male) 15, 17,

Larger well-designed controlled studies are urgently needed to confirm available preliminary results. Further studies should investigate not only the efficacy of CBM in the treatment of tics, but also their potency to improve typical psychiatric comorbidities in TS including ADHD, OCB, depression, anxiety, sleeping disorders, and rage attacks. Finally, the AE profile should be investigated in detail, since from available data, it is suggested that neuropsychological performance may improve—and not deteriorate—after treatment with CBM in this group of patients. So far, it is unknown, which CBM is the most effective and best tolerated in patients with TS. However, based on available reports, patients with TS seem to prefer CBM with median to high THC content.

Currently, a large randomized controlled trial in Germany is recruiting to further investigate efficacy and safety of nabiximols in patients with TS (ClinicalTrials.gov Identifier: NCT03087201). In this study, in addition, patients' fitness to drive will be investigated after treatment with nabiximols.

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Psychosomatic Research. 2009;**67**:475-483

med-9780199796267-chapter-1

Front Neuroscience. 2016;**10**(Sep)

Biobehavioral Reviews. 2013;**37**:1026-39

Syndrome. 2013

4003464

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While all published studies investigated the effects of different synthetic or plant-derived cannabinoids in the treatment of TS, unpublished data from a single dose pilot study in 20 adult patients suggests that also modulators of the endocannabinoid system—such as inhibitors of the monoacylglycerol lipase (MGLL)— might be effective in the treatment of TS (ClinicalTrials. gov Identifier: NCT03058562).
