Treatment with cannabinoid drugs for patients with nervous tics and Tourette syndrome

Repetitive movement disorders (tics) are defined by the presence of motor or vocal tics. Motors are abrupt simple or complex involuntary movements that can occur throughout the body, but often do so in the head and face. Vocal tics are characterized by simple sounds and noises, but they can also be more complex, as in the case of obscene words. Tourette syndrome (TS) is a complex neurological and psychiatric disorder defined by the presence of several motor tics and at least one vocal tics.

Repetitive movement disorders (nervous tics) and Tourette syndrome
ST is a disorder of nervous development and, therefore, the time of its onset occurs during childhood and most commonly is between 6 and 8 years. The vast majority of patients with TS, however, not only suffer from motor and vocal tics, but also present one or more behavioral problems, such as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive behaviors (OCD) , for “obsessive-compulsive disorders”), anxiety, depression, rabies attacks, self-injurious behaviors, sleep disorders or learning problems or the autism spectrum. Consequently, many patients suffer a substantial reduction in the quality of life.

Treatment of patients with repetitive movement disorders (tics) and Tourette’s syndrome
Due to the complexity of the symptoms and changes in the initial clinical picture over time, treatment of ST patients is often a challenge and, so far, the tics can not be cured. The established treatment strategies for these patients include behavioral therapy or pharmacotherapy with antipsychotics. Although behavioral therapy does not produce adverse events, on average only an improvement of 30% is obtained in the case of tics. Compared to behavioral therapy, pharmacotherapy with antipsychotics is more effective and usually achieves a reduction in tics of approximately 50%. However, not all patients benefit from antipsychotic medications and, in many patients, this treatment is associated with relevant side effects such as sedation, weight gain and sexual dysfunction. Patients who also suffer from clinically relevant psychiatric disorders need polytherapy, given that until now there is no known therapeutic approach that not only improves tics but also improves psychiatric comorbidities. Consequently, many patients with TS are not satisfied with the treatment strategies available to them and seek alternative medications.

Faced with this situation, new treatment strategies are urgently needed for this group of patients. Ideally, these new treatments (i) should be associated with fewer side effects compared to currently available substances, (ii) obtain a greater improvement (or even complete remission) of the tics, (iii) ) are also effective in patients with severe disease and resistant to other treatments and (iv) not only improve tics, but the full spectrum of the disease, including different psychiatric symptoms, such as ADHD, OCD and depression.

Cannabinoid medications for patients with repetitive movement disorders (tics) and Tourette syndrome
Clinical cases
In 1988, it was suggested for the first time that marijuana could be an alternative treatment option for patients suffering from TS. This report describes three male patients aged 15, 17 and 39 years who had experienced a reduction in motor tics and a sensation of premonitory urgency, an improvement in the tendencies of self-injurious behavior, of attention and of the hypersexual behavior, as well as a generalized feeling of relaxation, when smoking marijuana. There was no side effect and the effect of the treatment remained stable over time and was not reduced. Since this initial report, a small number of case studies have been published describing the beneficial effects of marijuana, as well as other cannabinoid drugs, in patients with TS. There are no reports of serious side effects or addiction to marijuana. In most of these case studies, the authors report beneficial effects in tics and psychiatric symptoms. In many of the patients, the use of pharmacotherapy with other substances (such as antipsychotics for the treatment of tics, methylphenidate for the treatment of ADHD or antidepressants for the treatment of depression, anxiety and OCD) could be stopped. ).

Retrospective studies of marijuana
In 1998, a survey was conducted in Germany in ST patients in which the frequency and effect of (illegal) use of marijuana were explored. Of 64 patients interviewed, 17 (27%) reported using marijuana, and of these, 14 (82%) reported that they believed that marijuana improved their tics and premonitory urges, as well as their behavioral symptoms, such as OCD and ADHD.

In line with these data, a group of researchers from Canada recently reported the results of a retrospective evaluation on the effectiveness and tolerability of marijuana in 19 adults with TS. On average, they found a reduction in tics of 60%, 95% of patients scored at least “much improvement” and in several patients, improvement of psychiatric problems was reported. Marijuana was tolerated, in general, well, and there were only mild side effects such as reduced concentration, motivation and short-term memory, anxiety, increased appetite, sedation and dry eyes and mouth.

In a retrospective study, we analyzed the data of 98 patients with ST (mean age = 28.2 years [+13.7]) who received treatment with different cannabinoid medications in our outpatient center specialized in Tourette in the Faculty of Medicine of Hanover (Hanover, Germany) (unpublished data). The majority of our patients used illegal marijuana (from different sources, 71%) for the treatment of TS. Only 37% of patients received treatment with tetrahydrocannabinol (THC, dronabinol, the most psychoactive ingredient in marijuana), 32% received treatment with nabiximoles (Sativex ®, an extract of marijuana with ONE amount of THC and cannabidiol [CBD]) standard in a 1: 1 ratio) and 22% obtained access to medical marijuana (standardized) from a pharmacy. The high percentage of illegal marijuana use (compared to the low percentage of medicinal marijuana treatments) is due to the fact that, in Germany, national legislation changed only in March 2017 and only since then can doctors prescribe marijuana for medicinal purposes. . Prior to that date, medical marijuana treatment was restricted to a small group of patients who had obtained special permission from the German federal opium agency. However, when patients were asked about the preferred type of cannabinoid medication (if available), 2/3 of the patients responded that they would prefer inhaled medicinal marijuana (from a pharmacy) instead of cannabinoid medications. In line with this preference among the different options, it was reported that medical marijuana was more effective in reducing tics than other cannabinoid medications (in descending order): in 100% (n = 21) of patients who used marijuana medicinal, in 90% (n = 67) in those who used illegal marijuana, in 77% (n = 35) of patients who used THC (dronabinol) and in 76% (n = 33) in patients who they used nabiximoles (Sativex® ) (several possible answers). Accordingly, the patients also evaluated that marijuana (both from illegal and medicinal sources of a pharmacy) was more effective than nabiximoles (Sativex ® ) and THC (dronabinol) in reducing psychiatric symptoms such as OCD. , ADHD, depression, anxiety disorders, self-injurious behaviors, rage attacks and problems sleeping. Overall, patients evaluated that marijuana was superior to both nabiximoles (Sativex ® ) and THC (dronabinol).

Placebo-controlled trials using THC
At present, only two preliminary controlled trials have been conducted to investigate the efficacy and safety of THC administered orally (dronabinol) in patients with TS. In a pilot study, a single dose of THC was compared with placebo in a crossover study of 12 adults. In a follow-up study, the efficacy and tolerability of THC were compared with those of placebo in a 6-week trial of 24 adults. In both studies, treatment with THC obtained a significant improvement in tics and there was no intense side effect, although there were some mild adverse events, such as dizziness and fatigue.

Side effect profile of cannabinoid drugs
Interestingly, there is evidence that the tolerability profile and side effects of marijuana and cannabinoid medications may be different in ST patients compared to healthy people. Parallel to the aforementioned controlled trials, neuropsychological performance and cognitive function have been investigated before, during and after treatment with THC (dronabinol). In these studies no harmful effect of THC was observed in any of the evaluations used and, in the measurement of immediate verbal memory, there was even tendency to improvement during treatment with THC (dronabinol). Coinciding totally with these results, in a single case study, the treatment with THC of a patient of 42 years with ST not only obtained a reduction of 75% in the tics,

Motivated by these promising data, several clinical studies have been initiated to investigate in more detail the efficacy and tolerability of different cannabinoid drugs in the treatment of ST patients, including nabiximoles (Sativex ® ), THC (dronabinol) and medical marijuana. In addition, pilot studies to investigate the effects of cannabinoid modulators, as well as the so-called ” entourage effect”, have already been initiated or are in preparation.»In this group of patients, which can be achieved by substances that improve the action of endogenous cannabinoids, such as anandamide. These studies receive their funding either from pharmaceutical companies or from the German Research Society (DFG, for its acronym in German). Therefore, our knowledge about the effects of marijuana-based drugs in patients with TS will definitely increase in the coming years. It is important and will be very useful for patients with ST, because so far (at least in Germany and many other European countries), many doctors hesitate to prescribe marijuana for medicinal purposes,