CBD Oil For Tics

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Dr. Genevieve Newton describes the state of the research on cannabis in the treatment of tic disorders and what her young son's experience with cannabis has been like. Cannabinoids have been used for hundred of years for medical purposes. To day, the cannabinoid delta-9-tetrahydrocannabinol (THC) and the cannabis extract nabiximols are approved for the treatment of nausea, anorexia and spasticity, respectively. In Tourette syndrome (TS) several anecdotal reports p … Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS. Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders. Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments. Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication. Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders. This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201).

Tic Disorder Management with Cannabis: A Family’s Tale Meets the Science

Shortly after the COVID pandemic hit in Winter 2020, life took a worrisome turn when my youngest son developed a severe motor tic disorder. My healthy son was 10 at the time. He suddenly became plagued with involuntary movements during all his waking hours. The lockdown and home schooling were almost a blessing. It meant that he wasn’t faced with the loss of his usual activities, like playing hockey and spending time with friends. Given the severity of his symptoms, these activities would have been impossible for him to do. Of course, it also raised the possibility that his condition had been triggered by the stress of the pandemic, which hit young people especially hard.

My son received an extensive medical diagnostic work up. He had a comprehensive blood analysis that included tests for strep antibodies (to rule out Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) and autoimmune encephalitis. All blood work was normal. He had a normal EEG. He had two MRI’s which showed a large cerebellar subarachnoid cyst and a cervical spine syrinx. But these were deemed as incidental findings that were unrelated to the tics. After an almost a week long stay in a pediatric hospital, we were given a diagnosis of a severe provisional tic disorder. It was deemed to be neuropsychological in origin.

The treatments we were offered were twofold. First we were recommended psychotherapy with a therapist specializing in family health. But my son was unable to sit still to participate in Zoom appointments, so he couldn’t participate in this process. His dad and I worked with the therapist to learn strategies to help with the emotional aspects of this difficult experience, including Emotion Focused Family Therapy. This helped us all to cope better, but it did nothing to reduce the tic severity. I also worked with another therapist who specializes in Cognitive Behavioral Therapy for Tics. She helped me to better understand the disorder and provided support through this difficult period. But because my son was not able to work with her in person, the benefit was limited.

Secondly we were offered drug therapies. These are typically reserved for children experiencing severe tics due to their significant side effect profiles. We began using Clonidine, a first line treatment for moderate to severe tics. 1 It was almost entirely ineffective. Next, we tried Risperidone as a second line treatment. 2 At first the Risperidone was combined with Clonidine. Then Clonidine was discontinued leaving Risperidone as a monotherapy. The severity of the tics did reduce a bit with the Risperidone. But the side effects were awful.

Within ten weeks of starting the medication, my son gained 23 pounds. For a very thin child who weighed 72 pounds at the outset of this ordeal, this was significant. It was also traumatic for him. After doing an extensive review of the scientific literature, I asked his doctor to change our drug regimen from Risperidone to Aripiprazole because there is evidence that it is better tolerated and has comparable efficacy. 3 Unfortunately, it also causes weight gain. Within nine months of starting pharmacotherapy, our son had gained 40lbs. And the medications were also only minimally effective at reducing tic severity.

As our journey continued, so did my search for alternatives. I quickly discovered that cannabis has been used in the treatment of tic disorders for many years. After finding a physician who specializes in the use of cannabis for pediatric neurological disorders, we were given a prescription for a cannabinoid medicine. We started using cannabis concurrently with Aripiprazole about five months after the onset of symptoms. After doing this for two months, we began using cannabis-based medicine exclusively.

I will describe the state of the research on cannabis in the treatment of tic disorders, as well as what we have personally experienced using a variety of different cannabis products.

Tic Disorders, Cannabis, and the Pandemic

Tics are involuntary, repetitive twitches, movements and sounds. There are both motor and vocal tics. There are three tic disorders listed in the DSM-V, including Tourette’s Syndrome, Persistent/Chronic Vocal or Motor Tic Disorder, and Provisional Tic Disorder. Tourette’s syndrome (TS) includes both motor and vocal tics. Those with provisional and persistent type disorders have one or the other. The only difference between persistent and provisional disorders is the length of the condition. In persistent disorders, tics have been present for more than a year. In provisional disorders, tics have been present for less than a year. 4 While my son was initially diagnosed with a provisional disorder, it is now considered a persistent disorder due to its duration.

During the COVID pandemic, there has been an increase in tic-like behavior among young people, especially girls. This condition has been termed Functional Neurological Disorder and is thought to be related to psychological distress. The tic patterns are different from the three previously mentioned disorders listed in the DSM-V. The tics in Functional Neurologic Disorder are also unique in that they aren’t preceded by an urge. 5 Although my son’s condition presented during the COVID pandemic, it did not fit the pattern of this disorder.

What the Literature Says

There are many scientific publications related to the use of cannabinoids in the treatment of tic disorders. A PubMed search using the terms “Tourette’s and Cannabis” yields 80 results, many of which are relevant. A search for “Tic Disorder and Cannabis” yields fewer results. This shows that the bulk of the literature has focused on the TS diagnosis. I will touch on some of the most notable publications related to observational research, clinical trials, and treatment recommendations.

Several observational studies have investigated the association between the use of cannabis and the symptoms of tic disorders. In 2019, researchers in Europe conducted a survey of patients with a history of using cannabis-based medicine to treat TS. They found that many preferred cannabis to pharmaceutical drugs. The majority reported a subjective improvement of tics and associated co-morbidities. The most striking finding was an improvement in quality of life in 93% of subjects. Patients also reported that they preferred cannabis to either nabiximols (a preparation with a specified quantity of specific cannabinoids and other phytoconstituents) or dronabinol (isolated THC). 6 Also in 2019, an Israeli group reported that 38 of 42 TS patients taking medical cannabis reported reduced tic severity, better sleep, and improved mood with treatment. 7 Similarly, a study published in 2017 found that 18 of 19 TS patients using medical cannabis reported that they were “much improved” with the use of cannabis. However, many reported side effects including feeling impaired and experiencing decreased concentration. 8 Unfortunately these studies don’t provide reliable information on the effective doses or the chemical profiles of the cannabis being used.

Several clinical trials have studied cannabis-based medicine in the treatment of tic disorders using controlled conditions. Some of the first studies were published in the early 2000’s by a research group from Germany. Initially, researchers investigated whether treatment with THC impaired cognitive performance in adults with TS. 9 After finding that cannabis didn’t impair cognitive function, a single dose, randomized placebo-controlled trial was conducted in 2002. It examined doses of THC at 5mg, 7.5mg, or 10mg. It was found that tic severity was reduced when the 7.5 and 10mg groups were pooled and analyzed as a single group, as was associated obsessive-compulsive disorder. The changes were correlated to plasma levels of THC, 11-OH-THC, and THC-COOH. 10 The next year, a six-week randomized controlled trial found a slight reduction in tics with THC at levels up to 10mg per day. 11

A more recent 2019 systematic review and meta-analysis published in Lancet Psychiatry concluded that the quality of clinical research evidence on cannabis for TS was low. The resulting findings are considered neutral. 12 An earlier review by the Cochrane Collaboration cited similar methodological concerns. 13 Currently, the CANNA-TICS study is underway which is a high quality, large randomized multicenter controlled trial. It is investigating the effect of nabiximols on tics. 14 Results are expected to be published soon after the time of this writing.

More recently, a new cannabinoid pharmaceutical has been developed called THX-110 that incorporates THC with other compounds. This product is manufactured by Therapix Biosciences Ltd and is “based on Dronabinol” and PEA (an endocannabinoid-like molecule) to “induce the entourage effect”. THX-110 consists of up to 10mg THC with 800MG PEA. 15 In autumn of 2021, results from a phase-2 pilot study of THX-110 found an improvement in tic symptoms in 16 adults with TS over a 12-week treatment period. 16

Because of the extensiveness of research using cannabis-based medicine for the treatment of tic disorders, comprehensive evidence reviews and treatment guidelines are available. A 2019 systematic review of treatments for people with TS and chronic tic disorders concluded that people with tics receiving THC are “possibly more likely than those receiving placebo to have reduced tic severity”. This study also reviewed risk of harm, such as weight gain and sedation. It did not find risk associated with THC treatment, unlike for pharmaceutical drugs like clonidine, risperidone, and aripiprazole. 17

What about treatment guidelines? A 2021 review on the use of cannabis-based medicine in the treatment of TS reported that the European Society for the Study of Tourette Syndrome (ESSTS) and the American Academy of Neurology (AAN) recommend behavioral therapy and pharmacotherapy with antipsychotics as first line treatments for tics. Cannabis-based medicine is classified as “an experimental intervention that should be applied to patients who are otherwise treatment-resistant”. 18 Given the experience of my family, this is a troubling recommendation. There is a high prevalence of side effects associated with the recommended pharmacotherapies. This is not the case with cannabis-based medicine.

There is very limited research on CBD in the treatment of tic disorders. A 2016 case study assessed whether Sativex (10.8mg THC and 10mg CBD) reduced severe motor and vocal tics. Treatment was over a four week period. The treatment resulted in a “marked improvement” in both the frequency and severity of both types of tics. 19 Similarly, a 2019 case report found that a daily dose of 10mg THC with 20mg CBD resulted in a “rapid and highly significant” reduction in tics. 20

While most of the published literature has examined adult patients with tics, a 2019 case report in the journal Medical Cannabis and Cannabinoids looked at the effectiveness of cannabis-based medicine in a pediatric subject. 21 A 12-year-old boy with TS experienced an initial reduction in tics when consuming vaporized THC equivalent to 4.4 mg. When the boy’s condition worsened, oral THC drops were added to the regimen at a daily dose of 12.5mg THC. No adverse events were reported. However, the author noted that treatment with cannabis in pediatric populations should be regarded as a “last-line treatment when well-established treatments have failed to improve tics”. As already mentioned, I would challenge that statement given the high incidence of significant side effects associated with the first-line pharmacotherapies. This general approach is consistent with the reluctance to use cannabis-based medicine as a first line medical therapy.

A study measuring levels of endocannabinoids in the cerebrospinal fluid of adult TS patients found that anandamide (AEA), 2-arachidonoylglycerol (2-AG), and palmitoylethanolamide (PEA) were significantly increased relative to controls. The authors hypothesize that this demonstrates alterations in endocannabinoid system function in patients with TS. This may be either a primary cause or a secondary change resulting from alterations in other systems. 23 A 2004 study investigated whether common polymorphisms in the CB1 gene were associated with TS. The researchers did not find an association in the population studied. 23 However, a 2020 study found a significant association between a CB1 gene variant and TS. 24 These results certainly implicate the ECS in TS, but this remains poorly understood.

Our Experience

CBD has been the primary cannabinoid that has been used for my son’s treatment over the last 15 months. We’ve mostly used oil-based preparations. These have taken several forms, including liquid products, gelcaps, water-soluble preparations, and inhalation. Here’s a breakdown the different modes of administration in regards to our experience:

Oils: Taking an oil preparation can be challenging for a child. At first, we used a broad-spectrum oil extracted from cannabis (not hemp). It had a very strong taste due to the terpene profile. To make it more palatable, I put it in some lemon syrup. Subsequently we moved onto a hemp-derived CBD isolate oil. It had a less diverse chemical profile but was mostly tasteless and odorless. I put the oil into his morning smoothie. Another challenge is the slow onset and poor bioavailability. When taken on an empty stomach, studies have shown that the bioavailability of oil soluble CBD is only about 6%. 25 If taken with a high fat meal, bioavailability goes up fourfold. 26 Peak levels of lipid-soluble CBD also take at least 90 minutes to achieve. 27 Tic severity varies widely during the day, waxing and waning in response to stress and fatigue. Therefore, when there is a flare, it is difficult to use CBD oil treatment because of the slow onset. However, it can be used on a regular dosing schedule. We use CBD oil in the morning as described. After school, he takes a CBD oil gel cap which makes consumption easier if we’re on the go with after school activities.

In our experience, oral CBD oil has only a modest effect on tic severity. The effects are complicated by issues including the “as needed” medicinal effects related to tic severity fluctuation. There is also the difficulty of timing peak concentrations due to limited absorption. However, we have noted an anxiolytic and calming effect.

My son noted that the CBD oil helps him to feel calm and focused in the morning. Our cannabis physician prescribed CBD oil starting at 20mg twice daily, with incremental increases to determine the optimal dose. We found that our optimal dose was 40mg twice daily.

Water-Soluble: Water-soluble CBD has been shown to be absorbed much faster than lipid soluble preparations. In fact, its bioavailability was shown to be 4.5 times greater in a recent pharmacokinetic study. It is also easily dissolved in water and has no taste or odor. In addition, it has a very fast onset and appears in the blood in as little as 15 minutes. 27 This makes it a viable option for treating “tic flares” when they arise.

I live in Canada. It is illegal to ship or transport cannabinoids internationally. There are water-soluble products available in my country. But their cost is extremely high. Also there has been limited research into the safety of nanoparticles. 28 Given my son’s young age, I prefer to err on the side of caution and avoid nano products. There are water-soluble CBD products that are in micromolar size. I have found that these provide a good alternative to lipid-soluble CBD. They have the added benefit of a quick onset and easy incorporation into any food or beverage.

The micromolar CBD products have provided an anxiolytic and calming effect with a modest change on tic severity. Because of the higher bioavailability of water-soluble CBD, a lower dose can be taken. We find that 15mg of water-soluble CBD provides comparable benefits to 40mg of CBD oil as a liquid or in gelcaps. For tic flares, 30mg of water-soluble CBD provides a rapid calming effect.

Inhaled: The fluctuating nature of tic disorders makes therapies with a fast onset a primary goal. This will not be the case with any orally ingested product, although water-soluble products will have a much faster onset than lipid-soluble preparations. Inhaled cannabinoids provide the fastest onset and greatest bioavailability, with an onset and peak within minutes following ingestion. 26 To treat my son’s acute tic flares, we occasionally use a CBD “puffer” that uses the same technology and delivery method as an asthma inhaler. These are metered inhalers which provide a measured dose of CBD, usually less than 5 mg per puff. We use a CBD-only inhaler and find that it provides some relief from the tics and anxiolytic effects at a dose of approximately 10mg.

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CBDA (cannabidiolic acid) is the precursor to CBD and the form found in the raw plant. CBDA undergoes degradation to CBD in the presence of heat, light, and oxidants, which begins spontaneously after the plant is harvested. 26 CBDA is more easily absorbed than CBD. CBDA decreases inflammation by inhibiting the activity of the enzyme cyclooxygenase-2 (COX-2) (which mediates the synthesis of pro-inflammatory prostaglandins) and is structurally similar to salicylic acid. 29,30

I became interested in trying CBDA after observing that my son’s tics were greatly diminished when taking Aleve to treat an ear infection. Like CBDA, Aleve is a COX2 inhibitor. Although I have been unable to find any published research looking at either Aleve or CBDA in the treatment of tics, NSAIDS have been found to decrease flares in the related conditions PANS and PANDAS. 31 Unfortunately, CBDA is not widely available outside of the United States. I did have access to it when we spent a few months living in Florida. We found CBDA to be quite effective at reducing tic severity.

In our experience, CBDA does a better job at reducing tic severity but does not have as much of a calming and anxiolytic effect as CBD. But they can be used together to complement each other. We use 10-15mg of CBDA per treatment dose.

As already described, research on using cannabinoids for tic disorders has primarily been focused on using whole plant cannabis and THC. I admit I had an initial reluctance to use THC with my son out of concern over its psychoactive effects. However, we found that he was able to take the initially prescribed dose of 2.5mg THC balanced with 5mg of CBD without any noticeable impairment. But this wasn’t a high enough dose to have much effect on the tics. We found that a dose of 5mg of THC was required for maximum effect. This is a level that induces some noticeable impairment. My son reports his eyes feel heavy and he becomes slightly lethargic. For this reason, we reserve the higher dose of THC only when we are in what I call a “tic crisis”. Also, THC can be balanced with CBD at a 2:1 ratio to reduce some of THC’s psychoactive effects.

We use THC taken in gelcaps, which presents the issue of delayed onset of action and low bioavailability. We have only ever used THC in the evenings for two reasons. First, we want to avoid any potential psychoactive effects in school. Second, my son’s tics are usually much worse in the evening. A more rapid onset of action could be achieved by using an inhalation delivery method. Inhalers are now available with different ratios of CBD and THC, but we have been unable to get one in Canada.

Pediatric Considerations and Product Safety Considerations

Using cannabis-based medication with a child can present challenges. It may be difficult to find a medical practitioner who has experience with pediatric populations. The coordination of care between the cannabis physician and regular pediatrician or GP can be tricky if they are not knowledgeable about these treatments. When we told our GP about our intention to medicate with cannabinoids, she seemed shocked. But she did not attempt to discourage us from doing so. Others may not be so lucky.

There is also a social stigma associated with pediatric cannabis use, which stems from the nearly 100-year prohibition of the plant. We have never had to ask our son’s school to administer cannabinoid medication because our dosing regimen does not require this. But if it does, one should be prepared with the appropriate medical documentation. Sharing this information with other parents can also be tricky. I always preface our son’s use of cannabis-based medication with a clarification that he has a medical cannabis prescription from a physician. I also share some of the research that has been done on cannabis and tic disorders. People with little knowledge about cannabis-based medicine may assume that products such as CBD and CBDA are psychoactive and think you are giving your child something to make them “high”. We should educate and inform others using the best available information.

When purchasing any cannabis product, it’s always important to do your due diligence. This is especially important when administering cannabinoids to children. Only buy products that have undergone third party testing for pesticides, residual solvents, molds, heavy metals, and mycotoxins and avoid unnecessary flavorings. Of course, you should buy products that have been recommended and prescribed by your physician. In Canada, the cannabis market is legalized and regulated which means that all products have undergone safety testing and approval. I always buy products through one of the dispensaries recommended by our cannabis physician. Although I have found on more than one occasion that the prescribed product has been unavailable through the dispensary. When this happens, I’ve had to purchase a comparable product through a government store.

Many people experience tic disorders decreasing in severity over time, especially into adolescence. 32 For us, the four-month period following sudden onset was very severe. Gradually the intensity of the tics lessened. When we started using cannabis-based medicine, we discontinued the use of pharmaceutical drugs. At that point, we found the condition to be quite manageable. My son does experience flare ups, though.

As described by the American Academy of Child & Adolescent Psychiatry, tics can be exacerbated by “anxiety, tiredness, and certain medications”. 33 We have certainly found this to be the case. Any stressful situation can bring on a tic flare. Late nights or early mornings are almost invariably followed by a “bad day” until sufficient rest is achieved. My son has also experienced an exacerbation following a concussion, probably due to the associated neuroinflammation. His most severe increase in symptoms was following the second dose of the COVID-19 vaccine. We managed it with cannabis-based medicine along with over-the-counter anti-inflammatories.

In Summary

With tic disorders, there are good days and bad days. Sometimes tics flare up when you least expect it. Thankfully, cannabis-based medicine is available in different forms for acute and ongoing treatment. For flare ups, delivery methods such as inhalation or water-soluble preparations provide a faster onset of action. Oils and gel caps can be taken on a regular schedule. CBD and CBDA are non-psychoactive cannabinoids that can help to reduce anxiety and tic severity. THC can be used when tics are more severe. We use a variety of different cannabinoids as our primary therapy and follow different regimens depending on the situation. This has been very effective and most of the time does not cause any side effects.

My family is grateful for the support of physicians who courageously support pediatric populations with cannabis-based medicine.

Dr. Genevieve Newton spent 19 years as a researcher and educator in the field of nutritional sciences. A series of personal health crises led her to discover the benefits of medicinal cannabis, and she soon found herself engrossed in studying the endocannabinoid system and therapeutic applications of cannabis/cannabinoids in mental health, pain, sleep, and neurological disorders. She is the Scientific Director at Fringe, a medical education company that is focused on whole person health.

More By Dr. Newton
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Treatment of Tourette syndrome with cannabinoids

Cannabinoids have been used for hundred of years for medical purposes. To day, the cannabinoid delta-9-tetrahydrocannabinol (THC) and the cannabis extract nabiximols are approved for the treatment of nausea, anorexia and spasticity, respectively. In Tourette syndrome (TS) several anecdotal reports provided evidence that marijuana might be effective not only in the suppression of tics, but also in the treatment of associated behavioural problems. At the present time there are only two controlled trials available investigating the effect of THC in the treatment of TS. Using both self and examiner rating scales, in both studies a significant tic reduction could be observed after treatment with THC compared to placebo, without causing significant adverse effects. Available data about the effect of THC on obsessive-compulsive symptoms are inconsistent. According to a recent Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials including a larger number of patients are missing. Notwithstanding this appraisal, by many experts THC is recommended for the treatment of TS in adult patients, when first line treatments failed to improve the tics. In treatment resistant adult patients, therefore, treatment with THC should be taken into consideration.

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The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders

Ewgeni Jakubovski 1 , Anna Pisarenko 1 , Carolin Fremer 1 , Martina Haas 1 , Marcus May 2 , Carsten Schumacher 2 , Christoph Schindler 2,3 , Sebastian Häckl 4 , Lukas Aguirre Davila 4,5 , Armin Koch 4 , Alexander Brunnauer 6,7 , Camelia Lucia Cimpianu 7 , Beat Lutz 8 , Laura Bindila 8 and Kirsten Müller-Vahl 1 *

  • 1 Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
  • 2 Clinical Research Center Core Facility, Hannover Medical School, Hannover, Germany
  • 3 Center for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
  • 4 Hannover Medical School, Institute for Biostatistics, Hannover, Germany
  • 5 Section Biostatistics, Paul-Ehrlich-Institute, Langen, Germany
  • 6 Department of Neuropsychology, Kbo-Inn-Salzach-Klinikum, Psychiatric Hospital, Wasserburg am Inn, Germany
  • 7 Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University Munich, Munich, Germany
  • 8 Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS.

Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders.

Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments.

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Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication.

Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders.

Clinical Trial Registration: This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201).

Introduction

Gilles de la Tourette syndrome (TS) is a common, complex, chronic neuropsychiatric disorder characterized by motor and vocal tics. It causes not only significant impairment in quality of life of the affected patients, but also significant economic costs in the German health care system as a whole (1, 2). The treatment options for chronic tic disorders (CTD) and TS are limited: to date haloperidol is the only approved drug in Germany, which is barely prescribed any more due to severe adverse events (AEs) (3). Instead, most clinicians prefer an off-label use of other antipsychotics such as aripiprazole and risperidone. However, due to AEs and/or lack of efficacy, a substantial number of patients is unsatisfied with this kind of treatment. First-line behavioral therapies (BT) such as Habit Reversal Training (HRT) and Exposure with Response Prevention (ERP) are not available to most patients, because of poor dissemination of these therapy techniques among psychotherapists (3, 4). Therefore, many patients with CTD are looking for complementary and alternative medicine (CAM) including self-medicating with cannabis (5).

Until today only a small number of case studies and series (all together including about 200 patients) is available, reporting about beneficial effects of different cannabis-based medicines including pure delta-9-tetrahydrocannabinol (THC, dronabinol), cannabis extracts, and cannabis flowers in patients with TS. Interestingly, in most of these studies not only a tic reduction is reported, but also an improvement of a broad spectrum of psychiatric comorbidities including attention deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), depression, anxiety, rage attacks, sleep disorders, and self-injurious behavior resulting in a significant improvement of patients’ quality of life. Most interestingly, in some of these cases, in addition, an improvement of premonitory urges proceeding the occurrence of a tic is described [for review see (6)].

So far only two small randomized controlled trials (including 12 and 24 patients, respectively), have been carried out to further investigate the treatment effects of cannabis-based medicines in patients with TS. In both of these studies pure THC, the most psychoactive ingredient of cannabis, has been used. According to these studies, THC resulted in a tic reduction and was well-tolerated without causing severe AEs or relevant neuropsychological impairment (7, 8).

This study aims to further examine the efficacy and safety of cannabis-based medicines in patients with CTD. At the time, when this study was designed, the only cannabis-based medicines that could theoretically be used in clinical trials in Germany were pure THC, the synthetic THC-analog nabilone, cannabis flowers, and the cannabis extract nabiximols. We decided to use nabiximols, a plant extract from Cannabis sativa L. that contains THC and cannabidiol (CBD) at a 1:1 ratio, for the following reasons: (i) at that time, nabiximols was the only officially licensed cannabis-based medicine in Germany (since 2010 licensed for the treatment of spasticity in multiple sclerosis) (9), (ii) compared to pure THC, it can be assumed that nabiximols – according to the so called entourage effect – is not only more effective [since CBD possesses its own effects (10)], but also better tolerated [since co-administration of CBD mitigates unwanted psychotropic effects of THC (11)], and (iii) compared to herbal products, for most patients preparation, application and intake is easier. Finally, GW Pharma Ltd. kindly agreed to offer nabiximols and placebo as investigational medical product (IMP) for this investigator-initiated study.

The introduction of a prescription of cannabis flowers in Germany in 2017 went along with an intensive and controversial debate on whether treatment with cannabis-based medicines may have a negative impact on patients’ driving ability and whether patients should be allowed to drive a car. While in the case of recreational use of cannabis, driving a car is generally not allowed as long as THC tests are positive, the German government stated that in contrast cannabis-based medicines – when prescribed and supervised by a medical doctor – should be handled comparably to other psychoactive drugs (12). This implies that the subject is responsible to accurately self-assess his or her driving ability before using a vehicle. With respect to nabiximols, it has been shown that driving ability is not impaired in patients with multiple sclerosis (13, 14). However, in patients with TS so far only one single case study has been published reporting an improvement of patient’s driving ability after treatment with THC (15). To increase our current knowledge regarding the effects of cannabis-based medicines on driving ability specifically in patients with TS, we plan to perform tests of driving ability at baseline and after treatment with nabiximols.

This study is designed as a multicenter randomized double-blind placebo controlled trial using nabiximols compared to placebo. We plan to include 96 adult patients at six large specialized TS centers all across Germany. The effects of nabiximols on tics, comorbidities, and patients’ driving ability as well as AEs will be assessed during and after treatment.

Methods and Analysis

Drug Information

Nabiximols is a complex botanical mixture derived from the Cannabis sativa plant. It contains different cannabinoids and terpenes with THC and CBD being the most abundant cannabinoids present. Nabiximols is a sublingually administered oromucosal spray that contains 10 ml solution in one spray container. The containers have to be stored in accordance with the German legal requirements [German Narcotic Drugs Act (“Betäubungsmittelgesetz,” BtMG)]. Nabiximols and placebo will be manufactured by GW Pharma Ltd., United Kingdom.

Study Design

This is a multicenter, prospective, randomized, double-blind, placebo controlled, parallel-group, phase IIIb investigator-initiated clinical trial. The time from first patient in to last patient out is expected to be 54 months including a recruitment period of ~28 months. The trial duration per patient will be about 17 weeks, including a 4 weeks up-titration, a 9 weeks maintenance phase, and 4 weeks of follow-up. The study flow is displayed on Figure 1.

Figure 1. Study Flow. MS, milestone.

Patients will be randomized to receive nabiximols or placebo with a ratio of 2:1 over the course of a 13-weeks double-blind treatment period. The treatment plan is identical for both treatment arms. In the placebo arm, patients will be treated with a placebo spray identical to nabiximols in visual appearance, taste, and odor. The study design is displayed on Figure 2.

Figure 2. Study Design.

Recruitment

A total number of 96 eligible patients will be included in the clinical trial across 6 participating German study sites. Study participants will be mainly recruited through the study centers’ outpatient clinics. In addition, the study will be announced in German self-help and advocacy groups, newsletters and annual meetings. During a screening visit, full information on the study design and the study medication (orally and in writing) will be provided. Before enrollment, a written informed consent will be obtained. Travel costs related to the study participation will be reimbursed. No further financial compensation will be offered.

Eligibility Criteria

The following inclusion criteria were defined:

• TS or chronic motor tic disorder (CMT) according to DSM-5 (CTD = TS + CMT)

• Yale Global Tic Severity Scale – Total Tic Score (YGTSS-TTS) > 14 for patients with TS or YGTSS-TTS > 10 for patients with CMT

• Clinical Global Impression Scale – Severity of Illness (CGI-S) ≥ 4

• If the patient will be on any medication (or deep brain stimulation) for tics or comorbidities, a stable dose will have to be obtained at least 30 days before entering the study and maintained during the study

• Signed written informed consent

• Capacity to understand the investigational nature, potential risks and benefits of the clinical trial

• Women of childbearing potential will need to test negative to a beta human chorionic gonadotropin (β-HCG) pregnancy test at screening

• Both sexually active men and women of child-bearing potential will need to agree to use valid methods of contraception.

The following exclusion criteria were defined:

• Psychiatric comorbidities in primary need of treatment

• Ongoing behavioral treatment for tics

• History of schizophrenia, psychosis, severe personality, or pervasive developmental disorder

• Presence of suicidal ideation (intent or plan) within the last 12 months

• Current diagnosis of substance abuse or dependence

• Secondary tic disorders and other significant neurological disorders

• Current or past severe cardiovascular diseases, hepatitis C, or other severe hepatic and renal disorders

• Any medical condition that might interfere with the patient’s participation in the study or pose a risk for the patient

• Use of cannabis or any cannabis-based medicine in the 30-day period prior to study entry and/or positive THC urine test at baseline

• Positive pregnancy test

• Pregnancy or lactation period

• Participation in any investigational medication study within 30 days prior to study entry or planned medication change during the study period

• Known or suspected hypersensitivity to any of the active substances or any excipients of the investigational medicinal product.

Blinding and Randomization

This is a double-blind clinical trial. To prevent unblinding, THC blood tests during the treatment phase will be sent to the laboratory of an unaffiliated institution (University Medical Center Mainz) and the results will be kept confidentially until the end of the study. In addition to examiner and self-assessments for tics, we will use a video-based tic rating as a secondary outcome measure. Since video evaluation will be done centrally by otherwise uninvolved blinded raters, this assessment will be robust against unintentional unblinding.

A permuted block randomization will be used to randomize the treatment allocation in a 2:1 ratio (nabiximols:placebo). Randomization will be conducted centrally and will be stratified by center. We decided in favor of a 2:1 randomization because uneven allocation (i) allows for more safety information in the active treatment group, (ii) enables more precise response rate estimation in the active treatment group, and (iii) facilitates patient recruitment. This study is sufficiently powered for a 2:1 randomization with a power of 90%.

Compliance

Medication (nabiximols and placebo) will be dispensed to the patients in limited amounts at each clinic visit. Empty spray bottles will be collected at clinic visits. At each clinical visit, a THC urine test will be done to check for compliance with the study medication on the one hand and any concomitant use of cannabis on the other hand (to avoid unblinding, analyses will be done centrally at the end of the trial).

Active Treatment Phase

The titration phase will last 4 weeks in all patients, independently of the maximum dose and the time for up-titration. The starting dose will be 1 spray/day (= 100 μl spray = 2.7 mg THC/2.5 mg CBD). The standard dose escalation will be the following: For the first 4 days, dose can be increased by 1 spray every 2 days, and thereafter by 1 spray every day up to a maximum dose of 12 sprays/day (= 1,200 μl spray = 32.4 mg THC/30 mg CBD). However, depending on individual tolerability and efficacy slower dose increase is possible. Patients will be allowed to increase their dose to achieve sufficient efficacy in both, the active and the placebo – treatment group to reflect that due to high inter-individual variability different patients may require different doses. Since no target dose is defined, dosage can be increased until the patient reaches his/her individually tolerated maximum dose (1–12 sprays/day) based on the patient’s judgment and investigator’s assessments. Different dose levels thus reflect different needs of patients with different patient characteristics and not a systematic dose-response investigation. For patients in the placebo arm, titration will follow the same scheme as for nabiximols.

After the 4-weeks titration phase, treatment will be continued at a stable dosage for another 9 weeks. However, dose adjustment will be possible. Thereafter, medication will be withdrawn without down-titration.

Study Visits and Assessment Instruments

A full assessment schedule for all study and phone visits is given in detail on Table 1.

Table 1. Schedule of Study Assessments and Visits.

Assessment Instruments

A test battery will be administered at clinical visits:

(i) Tics: YGTSS (16), Modified Rush Video-Based Tic Rating Scale (MRVS) (17), and Adult Tic Questionnaire (ATQ), a tic self-rating scale, which is parallel in format and content to the Parent Tic Questionnaire (18)

(ii) Premonitory urges related to tics: Premonitory Urge of Tics Scale (PUTS) (19)

(iii) Psychiatric comorbidities: Beck Depression Inventory (BDI-II) (20), Beck Anxiety Inventory (BAI) (21), Conners’ Adult ADHD Rating Scale (CAARS) (22), DSM-IV symptom list, Wender Utah Rating Scale (WURS-k) (23), Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (24, 25), Rage Attacks Questionnaire (RAQ) (26), Skala Impulsives-Verhalten-8 (I-8) (27), and Pittsburgh Sleep Quality Index (PSQI) (28)

(iv) Quality of life and overall impairment and severity of disease: Clinical Global Impression-Severity (CGI-S) (29), Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QoL) (30) and the 12-item short-form Health Survey (SF-12) (31)

(v) Safety assessments including the Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline version (32)

(vi) Driving test “Fitness to drive” (for details see 2.8.2).

In addition, blood will be drawn to measure levels of endocannabinoids and exocannabinoids.

Driving Test “Fitness to Drive”

The study part “Fitness to drive” has two main objectives: assessing the driving ability in subjects with TS/CMT in general and investigating the impact of nabiximols on driving ability in this group of subjects. At baseline, therefore, the following additional assessments will be performed: (i) subject’s specific traffic medical history, (ii) self-assessment of subjects’ general and current driving ability, and (iii) objective assessment of psychomotor skills using The Vienna Test System, a validated, CE-marked and well-established assessment in Germany, which will be carried out in accordance with the German driving license regulations.

“Fitness to drive” is conceived as a dichotomous criterion and is based on the guidelines of the German Federal Highway Research Institute (BASt). A subject will be considered unfit to drive, if he or she has a percent rank below 16 of at least one of the following tests: Reaction time and choice reaction (RT), Stress Behavior capacity (DT-Auslassungen), Stress Behavior performance quantity (DT-Mengenleistung), Concentration (COG), and Perceptual speed (ATAVT).

Data acquisition is carried out during the baseline visit and at visit 10 (after 9 weeks stable treatment) or before discontinuation of the study medication. In addition, at both baseline and follow-up “Fitness to drive” visits, subjects will be asked about their self-evaluation assessment of their general and current driving ability.

For organizational reasons, this study part will be carried out in only two study centers: Hanover (MHH) and Munich (LMU). For patients recruited at other study centers, a participation will be possible (if desired), but will entail additional study visits at MHH or LMU.

Outcome Measures

Primary Endpoints

The main objective of this study is to demonstrate that treatment with nabiximols is superior to placebo in patients with TS/CMT. The primary outcome variable will be response to treatment according to YGTSS-TTS, defined as a reduction in YGTSS-TTS of at least 30% (compared to baseline) after 9 weeks of stable treatment.

Secondary Endpoints

Key secondary analyses will be performed on the continuous YGTSS-TTS changes from baseline with an ANCOVA model adjusted for the baseline YGTSS-TTS and center. Further secondary outcomes are improvements on other clinical variables: YGTSS-Global Score (sum of TTS and global impairment), MRVS, CGI-I, CGI-S, ATQ, GTS-QoL, PUTS, BDI-II, Y-BOCS, CAARS, BAI, PSQI, I-8, SF-12, and RAQ. These measurements are recommended for clinical trials in TS in order to assess the full spectrum of the disease including psychiatric comorbidities and patients’ quality of life. Besides the YGTSS-TTS we will use the MRVS – an observational examiner tic assessment – as well as the ATQ, which is a self-assessment scale for tics. In addition, the YGTSS Global score takes into account the overall tic-related impairment on a patient’s life, similar to the CGI-I and CGI-S that measure overall clinical impairment and improvement. Finally, the GTS-QoL is used to assess disease specific quality of life. The PUTS is an instrument that measures premonitory urges often preceding the tics. To assess comorbid pathologies, we will use the BDI-II to assess depression, Y-BOCS for obsessions and compulsions, CAARS for ADHD, BAI for anxiety, PSQI for sleep disturbances, I-8 for impulsivity, RAQ for rage attacks, and SF-12 for overall health. Other secondary endpoints are the outcome variables from the study part on driving ability “Fitness to drive.”

Safety Assessments, Quality Assurance and Ethics

Safety assessments include (serious) (S)AEs, C-SSRS, blood pressure, and pulse at each clinic visit. With respect to subject’s driving ability, neurological and psychological impairment will be evaluated by a psychologist and a research physician and documented at each clinic visit.

To assure data quality and patients’ safety, regular monitoring visits will be performed and an independent data monitoring committee (DMC) will be established. The trial will be conducted following the principles of ICH-GCP, the German Drug Law (AMG), and the Declaration of Helsinki. Study protocol including possible amendments, patient information with consent and substantial amendments will be/were approved by the responsible ethics committees and the federal authorities.

Sample Size Calculation

The sample size calculation is based on a previous trial, in which 24 patients with TS had been randomized to 6 weeks of THC or placebo medication with a ratio of 1:1 (drop-out rate 17%: THC n = 3, placebo n = 1) (8). Under the assumption that the relative reduction on YGTSS-TTS is normally distributed in each treatment group, the probabilities for a reduction of at least 30% (criteria for treatment response) were calculated as 0.010 for placebo and 0.294 for the active arm. These calculations refer to an intention-to-treat (ITT) population, where missing values for YGTSS-TTS response at the end of treatment were set to non-response. This approach was chosen due to its higher robustness in regard to small datasets, obtaining more conservative values than the observed responder rates. The sample size calculations were conducted using nQuery 7.0 software and are based on an exact Fisher-test with a two-sided significance level of 5%, a power of 90%, and the above-mentioned responder rates (placebo = 0.010, THC = 0.294). Under a randomization ratio of 2:1, the resulting group sizes were n = 50 for nabiximols and n = 25 for placebo. To compensate for a potentially diminished treatment effect due to self-medication, non-compliance, and drop-out, we decided to increase the calculated sample size by ~30%. Thus, we decided to include 64 patients in the active arm and 32 in the placebo arm, adding up to a total sample of 96 patients.

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Statistical Analysis

Primary Analysis

The primary analysis will be carried out in the ITT population and use the YGTSS-TTS as criterion for a binary responder variable. A patient will be considered a responder, if a >30% decrease in YGTSS-TTS is observed as compared to baseline. The primary analysis of the responder proportion will be done with a Mantel-Haenszel estimate for the risk difference (active treatment minus placebo) stratified by center. If the lower bound of the corresponding 95%-confidence interval is above 0, superiority of the active treatment over placebo as assessed by YGTSS-TTS responder criterion is demonstrated. The two-sided type-I-error rate will be set to 5%.

Key Secondary Analysis

If the primary null hypothesis will be rejected and superiority of the active treatment over placebo will be demonstrated, non-inferiority of the active treatment compared to placebo will be hierarchically tested regarding the proportion of patients’ fitness to drive at the 2-sided significance level of 5% in all patients. The analyses will be done with a Mantel-Haenszel estimate for the risk difference (active treatment minus placebo) stratified by center. If the lower bound of the corresponding 95%-confidence interval is above the non-inferiority margin of −32%, non-inferiority of the active treatment over placebo regarding fitness to drive will be concluded.

Secondary and Safety Analyses

As secondary analysis, we will use YGTSS-TTS change from baseline at 9 weeks of treatment as continuous outcome variable. An ANCOVA will be computed with the covariates: baseline YGTSS-TTS and center. Additionally, a mixed model will be carried out to assess longitudinal changes in YGTSS-TTS (measured by YGTSS-TTS change from baseline to week 4 and week 9). The model will include repeated measures with a first-order autoregressive covariance structure, and include baseline YGTSS-TTS and center as covariates. For this model, the missing values will not be replaced. Further secondary endpoints will be analyzed with the same statistical methods. All secondary analyses are exploratory. Further exploratory analyses may investigate, whether the finally required dose can be related to baseline patient characteristics so that dose recommendations could be given to the patients.

Absolute and relative frequencies of (S)AEs will be calculated for the full analysis set and will be compared between treatment groups by using a chi-squared test.

Discussion

Clinical Implications

This will be the first well-powered controlled clinical trial investigating efficacy and safety of nabiximols in patients with TS/CMT. Thus, this study is not only the very first large controlled study in patients with tic disorders using a cannabis-based medicine, but also the first large controlled trial in a (hyperkinetic) movement disorder in general. Since we will also assess the effects of nabiximols on a variety of psychiatric symptoms (including ADHD, OCD, depression, and anxiety), this study will provide urgently needed data on the potential use of cannabis-based medicines in these conditions (33). This study will be of enormous health-economic relevance, because a substantial number of patients with TS/CMT (but also other psychiatric diseases such as ADHD) uses cannabis as self-medication. However, the current data basis is weak and, therefore, most physicians do not recommend cannabis-based medicines for their patients. Finally, this study will address an important practical question, whether treatment with nabiximols impairs driving ability in patients with TS/CMT.

We hypothesize that nabiximols will be effective not only in the treatment of tics, but also in a large spectrum of psychiatric comorbidities improving patients’ quality of life. Accordingly, we expect that patients’ driving ability will not be worsened by treatment with nabiximols. If these assumptions are to be proven correct, nabiximols would be a valuable treatment alternative in adult patients with otherwise treatment resistant TS/CMT.

Underlying Mechanisms

Several lines of evidence suggest a dopaminergic hypothesis in TS. More precisely, a dysbalance in presynaptic tonic and phasic dopamine is assumed to underly the pathophysiology of tics. However, there is also evidence for an involvement of other neurotransmitter systems and alterations in the dopaminergic system cannot explain the broad spectrum of psychiatric comorbidities seen in most patients with TS. Alternatively to the dopaminergic hypothesis, it can be speculated that TS is caused by a dysfunction in the endocannabinoid system (ECS), since the ECS is the most important neuromodulatory system in the brain. In line with this assumption, changes in cerebrospinal fluid (CSF) endocannabinoid levels have been reported (34). However, based on the complex interaction between the endocannabinoid and the dopaminergic system, it can also be speculated that stimulation of the ECS by use of exocannabinoids may attenuate dopaminergic hyperinnervation.

Limitations

Our study has the following possible limitations: (i) nabiximols constitutes a specific formulation of cannabis extract with a 1:1 ratio of THC:CBD and, therefore, results may not be generalized to all cannabis-based medicines; (ii) we defined 12 sprays of nabiximols as maximum dose, since this is the maximum dose licensed for the treatment of spasticity in multiple sclerosis. Theoretically, this maximum dose might be too low for patients with TS/CMT; (iii) although we decided for a quite long treatment period of 13 weeks (plus a follow-up visit), from this study no conclusions can be drawn on long-term effects; (iv) due to methodological limitations, the unlikely case of additional recreational use of cannabis in the nabiximols group cannot entirely be excluded; (v) theoretically, patients can unblind themselves by a THC test; (vi) recruitment and results might be biased by patients with prior use of cannabis; (vii) we used a 2:1 randomization scheme that has a lower power compared to a 1:1 randomization. Nevertheless, we plan on compensating for this with a higher sample size; (viii) driving performance can be more realistically assessed in on-the-road-tests than in an experimental design as used in this study; (ix) participation in the study part “fitness to drive” is only mandatory for a subgroup of patients in only two of six study sites.

Ethics Statement

The trial will be conducted following the principles of ICH-GCP, the German Drug Law (AMG), and the Declaration of Helsinki. The study protocol including amendments, patient information with consent and substantial amendments was approved by the ethics committee of Hannover Medical School (MHH) as the main committee and in addition by the ethic committees of all participating centers: the University of Lübeck, the Ludwig Maximilian University of Munich (LMU), the RWTH Aachen University, the University of Cologne and the University of Freiburg as well as the federal authorities.

Author Contributions

The first draft of this manuscript was written by EJ. AP contributed background information needed for the first draft of the manuscript, in addition AP is in charge of the study part Fitness to drive. AP, CF, MH, MM, CSchu and EJ are responsible for study assessments at MHH. CC was responsible for study assessments at LMU. AB and CC offered their expertise in the assessment of Fitness to drive. BL and LB helped with the study design and will measure levels of exo- and endocannabinoids. AK, LA, and SH contributed in the power calculation, determining the randomization protocol, and the selection and planning of the statistical analysis. MM helped at shaping the research protocol and at getting the study up and running. CShi was deputy PI and provided supervision and guidance to the team and input in coordinating and conducting the trial. KM-V was the PI of this study and contributed on all stages of the development of the trial and is the senior author of this article. All authors provided critical feedback and contributed to the final manuscript.

Funding

This study was funded by the DFG (MU 1527/2-1). GW pharmaceuticals Ltd. will provide nabiximols and placebo for this study. Almirall kindly offered funding for the study part Fitness to drive. Almirall was a Spanish pharmaceutical company with headquarters in Barcelona and holds the marketing rights to Sativex ® in Europe (except the United Kingdom).

Conflict of Interest

KM-V has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kroner Fresenius-Stiftung, and GW, Abide Therapeutics, Lundbeck, Syneos Health, Therapix Biosciences Ltd, Almirall Hermal GmbH, GW pharmaceuticals. She has received consultant’s honoraria from Abide Therapeutics, Tilray, Resalo Vertrieb GmbH, Columbia Care, Bionorica Ethics GmbH, Lundbeck and Eurox Deutschland GmbH. She is a consultant or advisory board member for Abide Therapeutics, Alirio, The Academy of Medical Cannabis Limited, CannaMedical Pharma GmbH, CannaXan GmbH, Columbia Care, Canopy Growth, Leafly Deutschland GmbH, Lundbeck, Nomovo Pharm, Nuvelution TS Pharma Inc., Resalo Vertrieb GmbH, Sanity Group, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, Wayland Group, Zynerba Pharmaceuticals, and CTC Communications Corporation. She has received speaker’s fees from Tilray, Wayland Group, Emalex, Eurox group, PR Berater, Aphria, Ever pharma GmbH, and Cogitando GmbH. She has received royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer. She holds shares of Nomovo Pharm. She served as a Guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects,” is Associate editor for “Cannabis and Cannabinoid Research” and Editorial Board Member for “Medical Cannabis and Cannabinoids.”

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank the German advocacy groups Tourette Gesellschaft Deutschland e.V. (TGD) and Interessenverband Tourette-Syndrom e.V: (IVTS) for their willingness to help with the recruitment of patients. We thank the Hannover Clinical Trial Center (HCTC) for their support in designing the study as well as Ms. Daniela Ihlenburg-Schwarz, Martina Lenz-Ziegenbein, Bettina Baltin, and Susanne Brunke for their continued support in several different parts of the study. Last but not least we thank the DFG for funding of the study.

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Keywords: cannabidiol, THC, tetrahydrocannabinol, cannabinoids, nabiximols, chronic tic disorder, tics, tourette syndrome

Citation: Jakubovski E, Pisarenko A, Fremer C, Haas M, May M, Schumacher C, Schindler C, Häckl S, Aguirre Davila L, Koch A, Brunnauer A, Cimpianu CL, Lutz B, Bindila L and Müller-Vahl K (2020) The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders. Front. Psychiatry 11:575826. doi: 10.3389/fpsyt.2020.575826

Received: 25 June 2020; Accepted: 02 November 2020;
Published: 26 November 2020.

Trevor Ronald Norman, The University of Melbourne, Australia

Seth Davin Norrholm, Wayne State University, United States
A. Cavanna, Birmingham and Solihull Mental Health NHS Foundation Trust, United Kingdom

Copyright © 2020 Jakubovski, Pisarenko, Fremer, Haas, May, Schumacher, Schindler, Häckl, Aguirre Davila, Koch, Brunnauer, Cimpianu, Lutz, Bindila and Müller-Vahl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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