CBD Oil For Tics

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Cannabis may help with various symptoms of Tourette's, a hereditary neuropsychiatric disorder which causes anxiety and frequent tics. 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).

Top 6 Benefits of Cannabis for Tourette’s Syndrome

Tourette’s syndrome is a hereditary neuropsychiatric disorder that manifests in childhood and is typified by physical and vocal tics, such as repetitive jerking movements or (often socially-unacceptable) speech. Cannabis may help with various symptoms of Tourette’s, including reducing anxiety and frequency of tics.

Cannabis research shows it may help ease symptoms of Tourette’s syndrome (TS). With roughly 200,000 Americans alone suffering from severe cases of Tourette’s (and as many as 10% of people experiencing milder symptoms), any possible treatment is worth looking into. Let’s take a look at the six main ways cannabis might be helpful.

1. Cannabis may decrease frequency of tics

There has been considerable interest in the potential for cannabis to reduce the frequency of tics in Tourette’s syndrome (TS) sufferers, and several papers have been published on the subject. A study by researchers in Hanover, Germany (Müller-Vahl et al, 1998) observed that 17 of 64 TS patients reported use of cannabis, and that 14 of those experienced partial or total relief of tics following its use.

The German researchers went on to conduct several further studies into cannabis and the reduction of tics, all of which found that the majority of patients experienced significant relief after using cannabis. They also found that very few patients experienced side-effects. It’s thought that cannabis can reduce TS tics in a similar manner to other dystonia-inducing conditions, such as Parkinson’s.

It’s not clear what this mechanism is, but it’s thought that it may lie in the densely-clustered cannabinoid receptors in the basal ganglia and hippocampus. These areas of the brain are fundamentally involved in the control of behaviour and movement, and are known to be abnormal in those suffering from this syndrome.

2. THC may ease obsessive-compulsive symptoms

Obsessive-compulsive disorder is the most common comorbid condition present in Tourette’s Syndrome patients. TS patients who also have OCD exhibit repetitive counting, touching, and “ordering” behaviours, and may also exhibit increased aggression compared to sufferers of OCD alone.

Another study conducted Müller-Vahl and her team supported the finding that patients treated with THC experienced a decline in obsessive-compulsive symptoms along with a reduction in tics.

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3. Cannabis can increase effectiveness of conventional Tourette’s syndrome drugs

As well as investigating cannabis as a standalone treatment for TS, there has been significant interest in its use as an adjunctive (add-on) therapy alongside certain conventional TS medications. Müller-Vahl et al observed in a 2002 case study of a 24-year-old woman that “THC may be useful in augmenting the pharmacological response to atypical NL such as amisulpride and risperidone in TS patients”, and that “no serious adverse reactions occurred”.

A much earlier study published in the journal Life Sciences in 1989 suggested that both cannabinoids and nicotine could “significantly enhance” the effectiveness of “neuroleptics” (antipsychotics) in motor diseases including TS.

Furthermore, the only two randomized controlled trials that have been conducted on cannabis and TS compare use of a cannabinoid as sole therapy and as adjunctive therapy against placebo. Both found that use alongside other medications yielded the most positive results. However, sample sizes were small for both these studies, and further investigation is required to confirm the results.

Interestingly, cannabis has also been noted since as early as 1988 to be effective in individuals who did not respond to conventional TS treatments at all.

4. Cannabis can alleviate sleep problems associated with Tourette’s Syndrome

Many patients who suffer from Tourette’s also experience sleep disorders. While there’s been no research specifically into the effect of cannabinoids on sleep disturbances in TS patients, there’s plenty of anecdotal evidence suggesting that cannabis can have a positive effect on this aspect of TS too.

For example, TS is known to cause increased sleep latency (delayed onset of sleep), while cannabis has been widely demonstrated to reduce sleep latency and lessen the difficulty of falling asleep in many individuals.

TS sufferers are also shown to have increased tic frequency during REM sleep, while cannabis use has been shown to reduce the duration of REM sleep altogether, which may cause TS sufferers to experience more restful sleep. TS sufferers are also less able to remain asleep through the night, another problem with insomnia that cannabis can help treat.

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5. Cannabis might be an anxiolytic for TS sufferers

Anxiety is a common symptom of TS for many sufferers.

The valuable research conducted by Müller-Vahl et al (and the various other research teams that have investigated the potential for cannabis to treat TS) generally found that cannabis use didn’t help anxiety levels. In one study, it even increased phobic anxiety. However, there are many other anecdotal reports of TS sufferers experiencing subjective improvement of anxiety.

There’s even a trademarked “cannabis pill” named Idrasil™ that is marketed at TS sufferers in the U.S. medical states. According to the manufacturer patients experience reduced tics and anxiety when taking Idrasil regularly.

6. Cannabis might reduce aggression and rage resulting from TS

Another common problem that comes with TS is aggression and rage outbursts. This is particularly common in children (affecting up to 25% of children with TS) but is also present in a significant minority of adults. These outbursts typically manifest as unpredictable displays of aggression that are greatly disproportionate to the perceived provocation, and may often present the risk of serious self-harm or injury to others.

Again, the potential for cannabis to treat symptoms of aggression in TS sufferers hasn’t been formally investigated. But there’s anecdotal evidence from TS sufferers that cannabis use has a positive effect on aggression.

Many individuals suffering from ADHD (a closely-related disorder that is often comorbid with TS) also report a subjectively positive effect on aggression.

This article is not a substitute for professional medical advice, diagnosis, or treatment. Always consult with your doctor or other licensed medical professional. Do not delay seeking medical advice or disregard medical advice due to something you have read on this website.

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62 thoughts on “Top 6 Benefits of Cannabis for Tourette’s Syndrome”

All of you with Tourette’s: be glad that medical marijuana is becoming legal everywhere. But for a different approach, go on the Internet and look up the Marshall Protocol. Trevor Marshall, an aussie, invented this approach to treat his own case of sarcoidosis. The protocol consists in alternating doses of an antibiotic, followed by the drug benicar which is an antagonist of the Vitamin D receptor, which in turn regulates the innate immune system. The way this works is, Tourette’s (and tics and OCD) is thought to be caused by a commensal bacterium such as Streptococcus B (think about how rheumatoid arthritis causes cardiac valve deposits). The antibiotic kills most (but not all) of the bacteria, which go into metabolic arrest to escape the drug, and are held immobilized and metabolically inert by the innate immune system. The benicar then releases the immune block and the bacteria become metabolically active again and hence susceptible to the antibiotic. The problem with this simple cycle is that it may take many as 50(?) turns of the crank at 2 weeks per turn before all the bacteria are killed, and few physicians are willing to carry on this regimen for the 2-3 years it may require for the last of the bugs to die. MJ is easy and quick but is not a cure. MP is lengthy and controversial, but is advertised as a cure. I once knew a man with Tourette’s that manifested as coprolalia. You decide.

My grandson is 15, has tourettes, which affects his speech, He stutters so bad, some days he cannot talk, he has to write things down. Just heard about this oil today, you think it might help? Im not up on this product, does it show up in a drug test?
THanks for info

Thank you for your comment. We are sorry to hear about your situation. As Sensi Seeds is not a medical agency or practitioner, we cannot give any kind of medical advice other than to consult our registered healthcare professional. This article about the potential benefits of medicinal cannabis might be useful for you to show your healthcare provider if they are not familiar with it.

You may also find it helpful to contact a support group for medicinal cannabis patients. In the UK there is the United Patients Alliance, and throughout much of the rest of the world there is NORML, who should be able to put you in touch with a group in your area (search United Patients Alliance or NORML followed by your area name).

This are our pages on medicinal cannabis and medicinal cannabis strains, which you might also find interesting.

With best wishes,

Hello, my son is 14 and just developed vocal tics from TS in Nov 2017. He had some motor tics when he was younger, but this came out of nowhere. Now, here we are trying cannabis. We are trying 1:1 ThcA:CBD. I’m not sure the ThcA is the way to go or if he will need the THC specifically. Anyone else try the ThcA with positive results? It supposedly doesn’t cross the blood brain barrier and has no “high” effect. If this doesn’t work we will try a Thc:CBD 1:1 ratio and see if that has a different effect on his tics.

He has smoked a joint once and his tics completely disappeared for 1 full hour so I know we are at least in the right ballpark.

With vaping he hasn’t seen the same results. We are trying to stay away from smoking vaping to see if the tinctures will help.
Wishing everyone here luck.

My daughter is 10 yrs and has TS, mild OCD, sleep disturbances and anxiety which she has had since she was a toddler and diagnosed at 7. It always gets worse in the winter time and this winter she developed spitting tics, even spits in herself. It has been devastating for her and she cries all the time. She gets bullied endlessly at school. Often asking why she must suffer like that. Her neurologist was pushing for psych meds and I refused. I’ve done extensive research on alternative remedies. Nothing have truly worked. I purchased 550mg cbd oil which came in he mail today. She tried it twice under her tongue and and a couple of hours later the tics stopped. I don’t think she realizes it’s gone and I won’t mention it either as to avoid bringing attention to it. I’m so happy I just want to cry. For parents out there, advocate for your child. Research, research and do your diligent investigative work to help your child and/or yourself. CBD oils are expensive and it’s going to break my bank but helping my child far outweighs cutting costs on far less important things in our lives. Big pharma is not the way to go to help my child with Tourette’s not today and definitely not tomorrow.

Kat- this is so encouraging! I hope a month later your finding the oil to be helping tremendously. If you’d be willing to share an update — please do!
I’ve only heard about the CBD oil this morning and found this thread as I search to understand more.
Thank you !

Can you please share the name of the CBD oil, where you got it and how much you use?

I am a 45 yr old male with Tourette Syndrome. I have had rage symptoms since early childhood, adhd, ocd, and a strong bout of tics for two years (14-16yrs old). I struggled in school because of my attention to controlling my behaviors rather than being able to focus on academics and social interactions. I moved away from home at the age of 19 and this is where my life changed forever. I was introduced to marijuana at a social gathering and I remember being completely amazed at how calm I felt, how I could focus on one thing at a time rather than all sounds and conversations at the same time. For the first time, I felt in control. I began using marijuana to help me focus on academics while boasting a 4.0 gpa. I had never even finished an assignment in high school or middle school but was now crushing college. I realized that I am not stupid, slow, or special. I am the recipient of an inefficient brain that, at times, focuses on what it want rather than what I want. Marijuana changed my life in a medicinal way and once I found it (or it found me) I looked back at my youth and realized how much more academic success and social confidence I may of had if I had been given the option. You are all awesome in your own unique way and don’t ever forget it. Find what works for you and don’t let others stand in your way!

14 year old son. TS/ ADD and anxiety. He is on three meds-abilify/Concerta and clotrolepam(sp?) his tics have increased and now has vocal tics. We are in Canada. Don’t know what to do anymore…

My son developed TS at four. Before junior high I found the American academy of environmental medicine. Within one month his tics and symptoms were gone. My son has a blood disorder called MTHFR which is treated with methyl b12. Also 25 food allergies and nutritional deficiencies. We are very careful what we eat breath and touch. Organic foods and no chemicals.

Hi Guys!
I’m a TS sufferer since about 6 or 7. I have been through the teasing gauntlet, the family gauntlet, and work gauntlet, and worst of all, the MEDICAL gauntlet. Meds RARELY work, and never without side effects often worse than the TS.
Back in the late 70s a friend brought in some of his “special” brownies and gave me one. HALF of that brownie shut down tics by at least 90% AND greatly increased my ability to concentrate and remember. The best year of high school ever! Sadly I have NO IDEA what kind of pot was in those. I just knew I didn’t really have a “high” effect and even my OCD nearly disappeared. Over the years I have worked to inform many doctors and sufferers alike. I have met very many with TS. ONE thing I have noticed about those I have met. EVERY ONE of them ALSO was dealing with OCD. To different degrees, certainly, but we all seem to have it.
Cannabis definitely helps, and CBD alone doesn’t cut it. So, if you are in a place, like I am, in the central US, you suffer or take your chances. Too many draconian lawns, yet we persevere. DON’T GIVE UP!
I’m trying different combinations of stuff to see what works or not. I’m still looking for help as medical doctors are learning from US! WE rarely learn from them. I spent years teaching many doctors what TS was. Now, if you have, as I do, a good doctor who wants to learn, you have to let them know so they can inform others, even if secretly. It is SO sad we cannot get real research, real testing, for a disorder that is largely ignored my the medical community.
BTW, I have some interesting tics. I have the vocal sounds that i have learned to hide in my words, I have others that are annoying. I have the head whip that threatens to break my neck and causes whiplash! I have tics that tie in with the OCD in that I must tic multiple times before I can continue talking. Embarrasing to say the least. Tics that cause a lot of pain and because I am reaching the end of my rope, I am taking chances with the crazy lawns to get the relief that I have needed for so long. Cannabis IS THE WAY TO GO! But finding the right MIX of oils and such is nearly as aggravating.
If you have experience with relief without getting high, pass it along wherever you can. We need your help. The only research being done are those of us willing to try to find out ourselves by trial and error. PLEASE, if you have success, pet us know HOW. I KNOW FULLY we are all different, but it might give us a place to start.
I will rarely smoke, I hate smoking anything. But there are pills, oils, salves, patches, edibles of many many kinds, tinctures and even VAPE options. NO ONE I have talked to knows a dang thing about what WORKS. Most of the people selling it rarely know what Tourettes is! Please don’t be afraid to post on places like this for those of us searching, often vainly, for answers.
Talk to us. There has to be some real “Experts” out there!
Thank You for reading this far. This novel is over…. for now! heh

Cory
frustrated, but pressing on!

hi, my son is nearly 9 years old and we live in belfast, northern ireland. we have cannabis oil here and im considering usage. any advise on dosage etc?

Thank you for your comment. We are sorry to hear about your situation. Unfortunately, as Sensi Seeds is not a medical practice, we are not able to provide any advice relating to medical situations other than to consult your doctor or other licensed medical professional. This article, written specifically for healthcare providers who may not be aware of the many properties of cannabis, may be useful to you in talking with your doctor. You could also try to contact local medicinal cannabis support groups, if you have not already done so. In the UK, there is the United Patients Alliance (you can find them on Facebook) and in the US and EU there are many branches of NORML (google NORML followed by your area name). We hope this is helpful.

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With best wishes,

Hello we are from Australia. We have a 9 year old son who has been diagnosed with Aspergers, OCD, Schizotypal PD and Tourettes Syndrome. It has been a difficult journey. We have tried many different, medications from Abilify, risperadone being the best but still not effective. We don’t trust the medication 100%.
Our doctor isn’t able to advocate or point us in the right direction in regards to cannibis oil.. We wrote to universities to no avail. we have basically been told ‘it’s too new age, not a lot of research has been done with cannibis oil and it’s effectiveness in Tourettes and scizotypal disorder, and we should perhaps just accept his legacy and continue to use what the pharmacuetical companies allow us to use.
We are beside ourselves in knowing that there could be a natural alternative in allieviating all of these symptoms.
Can someone please help us with alternate information. Or point us in the right direcrion.
Thank you

Thank you for your comment. We are sorry to hear about your situation. Unfortunately, as Sensi Seeds is not a medical practice, we are not able to provide any advice relating to medical situations other than to consult your doctor or other licensed medical professional. This article, written specifically for healthcare providers who may not be aware of the many properties of cannabis, may be useful to you in talking with your doctor. You could also try to contact local medicinal cannabis support groups, if you have not already done so. In the UK, there is the United Patients Alliance (you can find them on Facebook) and in the US and EU there are many branches of NORML (google NORML followed by your area name). We hope this is helpful.

With best wishes,

PS This article might have some helpful links, and the contact details for NORML Australia are here. I really wish I could be more help, good luck x

Hi, my son was diagnosed with complex tourettes syndrom at the age of 8yrs old his doctor tryed several different meds on him and none worked just made them worse…was just wondering about trying this for him his tics have got worse since he has hit teenage years..he is 14 now and gets made fun of and it breaks my heart just grasping for straws here. Willing to try it if it would help him…he pops his neck repeatedly and it scares him and me…please help us.

Thank you for your comment. We are sorry to hear about your situation. Unfortunately, as Sensi Seeds is not a medical practice, we are not able to provide any advice relating to medical situations other than to consult your doctor or other licensed medical professional. This article, written specifically for healthcare providers who may not be aware of the many properties of cannabis, may be useful to you in talking with your doctor. You could also try to contact local medicinal cannabis support groups, if you have not already done so. In the UK, there is the United Patients Alliance (you can find them on Facebook) and in the US and EU there are many branches of NORML (google NORML followed by your area name). We hope this is helpful.

With best wishes,

Hello…I was wondering which one is it that is being said to help seizures & tourettes? Is it the THC or CBD because what my daughter is taking is a 50/50 mixture. We have scene some promising results after only 4 doses, but I feel that I’m not giving her enough maybe?! I’ve looked at the CBD oils and things, but I have no clue what to get her or even how much?? How can I find out how much and how often she can take it, and which one she needs?? Thanks!!

I have a 22 year old daughter who has just started taking the drops,and I really hope it works. I do believe I saw some improvement within an hour after taking her first dropper full.
please keep your fingers crossed that this works!! Thanks.

Thanks for your comment Our fingers are crossed for you and your daughter.

With best wishes,

I’m interested in knowing how your daughter is now. Has the drops helped?

I’ve been on every medication known to man for my terets. They have not done anything I’m thinking about suicide everyday how do I try this medical weed.

Thank you for your comment, I am sorry to hear about your condition, please don’t give up! Obtaining medicinal cannabis depends a lot on where you live. If you are in an area with legal medicinal cannabis, you can talk to your doctor (this article, aimed at medical professionals who might not be aware of the things cannabinoids can do, might help). If not, I’m afraid your situation is harder and obviously I cannot recommend or encourage you to break the laws of the area you live in. If you are in the UK, I strongly recommend you contact the United Patients Alliance (they are on Facebook) as you can at least get some moral support and maybe connect with people who share your situation. If you are in the US, NORML have branches almost everywhere (google NORML plus your area).

Something that may well be worth trying and is easier to get than medicinal cannabis is CBD oil, which is still legal and sold as a food supplement. You can order it from us, or if you are in an area we cannot ship to, try in good health food shops. As I am not a medical professional I cannot make any claims that this would definitely help you, but as a fellow human I would say it is worth a try.

With best wishes,

Both my son and I have TS. I’m over 70 and growing up I just thought it was nervous tics. Dealt with teasing in middle school. By the time I was married and had children I was fully aware that I had TS and did quite a bit of research. When my son turned up with it I got the name of a pediatric neurologist that started him on Tenex, which is a blood pressure medication. At first there was not much improvement but over time and with an increased dosage it took affect. In the interim, when it looked like it wouldn’t work, the neurologist prescribed Orap, an anti psychotic. I looked it up and found one of the side effects was tics which would become permanent even after the medication was stopped. I decided not to give to my son. He’s doing very well now with minimal minor tics. From what I was told by our now former pediatrician, kids are too old for one now, Tenex has been reformulated to work better with TS but is not needed by my son anymore. Also I’ve been told that it is only effective on young children that after a certain age it is no longer effective. I still have both minor and gross motor tics which I can keep mostly under control when in the presence of others. When alone they tend to burst out. I am at the point where I will be trying CBD gel caps as I would like to see how it feels not to feel like an out of control wind-up toy when I’m alone.

First, sorry for my english, not is my main lenguage. I like to know if some type / genetic of cannabis is better than other to treat TS. I have a nephew who has 8 years with TS, is to young to smoke. what is the best form to get cannabis treatment without get high? CBD helps? or only THC? has several problems to sleep, agression episodes and self injured inside his mouth.

Thank you for your comment. We are sorry to hear about your nephew. As Sensi Seeds is not a licensed medical practitioner, we cannot give medical advice, and must recommend that you consult your doctor or other registered healthcare professional for all medical matters. When you do so, you might find this article which was written specifically for professionals who might not have researched cannabis as a medicine. Depending on what country you are in, you may be able to order our CBD Oil which is sold as a food supplement and has been known to have relaxing properties but I cannot recommend its use as a medicine or make any claims about if it would help with TS or not.

With best wishes,

I’ve had the worst case of Tourette’s since I was seven years old. I’ve tried all the pills there are and the only one that slightly works is Ability. Only cannabis works 100%.and marinol doesn’t. Too synthetic and missing too many cannibinoids. also I notice I’m highly allergic to 74 different things especially blue and red dyes in food plus aspartame and other sugars. I’ve used cannabis since I was seven in the early sixties. I was one of the first medical marijuana patients licensed in California. I help build 2 dispensaries. I went through the Air Force with full blown T.S. they took me even though they knew I had it because I had a high I.Q. now I have trouble paying for mm .I’ve been on S S d I(social security) since age 23 for t.S. because of Tourette syndrome.

Thank you for your comment and sharing your story! I fixed the autocorrect error so I’ve removed your other comment asking for the correction.

With best wishes,

Valiant Gordon would you mind sharing which strain and ratio seems to work best for ts? I have a 7 yr old x

Great article thank you for breaking down the study.

Did anyone get an answer about then strain and ratio?
I also have a child with TS.

MY SON(11) AND MY SELF BOTH SUFFER FROM TS. I USE WEED TO CONTROL IT BUT MY SON IS TO YOUNG FOR THIS. HOPING TO GET OILS OR ANOTHER MEANS OF FINDING STUFF FOR HIM TO USE, AT LEAST UNTIL HE IS OLDER. IT HELPS ME A LOT, HOPING IN THE FUTURE IT WOULD HELP HIM TO. LOVE THIS ARTICAL, LOTS OF INFORMATION. THANKS TO ALL WHO WROTE IN, HELPS ME KNOW I’M NOT ALONE IN THIS.

I’m now in my late thirties and had very bad tics. I started using canabis at 18 and have significantly overcome/reduced my tics since then. If i stop usage, my wife and I notice my tics return, albeit I’ve learned to control them to a degree in comparison to my youth. Unfortunately, my state has not legalized usage (yet) and I must obtain canabis with risk of legal action. None the less, I am a fully functional adult with a solid career record, brilliant children and a strong desire to stay far away from the pharma industry.

Ugh! My son was diagnosed at age 3 (the youngest TS patient ever diagnosed at Dell Children’s in Austin). ADD meds made his tics worse and sleeping almost impossible. The only thing that has worked for him in the last few years is cannabis; he’s 19. He is currently facing a possession charge for having a joint in his backpack while driving through a small town here in south Texas. This is a nightmare. Now looking for an attorney so this doesn’t ruin his life.

My son was diagnosed at 3 as well. He’s 9 now and his tics are so bad he’s screaming profanities. I’m looking into every avenue possible to help him.

My brother has tourettes, hes 11 years old and the tics are really bad at the moment. And none of theses pills there giving him are working they want to put him on adhd meds and I don’t think that’s the answer. I live in Wisconsin. Do I have any options at this moment.

Try a magnesium powder like Natural Calm. Also a b-complex and omega. Tell him to try and stay away from any artificial flavors and colors as those can increase frequency of tics. Doing all of these things has improved my sons ticks tremendously.

I would recommend he stay off wheat as well. GMO foods. Has he been tested for allergies by an environmental doctor??

My son had mild TS and they put him on adhd meds. They made his tics 100 times worse! He is now the worst case of Tourette’s. I called the doctor and asked him about the add medicine my son had been taken and he said that that is the reason my sons tics got worse. Don’t do it.
He was taking focalin

Based on neuroscientific evidence, ADD/ADHD medications will very likely exacerbate tics in a person with Tourette’s. This is because these medications work in the direct opposite way that TS medications work. TS medications work by decreasing the level of dopamine transmission in your brain. Most ADD/ADHD medications are classified as amphetamines, and these have the opposite effect of increasing dopamine transmission. Please be cautious when a doctor recommends putting a TS patient on ADD/ADHD medication!

Ask your son’s Doctor about the marijuana based pill called Israel. Read up about it.My son also has mild TS, marijuana helps bring his tics from a 9 down to a -1,i s how he describes it.

Nicole,
My son has Tourettes also and if you had read up on Focalin, it clearly states not to give to children with tics. Next maybe you research your son’s medications before you give them to him. My daughter takes Focalin and it’s working wonders for her. She doesn’t have Tourettes. My son takes Concerta but it doesn’t make his tics worse, you have to see what works for your child. I am interested in trying this for my son since he is on slot of meds bc of his Tourettes

My son was diagnosed with TS last year, at 10yrs old. Our pcp and neurologist tried to push meds on us but I wasn’t about to pump his body full of chemicals that may or may not work. So we tried acupuncture. It did amazing things for him! His tics were far less severe and further between, and his OCD was calmed dramatically! He was nervous about the needles at first but they seriously are so small he couldn’t feel them.

Adult TS patient who recently finished graduate school with a Phd. I look back on my younger years when I was misdiagnosed and my family didn’t want to put me on medications. I almost failed out of high school and failed out of my first college. It wasn’t until my mid-20s, when symptoms settled down considerably, that I returned to college. I graduated with a 4.0GPA, 2 degrees and a fellowship to graduate school where I got my Phd. I can only imagine how different my life would have been if I’d been treated earlier in life. I probably could have earned scholarships to undergrad instead of drowning in debts. I wouldn’t have felt like a defective, horrible person because I didn’t turn in schoolwork and was an inattentive disruption in class. I was embarrassed by my tics and suffered torment from the OCD and anxiety. Seriously, work with your doctors and treat your children. Yes, you have to be careful of what medications they get, but going med-free can have lifelong consequences.

Halez – I feel your brother’s pain!! I’m 44 years old with severe Tourette’s, and I was diagnosed at Mayo Clinic when I was 12. I’ve been on every medication known to man for Tourette’s, and the only one I’ll ever recommend again is Cannabis!! Cannabis has put my physical & verbal tics’ into 95% remission, or there about. I use a homemade tincture 4 – 6x daily, and fill in with smokeable form in between tincture doses. Without it, I’d most likely snap my neck. I could go on forever!! Tell your brother to hold his head up high, ’cause he’s no different than anyone else. I know its really hard to ignore other people, but just laugh with ’em. Cannabis is the best direction for your brother. Take Care & GOD BLESS. Jeffrey

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.

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.

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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.

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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