Tetrahydrocannabinol and Cannabidiol in Tourette Syndrome

pubmed logo

“This randomized controlled crossover trial examined the use of oral tetrahydrocannabinol (THC) with cannabidiol (CBD) to reduce tics in patients with severe Tourette syndrome. Treatment with THC and CBD for 6 weeks led to a significant reduction in tics as measured by the total tic score on the Yale Global Tic Severity Scale, without major adverse effects.”

https://pubmed.ncbi.nlm.nih.gov/38320199/

“BACKGROUND

Tourette syndrome is characterized by chronic motor and vocal tics. There is preliminary evidence of benefit from cannabis products containing Δ9-tetrahydrocannabinol (THC) and that coadministration of cannabidiol (CBD) improves the side-effect profile and safety.

METHODS

In this double-blind, crossover trial, participants with severe Tourette syndrome were randomly assigned to a 6-week treatment period with escalating doses of an oral oil containing 5 mg/ml of THC and 5 mg/ml of CBD, followed by a 6-week course of placebo, or vice versa, separated by a 4-week washout period. The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range, 0 to 50 [higher scores indicate greater severity of symptoms]). Secondary outcomes included video-based assessment of tics, global impairment, anxiety, depression, and obsessive-compulsive symptoms. Outcomes were correlated with plasma levels of cannabinoid metabolites. A computerized cognitive battery was administered at the beginning and the end of each treatment period.

RESULTS

Overall, 22 participants (eight female participants) were enrolled. Reduction in total tic score (at week 6 relative to baseline) as measured by the YGTSS was 8.9 (±7.6) in the active group and 2.5 (±8.5) in the placebo group. In a linear mixed-effects model, there was a significant interaction of treatment (active/placebo) and visit number on tic score (coefficient = −2.28; 95% confidence interval, −3.96 to −0.60; P=0.008), indicating a greater decrease (improvement) in tics under active treatment. There was a correlation between plasma 11-carboxy-tetrahydrocannabinol levels and the primary outcome, which was attenuated after exclusion of an outlier. The most common adverse effect in the placebo period was headache (n=7); in the active treatment period, it was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration (n=8).

CONCLUSIONS

In severe Tourette syndrome, treatment with THC and CBD reduced tics and may reduce impairment due to tics, anxiety, and obsessive-compulsive disorder; although in some participants this was associated with slowed mentation, memory lapses, and poor concentration.”

https://evidence.nejm.org/doi/10.1056/EVIDoa2300012

The Effect of Nabiximols on Driving Ability in Adults with Chronic Tic Disorders: Results of a Substudy Analysis of the Double-Blind, Randomized, Placebo-Controlled CANNA-TICS Trial

pubmed logo

“Background: The multicenter, randomized, double-blind, parallel-group, phase IIIb CANNA-TICS (CANNAbinoids in the treatment of TICS) trial showed clear trends for improvement of tics, depression, and quality of life with nabiximols versus placebo in adult patients with Gilles de la Tourette syndrome and other chronic tic disorders. Although in general nabiximols was well tolerated, it is unclear whether treatment using this cannabis extract influences driving skills in patients with chronic tic disorders. 

Methods: Here we report results of the “Fitness to Drive” substudy of the CANNA-TICS trial. The key endpoint was fitness to drive as a binary criterion with a computerized assessment at baseline and after 9 weeks of stable treatment (week 13) with nabiximols or placebo. A patient was considered unfit to drive according to the German Federal Highway Research Institute guidelines. 

Results: In the substudy, a total of 64 patients (76.6% men, mean±standard deviation of age: 36.8±13.9) were recruited at two study sites. The number of patients who were fit to drive increased from 24 (55.8%) at baseline to 28 (71.8%) at week 13 among 43 patients treated with nabiximols, and decreased from 14 (66.7%) to 10 (52.6%) among 21 patients who received placebo. The risk difference (nabiximols – placebo) was 0.17 (95% confidence interval=-0.08 to 0.43) in favor of nabiximols. Specifically, only 2 of 24 (8.3%) patients in the nabiximols, but 4 of 14 (28.6%) patients in the placebo group changed for the worse from fit (at baseline) to unfit (at week 13) to drive, whereas 8 of 19 (42.1%) patients in the nabiximols, and only 2 of 7 (28.6%) patients in the placebo group improved from unfit to fit. 

Conclusion: Treatment with nabiximols does not impair skills relevant to driving in those patients with tic disorders who were fit to drive at baseline and even improved fitness to drive in a subset of patients who were unfit to drive before start of treatment.”

https://pubmed.ncbi.nlm.nih.gov/38265476/

https://www.liebertpub.com/doi/10.1089/can.2023.0114

Use of Medical Cannabis in Patients with Gilles de la Tourette’s Syndrome in a Real-World Setting

View details for Cannabis and Cannabinoid Research cover image

“Objective: Tourette’s syndrome (TS) is a neurodevelopmental disorder characterized by vocal and motor tics and other comorbidities. Clinical recommendations for the use of medical cannabis are established, yet further guidance is needed. The aim of this study was to describe the experience of patients with TS with medical cannabis. 

Materials and Methods: TS patients were recruited from a registry of patients (“Tikun Olam” company). Questionnaires were answered before and after 6 months of treatment. Patients were divided into two groups: (A) patients who responded and (B) patients who did not respond to the follow-up questionnaire. In group A, an analysis was made to evaluate the presence and frequency of motor and vocal tics. The patients’ general mood, employment status, quality of life, and comorbidities were also included in the analysis. 

Results: Seventy patients were identified. The tetrahydrocannabinol and cannabidiol mean daily dose was 123 and 50.5 mg, respectively. In group A, a statistically significant improvement was identified in quality of life (p<0.005), employment status (p=0.027), and in the reduction of the number of medications (p<0.005). Sixty-seven percent and 89% of patients with obsessive-compulsive disorder and anxiety comorbidities, respectively, reported an improvement. No statistically significant improvement was identified in motor tics (p=0.375), vocal tics (p>0.999), tics frequency (p=0.062), or general mood (p=0.129). The most frequent adverse effects were dizziness (n=4) and increased appetite (n=3). 

Conclusion: Subjective reports from TS patients suggest that medical cannabis may improve their quality of life and comorbidities. More studies are needed to evaluate the efficacy and safety of medical cannabis.”

https://pubmed.ncbi.nlm.nih.gov/36342913/

https://www.liebertpub.com/doi/10.1089/can.2022.0112

Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications

BMC Medicine logo

“Background: Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events.

Results: In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD – 0.5[CI – 0.62, – 0.38] high grade) and Parkinsonism (- 0.41[CI – 0.75, – 0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (- 0.31[CI – 0.46, – 0.15]), appetite (- 0.51[CI – 0.87, – 0.15]) and Tourette (- 1.01[CI – 1.58, – 0.44]) and moderate evidence for nabiximols on chronic pain (- 0.25[- 0.37, – 0.14]), spasticity (- 0.36[CI – 0.54, – 0.19]), sleep (- 0.24[CI – 0.35, – 0.14]) and SUDs (- 0.48[CI – 0.92, – 0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid.

Conclusions: Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.”

https://pubmed.ncbi.nlm.nih.gov/35982439/

“Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.”

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02459-1

Medical Cannabis for Gilles de la Tourette Syndrome: An Open-Label Prospective Study

logo

“Objectives: Assessing the effectiveness and tolerability of medical cannabis (MC) treatment on Gilles de la Tourette syndrome (GTS) patients.

Methods: We report on an open-label, prospective study on the effect of MC on adult GTS patients. MC mode of use was decided by the treating neurologist and the patient. Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) content within MC product and monthly dose were titrated during the study. Following treatment initiation, patients were assessed after 4 and 12 weeks for efficacy, tolerability, and side effects.

Results: Eighteen patients entered the study. Baseline Yale Global Tic Severity Scale- (YGTSS) Total (range 0-100) was 60.3 ± 17.1. Three patients did not reach the end of follow-up period. The most common mode of administration was smoking (80%). Following twelve weeks of treatment, a significant 38% average reduction (p = 0.002) of YGTSS-Total and a 20% reduction (p = 0.043) of Premonitory Urge for Tic Scale (PUTS) were observed. Common side effects were dry mouth (66.7%), fatigue (53.3%), and dizziness (46.7%). Three patients suffered from psychiatric side effects including worsening of obsessive compulsive disorder (stopped treatment), panic attack, and anxiety (resolved with treatment modification). Six patients (40%) reported cognitive side effects regarding time perception, visuospatial disorientation, confusion, slow processing speed, and attention.

Conclusions: MC treatment demonstrates good efficacy and tolerability in adult GTS patients. Predilection for smoking rather than using oil drops requires further comparative studies to evaluate the efficacy of each. Cognitive and psychiatric side effects have to be monitored and addressed.”

https://pubmed.ncbi.nlm.nih.gov/35310886/

“Our results are in line with a number of other studies suggesting that MC is effective and well tolerated in adults with GTS. From our data, it is suggested that MC might be a treatment option for resistant TS patients, and MC has a significant effect on tics, premonitory urges, and patients’ overall quality of life. In our sample, patients favored THC-rich cannabis strands and smoking/inhaling MC over sublingual oil.”

https://www.hindawi.com/journals/bn/2022/5141773/

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

ijms-logo“Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes.

The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors.

The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.”

https://pubmed.ncbi.nlm.nih.gov/33466734/

https://www.mdpi.com/1422-0067/22/2/778

Medical Cannabis in Children.

 Logo of rmmj“The use of medical cannabis in children is rapidly growing.

While robust evidence currently exists only for pure cannabidiol (CBD) to treat specific types of refractory epilepsy, in most cases, artisanal strains of CBD-rich medical cannabis are being used to treat children with various types of refractory epilepsy or irritability associated with autism spectrum disorder (ASD).

Other common pediatric disorders that are being considered for cannabis treatment are Tourette syndrome and spasticity.

As recreational cannabis use during youth is associated with serious adverse events and medical cannabis use is believed to have a relatively high placebo effect, decisions to use medical cannabis during childhood and adolescence should be made with caution and based on evidence.

This review summarizes the current evidence for safety, tolerability, and efficacy of medical cannabis in children with epilepsy and in children with ASD. The main risks associated with use of Δ9-tetrahydrocannabinol (THC) and CBD in the pediatric population are described, as well as the debate regarding the use of whole-plant extract to retain a possible “entourage effect” as opposed to pure cannabinoids that are more standardized and reproducible.”

https://www.ncbi.nlm.nih.gov/pubmed/32017680

Treatment of Gilles de la Tourette Syndrome with Cannabis-Based Medicine: Results from a Retrospective Analysis and Online Survey.

View details for Cannabis and Cannabinoid Research cover image“Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder that is characterized by motor and vocal tics and psychiatric comorbidities, including attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive behavior/disorder (OCB/OCD). From anecdotal reports and preliminary controlled studies, it is suggested that cannabis-based medicine (CBM) may improve tics and comorbidities in adults with GTS. This study was designed to further investigate efficacy and safety of CBM in GTS and specifically compare effects of different CBM.

Results: From medical records, we identified 98 patients who had used CBM (most often street cannabis followed by nabiximols, dronabinol, medicinal cannabis) for the treatment of GTS: Of the 38 patients who were able to judge, 66% preferred treatment with medicinal cannabis, 18% dronabinol, 11% nabiximols, and 5% street cannabis. Altogether, CBM resulted in a subjective improvement of tics (of about 60% in 85% of treated cases), comorbidities (55% of treated cases, most often OCB/OCD, ADHD, and sleeping disorders), and quality of life (93%). The effects of CBM appear to persist in the long term. Adverse events occurred in half of the patients, but they were rated as tolerable. Dosages of all CBM varied markedly. Patients assessed cannabis (with a preference for tetrahydrocannabinol [THC]-rich strains) as more effective and better tolerated compared with nabiximols and dronabinol. These data were confirmed by results obtained from the online survey (n=40).

Conclusion: From our results, it is further supported that CBM might be effective and safe in the treatment of tics and comorbidities at least in a subgroup of adult patients with GTS. In our sample, patients favored THC-rich cannabis over dronabinol and nabiximols, which might be related to the entourage effect of cannabis. However, several limitations of the study have to be taken into considerations such as the open uncontrolled design and the retrospective data analysis.”

https://www.ncbi.nlm.nih.gov/pubmed/31872061

https://www.liebertpub.com/doi/10.1089/can.2018.0050

The Potential of Cannabinoid-Based Treatments in Tourette Syndrome.

“Novel pharmacological treatments are needed for Tourette syndrome.

Our goal was to examine the current evidence base and biological rationale for the use of cannabis-derived medications or medications that act on the cannabinoid system in Tourette syndrome.

There is a strong biological rationale regarding how cannabis-derived medications could affect tic severity. Anecdotal case reports and series have noted that many patients report that their tics improve after using cannabis. However, only two small randomized, placebo-controlled trials of Δ9-tetrahydrocannabinol have been published; these suggested possible benefits of cannabis-derived agents for the treatment of tics.

Trials examining other agents active on the cannabinoid system for tic disorders are currently ongoing.

Cannabinoid-based treatments are a promising avenue of new research for medications that may help the Tourette syndrome population.”

Dark Classics in Chemical Neuroscience: Δ9-Tetrahydrocannabinol.

 ACS Chemical Neuroscience

“Cannabis (Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally.

The main psychoactive component of cannabis is (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), a molecule with a diverse range of pharmacological actions. The unique and distinctive intoxication caused by Δ9-THC primarily reflects partial agonist action at central cannabinoid type 1 (CB1) receptors.

Δ9-THC is an approved therapeutic treatment for a range of conditions, including chronic pain, chemotherapy-induced nausea and vomiting, and is being investigated in indications such as anorexia nervosa, agitation in dementia, and Tourette’s syndrome.

It is available as a regulated pharmaceutical in products such as Marinol®, Sativex®, and Namisol®, as well as in an ever-increasing range of unregistered medicinal and recreational cannabis products.

While cannabis is an ancient medicament, contemporary use is embroiled in legal, scientific, and social controversy, much of which relates to the potential hazards and benefits of Δ9-THC itself.

Robust contemporary debate surrounds the therapeutic value of Δ9-THC in different diseases, its capacity to produce psychosis and cognitive impairment, and the addictive and “gateway” potential of the drug.

This review will provide a profile of the chemistry, pharmacology, toxicology, and recreational and therapeutic uses of Δ9-THC, as well as the historical and societal importance of this unique, distinctive, and ubiquitous psychoactive substance.”

https://www.ncbi.nlm.nih.gov/pubmed/30689342

https://pubs.acs.org/doi/10.1021/acschemneuro.8b00651