Tourette syndrome (TS) is a neuropsychiatric disorder that is characterized by involuntary, repetitive movements and vocal or phonic tics. Simple motor tics are characterized by movement problems such as impaired or uncontrolled jaw movements, eye blinking, facial movements, shoulder shrugging, arm jerking and neck stretching; while complex motor tics involve multiple muscles and their abnormal movements. Vocal/phonic tics are characterized by abnormal sounds such as hooting, throat clearing, etc. Patients with complex vocal tics speak out inconsistent or unrecognizable words, and in some cases words may be inappropriate or socially unacceptable. TS patients usually suffer at least two motor tics and at least one vocal or phonic tic that persists more than one year.
The onset of TS typically occurs between the ages of 5-7 years with presentation of a motor tic of the head or neck area, resulting in impaired neurodevelopment. The frequency and severity of tic tends to increase between the ages of 8-12 years. Most TS patients experience improvement in late adolescence and possibly become asymptomatic. However, some patients suffer persistent and severe forms of tics even into adulthood, and require medical attention. The exact cause of TS is unknown, and the severity of TS varies widely among patients. Experts believe hereditary, developmental and environmental factors play a vital role in the onset of TS.
The co-morbidity of TS includes other neuropsychiatric and neurodevelopmental disorders that cause more harm than tics. The co-occurrence of obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) is common in TS and tic disorders.
As of now, no cure is available for TS; however, as stated before, the condition generally improves with age in many patients.
Relevance of CB1 receptors in TS pathophysiology
Based on the supportive evidence, we can speculate the role of the CB1 receptor system in the pathophysiology of TS. If we look into the fact CB1 receptors are densely present in the molecular layers of the cerebellum, basal ganglia and hippocampus, we can understand the importance of CB1 receptor activation for treatment of tic disorders.
Neurophysiological studies have shown the presence of CB1 receptors at higher concentrations in the hippocampal dentate gyrus, output nuclei of the basal ganglia and forebrain, which is associated with cognitive functions. Sparsely dense presence of CB1 receptors in the lower brainstem regions, which regulate respiratory and cardiovascular functions, actually explain why THC is not lethal – even at higher doses.
Several studies have provided evidence suggesting a complex interaction between the dopaminergic system and CB1 receptor system in TS patients. Nonetheless, only one study has investigated the effect of the CB1 agonist (synthetic) on central CB1 receptors in six TS patients. The binding effects of THC were compared before and after administration by employing single photon emission computed tomography (SPECT).
Although studies have reported that the pathogenesis of TS is caused by genetic variations or polymorphism in the cannabinoid receptor (CNR1) gene, this study has reported moderate CB1 receptor specific binding of agonists with CB1 receptors. These results were confirmed by another study. In line with this evidence, one study has reported significant reduction of TS-related symptoms after 9-THC treatment. We can see that the pathology of tics is not related to genetic polymorphism of cannabinoid receptors, and could be the possible involvement of pre-existing dysfunctional CB1 receptors. We have adequate grounds to assume that THC administration might improve cognitive functions in TS patients; however this influence might be different in healthy users due to functional involvement of the CB1 receptor system in the regulation of cognitive function, attention and memory. The role of cannabis use in cognitive impairment in healthy users remains a controversial debate to date.
Cannabinoids for TS
Two studies, published in 2003 and 2013 respectively, have acknowledged the use of delta-9-THC for treatment of TS, if other well-established, conventional therapies either fail to achieve symptomatic improvement or cause an unacceptable degree of adverse events in patients. These are not the only studies that suggest THC might be a successful alternative option for management of severe, treatment-refractory TS. Delta 9-THC might be particularly helpful for treatment of stimulant-induced exacerbation of tics and related co-morbidities by enhancement of intra-cortical inhibition and induction of neurotransmitter release.
Cannabinoids can modulate brain neurotransmitter systems, such as glutamine and GABA, by which it is possible to treat TS or reduce the behavioral symptoms of tics.
A systematic review study by German researchers reported successful treatment of a 25-year old male TS patient with a single dose of 10 mg of THC. Although the study design was open-labeled and uncontrolled, the therapeutic benefit remains irrefutable.
Subjective evidential studies have suggested that delta-9-THC has the potential to reduce tics and related behavioral disorders. To confirm this, a team of researchers conducted a double-blind, placebo-controlled, randomized single-dose study to investigate the safety and efficacy of various doses of THC in 12 TS patients. The tested doses were 5.0, 7.5 and 10.0 mg of delta-9-THC. The severity of tic was assessed by Tourette Syndrome Symptom List, or TSSL (self-reported), which was cross-checked by clinical examiners’ rating scales, including Tourette Syndrome Severity Scale, Yale Global Tic Severity Scale etc, in addition to assessment of behavioral disorders such as obsessive compulsive behavior/disorder (OCB/OCD). The maximum plasma concentrations of THC and its metabolites (11-OH-THC and THC-COOH) were correlated with the clinical improvements or changes.
Significant improvement in tics and OCB was observed using the TSSL, compared to the placebo group. These benefits were concordant to the examiners’ ratings, with significant improvement in the scores of simple motor tics, vocal tics and complex motor tics. Surprisingly, the severity score dropped from 41 to 7 within two hours of delta-9-THC administration. The treatment benefit lasted for several hours without causing significant adverse events in the treated subjects, except occurrence of mild psychoactive side effects. Plasma analysis revealed a significant relationship between higher 11-OH-THC plasma concentration and tic improvement after single dose THC administration. These results suggest that the therapeutic effects of 9-delta-THC are attributed to its metabolite 11-OH-THC. The study concluded that delta-9-THC is safe and effective in treating tics and associated behavioral problems.
To confirm these findings, the investigators conducted two follow-up studies including one randomized-controlled study involving 24 TS patients who received daily doses of up to 10 mg of THC for 6 weeks. Upon completion of dosing, the patients experienced clinically significant reduction in tics. This study was followed-up by a single-dose, cross-over study that enrolled 12 TS patients who received 10 mg of delta-9-THC. Statistically significant and clinically meaningful improvements were observed in the treatment group when compared with the placebo group, without causing any serious adverse events. This evidence suggests THC is a safer and effective treatment option for tics. These results were confirmed in other studies as well. None of these studies reported risk or occurrence of acute or long-term cognitive deficits in THC-received study subjects.
Not only clinical studies, but even individual case studies provide supportive evidence for treatment of tics and related behavioral symptoms in TS patients. One case study that observed the effects of cannabis smoking in three male TS patients who were 15-39 years of age reported clinical improvement of tics. Additionally, the patients reported improvement of attention span, self-mutilatory behavior, premonitory urges and hypersexuality upon smoking cannabis every day. Another single case study that looked into a 36-year old TS patient reported symptom-free remission of tics for over a year, and the patient was taking one ‘cone’ of cannabis every night but was not on any other treatment. This evidence suggests that cannabis may have beneficial effects for treating TS symptoms.
Although one Cochrane review study has noted these benefits are small, we should note that the two studies included for the analysis have reported positive effects of THC treatment, as evidenced by improvements in tic frequency and severity of disease. To sum up, cannabis could be a safer, more effective alternate treatment option to treat tics and behavioral symptoms of TS, particularly for treatment-refractory TS patients.