Cerebrospinal fluid endocannabinoid levels in Gilles de la Tourette syndrome

Gilles de la Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by the presence of motor and vocal tics as well as psychiatric comorbidities such as attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), depression, and anxiety. The underlying cause of the disease is still unknown, but several lines of evidence suggest a paramount role of the dopaminergic system. Based on the clinical observation that cannabis-based medicine including cannabis and delta-9-tetrahydrocannabinol (THC, dronabinol) may improve TS, alternatively, an involvement of the endocannabinoid system (ECS) has been suggested. In this study we measured cerebrospinal fluid (CSF) levels of the two most important endocannabinoids N-arachidonoylethanolamine (AEA, anandamide) and 2-arachidonoylglycerol (2-AG), the endocannabinoid-like molecule palmitoyl ethanolamide (PEA), and the lipid arachidonic acid (AA) in a sample of adult patients with TS (n = 20) compared with controls (n = 19) using liquid-liquid lipid extraction and simultaneous quantification by liquid chromatography multiple reaction monitoring (LC/MRM). CSF levels of AEA (p = 0.0018), 2-AG (p = 0.0003), PEA (p = 0.02), and AA (p < 0.0001) were significantly increased in TS compared with controls. Levels of 2-AG correlated with the severity of comorbid ADHD (p < 0.01). This is the first study, demonstrating alterations in the ECS suggesting an involvement of this system in the pathophysiology of TS. It can be speculated that elevated endocannabinoid levels either represent secondary changes in order to compensate for alterations in other neurotransmitter systems such as the dopaminergic system, are simply an epiphenomenon or, alternatively, represent the primary cause of TS.