Cannabinoids in Parkinson’s Disease, Mario Stampanoni Bassi et al., 2017

Cannabinoids in Parkinson’s Disease

Mario Stampanoni Bassi, Andrea Sancesario, Roberta Morace, Diego Centonze, and Ennio Iezzi

Cannabis and Cannabinoid Research, 2017, Volume 2.1

DOI: 10.1089/can.2017.0002


The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (c-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson’s disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results fromclinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies.

Keywords : basal ganglia; cannabinoids; dopamine; levodopa-induced dyskinesia; Parkinson’s disease



The endocannabinoid system (ECS) modulates a huge range of physiological functions, including mood, cognition, motor control, feeding behavior, and pain.1–5 In recent years, a number of studies explored the role of cannabinoids (CBs) in different pathological conditions.

Approximately 105 CBs have been extracted so far from cannabis.6 These phytocannabinoids include D9- tetrahydrocannabinol (THC) and cannabidiol (CBD).7 Several CB-based medicines are currently approved for clinical indications, including pain, anorexia, spasticity, chemotherapy-induced nausea, and severe refractory epileptogenic encephalopathies of the childhood.5,8

The ECS is highly represented in the basal ganglia and has been found altered in several movement disorders, including Parkinson’s disease (PD).9–11 Preclinical research suggests that modulating CB signaling could improve motor symptoms.12,13 Among motor symptoms, levodopa-induced dyskinesias (LIDs) dramatically complicate long-term pharmacological treatment in PD patients. LIDs are thought to arise from pulsatile stimulation of dopamine (DA) receptors with progressive sensitization of DA receptorassociated striatal signaling.14,15 So far, despite an increased knowledge of CBs–DA interactions at molecular level, the clinical relevance of CB-based therapies on PD motor symptoms and LIDs has been poorly detailed. The aim of this minireview is to provide an overview of the biochemical interactions between CBs and DA. Furthermore, results from preclinical and clinical studies involving CB-based therapies in PD will be discussed.

Endocannabinoid System and Dopamine

The ECS is constituted by endocannabinoids (eCBs), biosynthesizing (N-arachidonoyl-phosphatidyl-ethanolamine [NAPE]-specific phospholipase D and diacylglycerol [DAG] lipase-a) and degrading (fatty acid amide hydrolysis [FAAH] and monoacylglycerol lipase [MAGL]) enzymes, and CB receptors (CBRs).

The best characterized eCBs (N-arachidonoylethanolamine [AEA] or anandamide and 2-arachidonoyl-glycerol [2-AG]) interact with the two main CBRs subtypes (CB1R and CB2R) and also with other receptors, including the transient receptor potential vanilloid type 1 (TRPV1) cation channel,16 the GTP-binding protein-coupled receptor GPR55,17 the abnormal-CBD receptor,18 and the peroxisome proliferator-activated receptor (PPAR).19

eCBs regulate synaptic transmission producing a physiological feedback mechanism aimed to prevent an excess of excitation or inhibition.20 This ‘‘retrograde signaling’’21 results in depolarization-induced suppression of inhibition (DSI) at c-aminobutyric acid (GABA)ergic synapses and in depolarization-induced suppression of excitation (DSE) at glutamatergic synapses.22–24 The presynaptic location of CB1R, also allows eCBs to directly modulate other neurotransmitters, including opioid peptides, acetylcholine, and 5-hydroxytryptamine (5-HT).25,26

Although nigrostriatal dopaminergic neurons seem not to express CB1R,27,28 they are significantly affected by either the activation or the blockade of the ECS.29,30 These effects are likely mediated by CB1R located in other neuronal subpopulations (i.e., GABAergic, glutamatergic, and opioidergic neurons) located near to and connected with dopaminergic neurons.10,31,32 Indeed, it should be reminded that dopaminergic neurons may, in turn, produce eCBs from their somata and dendrites,
33,34 thus facilitating the retrograde signaling at excitatory and inhibitory synapses.35

Additional direct mechanisms have been proposed to explain the modulation of eCBs on DA transmission. Some eCBs, including AEA, have been found to interact with TRPV1 receptors,36 which are expressed in dopaminergic neurons.37 CB1R can form heteromers with other metabotropic receptors, including the dopamine D1 and D2 receptor.38 Finally, CB2R have been identified in human nigrostriatal dopaminergic neurons,12 this may support a direct role of eCBs in modulating dopaminergic transmission.