Cannabis Therapeutics and the Future of Neurology

Ethan B. Russo  (October 2018)

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As early as 1888, Gowers noted benefits of “Indian hemp” on a parkinsonian syndrome (Gowers, 1888; Russo, 2007). Because of the density of cannabinoid receptors in basal ganglia, PD has been an area of active research, but with mixed results therapeutically. An oral THC:CBD extract showed no significant benefits on dyskinesia or other signs in 17 patients (Carroll et al., 2004), but CBD was helpful in five PD patients with psychosis (Zuardi et al., 2009) and 21 patients with more general symptoms (Chagas et al., 2014b) and more specifically on rapid eye movement sleep disorder in four patients (Chagas et al., 2014a). An observational study showed 22/28 patients tolerated smoked cannabis (presumably THC-predominant) and showed acute benefits on tremor, rigidity and bradykinesia (Lotan et al., 2014). Five of nine patients using cannabis reported great improvement, particularly on mood and sleep (Finseth et al., 2015).

Identification of metabolite biomarkers for L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease by metabolomic technology

YongWangGe-JuanZhangYi-NaSunLuYaoHui-ShengWangCheng-XueDuLiZhangJianLiu  (March 2018)

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L-DOPA-induced dyskinesia (LID) is a frequent complication of chronic L-DOPA therapy in the clinical treatment of Parkinson’s disease (PD). The pathogenesis of LID involves complex molecular mechanisms in the striatum. Metabolomics can shed light on striatal metabolic alterations in LID. In the present study, we compared metabolomics profiles of striatum tissue from Parkinsonian rats with or without dyskinetic symptoms after chronic L-DOPA administration. The results showed that the metabolic pathways of “Retrograde endocannabinoid signaling”, “Phospholipase D signaling pathway”, “Glycerophospholipid metabolism” and “Sphingolipid signaling”, etc. were dysregulated in LID rats compared to non-LID controls. Moreover, integrated pathway analysis based on results from the present metabolomics and our previous gene expression data in LID rats further demonstrates that aberrant “Retrograde endocannabinoid signaling” pathway might be involved in the development of LID.

The Endocannabinoid System and Parkinson Disease

Andrea Giuffrida and Alex Martinez  (October 2017)

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Dysregulation of the endocannabinoid system has been implicated in several neurodegenerative disorders including Parkinson disease (PD). Within the motor areas of the brain, cannabinoid and dopamine systems regulate motor function and synaptic plasticity by modulating excitatory and inhibitory neurotransmission. Alterations of this cross talk have been linked to the pathophysiology of PD and the maladaptive plasticity associated with the disabling motor complications caused by long-term use of L-DOPA.

Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson’s disease

NoemiPasquarelliChristophPorazikHannaBayerEvaBuckStefanSchildknechtPatrickWeydtAnkeWittingBorisFerger (August 2017) 

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The modulation of the brain endocannabinoid system has been identified as an option to treat neurodegenerative diseases including Parkinson’s disease (PD). Especially the elevation of endocannabinoid levels by inhibition of hydrolytic degradation represents a valuable approach. To evaluate whether monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) inhibition could be beneficial for PD, we examined in parallel the therapeutic potential of the highly selective MAGL inhibitor KML29 elevating 2-arachidonoylglyerol (2-AG) levels and the highly selective FAAH inhibitor PF-3845 elevating anandamide (AEA) levels in a chronic methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/probenecid) mouse model of PD. Chronic administration of KML29 (10 mg/kg) but not PF-3845 (10 mg/kg) attenuated striatalMPTP/probenecid-induced dopamine depletion.

Cannabinoids in Parkinson’s Disease

Mario Stampanoni Bassi, Andrea Sancesario, Roberta Morace, Diego Centonze and Ennio Iezzi  (February 2017)
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 (γ-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.

The Endocannabinoid System in Parkinsons Disease

Massimiliano Di Filippo, Barbara Picconi, Alessandro Tozzi, Paolo Calabresi (February 2008)

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The evidence that ECBs (endocannabinoids) play a central role in regulating basal ganglia physiology and motor function and the profound modifications occurring in ECB signaling after dopamine depletion in both experimental models of PD and patients suffering from the disease, provide support for the development of pharmacological compounds targeting the ECB system as symptomatic and neuroprotective therapeutic strategies for PD.