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The Medical Use of Marijuana in Huntington's Disease
The endocannabinoid system (ECS) has been intensively researched as a potential therapeutic target in the treatment of Huntington's disease (HD) in pre-clinical cell culture and animal models . Relatively little, however, is known regarding the safety and efficacy of cannabinoid-based therapeutics specifically for HD patients . In this continuing education module, we will describe and discuss the existing clinical literature for cannabinoid-based medicines in HD.
The effect of cannabinoids on HD patients may be unique compared to other populations, as HD is characterized by widespread dysfunction in the ECS [3-8]. Analyses of human tissue have consistently found that type 1 cannabinoid receptor (CB1) levels and ligand binding decline by 50% in the caudate and putamen (CPu), and 25% in the cortex, in early symptomatic HD patients that have presented with chorea for 1 year [3-9]. Also, a polymorphism in the (AAT)n repeat of the CB1 gene 3'UTR associated with reduced transcript stability is correlated with younger age of onset in HD patients . Levels of type 2 cannabinoid receptors (CB2) and fatty acid amide hydrolase (FAAH) are higher, while levels of N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) are lower in CPu tissue from late-stage (von Sattel stage 4) HD patients [1,6,7]. Therefore, cannabinoid-based therapy is highly likely to differentially effect HD patients compared to other populations. Importantly, cannabinoid therapies may have different effects depending on the stage of HD and specific symptom presentation for any given patient.
The first case report of a cannabinoid producing a beneficial effect in HD described a reduction in chorea following oral administration of synthetic cannabidiol (CBD) encapsulated with sesame oil (600 mg/day) for 2 weeks in 3 HD patients (aged 30 - 56) that had exhibited HD symptoms for 7 - 12 years and were not taking other medications to control their HD symptoms . Mild, but statistically significant, improvements in choreiform movement (5 - 15%) were observed using the chorea severity evaluation scale in the first week, and further improvements (20 - 40%) were observed in the second week in all 3 patients receiving CBD . Choreic movements returned to a pre-CBD state 48 h after withdrawal from CBD . A small follow-up study of this work reported a significant reduction in dystonia following oral administration of CBD (100 - 600 mg once daily for 6 weeks) in 5 HD patients that had exhibited symptoms for 8 - 12 years . Side effects included hypotension, dry mouth, lightheadedness, sedation, and exacerbation of Parkinsonian hypokinesia in 2 patients receiving greater than 300 mg/day CBD . Since this case report, 2 additional case reports have found no beneficial or toxic effects of oral CBD in HD patients [13,14]. Use of other medications was not reported in these reports of CBD use [12-14]. Nabilone, a synthetic Δ9-tetrahydrocannabinol (THC) derivative, at a single dose of 1.5 mg, exacerbated chorea (chorea severity evaluation scale) and motor impairment for 2 days in a 58 year-old male HD patient that had exhibited chorea for 6 years and not receiving other medications . However, a second case report found that 1 mg/day nabilone for 2 weeks reduced chorea for several hours following oral administration in a male patient that had been diagnosed with HD 7 years prior to the report [16,17]. The case reports do not describe any effects of CBD or nabilone on cognition, behavior, or metabolism . These case reports did not state whether the patients were cannabis naïve [11-17]. No case reports of THC, Sativex®, synthetic or endogenous cannabinoids exist in the literature . No case reports of oral, oromucosal, or smoked cannabinoids for the treatment of HD, or used by HD patients for recreational purposes, exist in the literature .