Objective: To assess the effect of acute and subchronic oral administration of nabiximols (JZP378), a complex botanical cannabinoid drug mixture with Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the most abundant cannabinoid constituents, in a harmaline-induced model of essential tremor (ET) in rats.

Background: ET is one of the most prevalent movement disorders.  It is a progressive and debilitating neurological disease that impairs quality of life [1]. The pathophysiology of ET is poorly understood but appears to be caused by a critical disbalance in cerebello-thalamo-cortical pathways [2]. The rat harmaline model of ET utilizes the pharmacological toxin harmaline, which acts on inferior olivary nucleus neurons to modulate rhythmicity, resulting in generalized tremor with a frequency of 8-12 Hz in rats, similar to human ET (4-12 Hz). [2]. Propranolol is the only FDA-approved drug for the treatment of ET but shows mixed clinical efficacy [3]. Preclinically, there is evidence to suggest cannabinoids may mitigate tremor [4,5].

Method: Acute (single dose) and subchronic (10 days, uid) studies were performed in male SD rats (6-8 wks old). On test day, nabiximols (5.2, 10.4, 20.8 mg/kg p.o.) was dosed 100 min prior to harmaline (10 mg/kg i.p.); (±)-propranolol (20mg/kg i.p.) (positive control) was administered 30min prior to harmaline. Observational Scoring (OS) was carried out prior to placement in a tremor monitor (SDI, USA) for the calculation of Tremor Index (TI) and Motion Power Percentage (MPP) at 9-12Hz, at 20-, 40-, and 60-min post harmaline. Data were analysed using nonparametric and parametric statistical methods (p<0.05).

Results: Propranolol (20mg/kg) and acute and subchronic nabiximols significantly antagonized harmaline-induced tremor at 10.4 and 20.8mg/kg, respectively, for each parameter: OS, TI, and MPP. For acute administration this was significant at all time points. Sub-chronic administration showed significant attenuation for OS at 20 & 40 mins, TI at all time points and MPP at 40 & 60mins post-harmaline.

Conclusion: These data suggest efficacy of acute and subchronic nabiximols to reduce tremors, based on OS, TI and MPP readouts. Overall, the minimal effective dose (MED) was ≤10.4mg/kg p.o. for each parameter. These data are the first to indicate the preclinical effects of oral nabiximols in an animal model of ET.

References: [1] Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Álvarez I, Pastor P, Agúndez JAG. (2021) Genomic Markers for Essential Tremor. Pharmaceuticals (Basel). 14(6):516.
[2] Handforth A. Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor (2012). Tremor Other Hyperkinet Mov (N Y). 2:02-92-769-1.
[3] Rajput AH, Rajput A. Medical treatment of essential tremor. (2014) J Cent Nerv Syst Dis. 21(6):29-39.
[4] Abbassian H, Whalley BJ, Sheibani V, Shabani M. (2016) Cannabinoid type 1 receptor antagonism ameliorates harmaline-induced essential tremor in rat. Br J Pharmacol. 173(22):3196-3207.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/anti-tremor-efficacy-of-nabiximols-jzp378-in-a-rat-model-of-essential-tremor/