2-, 3-octanol, and octanoic acid in Essential Tremor

Essential tremor (ET) is a frequent movement disorder affecting 0.4 - 3.9% of the general population. Tremor can respond well to medical therapy such as propranolol and primidone, but the use of these substances for first-line therapy is often limited especially in the elderly population because of frequently observed side effects. Furthermore, due to a progressive course of the disease, a significant proportion of patients can develop disabling tremor intensities despite therapy, which can cause meaningful impairment in activities of daily living such as drinking and writing. The intake of alcohol leads to a significant reduction in tremor intensity in the majority of patients - an observation recognized as a characteristic feature of Essential Tremor. Due to alcohol`s acute and long-term toxic effects, it cannot be rationally recommended as symptomatic therapy in Essential tremor. Long chain alcohols such as octanol, which both block gap junctions and the low threshold calcium current, have additionally shown beneficial effect on tremor severity in the harmaline-induced animal model of ET. Furthermore, in recent studies on 1-octanol in human ET-patients, the substance was considered as safe and effective in reducing tremor intensity in dosages up to 64 mg/kg body weight. Isomeres of octanol (2-, and 3-octanol) have also been demonstrated to be effective as tremor reducing agents in the animal model of ET. No studies on 2-, and 3-octanol as well as octanoic acid, an octanol metabolite, have been conducted in human ET patients so far. We propose a study to examine the safety and efficacy of 2-, 3-octanol, and octanoic acid in 16 patients with alcohol-responsive ET. These substances showed promising results in preclinical trials and are already approved substances for the use as food additives, and received the status "Generally Recognized As Safe" (GRAS) by the FDA. These substances will be tested in a double blind, randomized, placebo-controlled, cross-over design in a low dose, which is recommended by the FDA as acceptable for daily intake (ADI). The outcome measures will be the change of tremor severity measured by accelerometry, spiral drawing, and long-period tremor monitoring using actigraphy. The second outcome parameter is the safety of the proposed substances, which will be monitored systematically using laboratory testing, documentation of vital signs, and interviews regarding adverse events. The proposed study will bring the first human data regarding novel therapeutic agents in Essential Tremor.