BDNF and amyotrophic lateral sclerosis: The use of carrier-free recombinant BDNF represents the most simplistic method attempted; in a phase III clinical trial of amyotrophic lateral sclerosis patients, the survival benefit seen only in patients on high-dose subcutaneous BDNF reflects on the problems associated with its short half-life and limited blood–brain barrier (BBB) permeability [7], and despite the feasibility of intrathecal BDNF, evidence on clinical efficacy is lacking [8,9].