TABLE 1.

Clinical and experimental studies reporting beneficial effects of lithium in ALS.

ALS patients	In vivo ALS models	In vitro ALS models
16 ALS patients received riluzole plus lithium, and 28 received riluzole only. At 15 months, all 16 patients treated with lithium and riluzole were alive, whereas 8 of 28 treated only with riluzole died (survival rate 100 vs. 71%). Lithium delayed disease progression in ALS patients as assessed by quantitative measurement of the muscle strength (by the MRC scale) and preservation of the pulmonary function (by FVC) (Fornai et al., 2008a).	Lithium enhances survival and motor function while protecting spinal cord motor neurons in G93A-SOD-1 mice from oxidative stress and Fas-related apoptosis. These effects are potentiated upon combined treatment with lithium and the anti-oxidant agent Neu2000 (Shin et al., 2007). Lithium delays the onset of disease symptoms prolonging the lifespan and decreasing the neurological deficit scores in G93A-SOD-1 mice while conferring neuroprotection through GSK3 inhibition in the brain and lumbar spinal cord. These effects are potentiated upon combined treatment with lithium and valproic acid (VPA, Feng et al., 2008). Lithium confers neuroprotection, delays disease onset and duration and augments the life span in G93A SOD-1 mice, through activation of autophagy, stimulation of mitochondriogenesis, and suppression of reactive astrogliosis (Fornai et al., 2008a).	Lithium pretreatment protects primary rat cerebellar granule against glutamate-induced excitotoxicity cells through GSK3 inhibition (Leng et al., 2008). Lithium protects mice primary motor neurons and organotypic chick embryo spinal cord neurons against kainic acid-induced excitotoxicity through GSK3b inhibition and activation of autophagy (Calderó et al., 2010; Fulceri et al., 2011).
The study enrolled 18 ALS patients to be compared with 31 ALS out-patients. Lithium and valproate co-treatment significantly increased ALS patients’ survival and exerted neuroprotection by increasing antioxidant defense markers assayed at baseline, and 5 and 9 months in plasma samples. The trial stopped after 21 months, due to the late adverse events of the treatment (Boll et al., 2014).	Lithium attenuates neurodegeneration in the brainstem (trigeminal, facial, ambiguous, and hypoglossal nuclei) of G93A SOD-1 mice while rescuing hypoglossal recurrent collaterals (Ferrucci et al., 2010). Lithium induces mitophagy and mitochondriogenesis to reverse the severe subcellular pathology, which occurs mostly within peripheral motor axons and muscles of G93A SOD-1 mice (Natale et al., 2015).	Lithium protects primary cultures of embryo rat motor neurons from neurotoxicity which is induced by cerebrospinal fluids (CSFs) from ALS patients (Yáñez et al., 2014).
Data from 3 randomized trials on 518 participants showed that although lithium does not improve overall 12-month survival rate in the general ALS population, in UNC13A carriers, it increases the 12-month survival probability from 40.1% to 69.7% (van Eijk et al., 2017).	Lithium suppresses the upregulation of Notch signaling and the postsynaptic protein Homer1b/c in the spinal cord of G93A SOD-1 mice to confer neuroprotection by increasing the Bcl-2/Bax ratio. These effects are potentiated upon combined treatment with lithium with VPA (Wang et al., 2015; Jiang et al., 2016).	Lithium suppresses the upregulation of Notch signaling and the postsynaptic protein Homer1b/c to confer cytoprotection in mtSOD1 (G93A) NSC34 cells (hybrid cell line of mouse neuroblastoma and embryonic spinal motor neurons) by increasing the Bcl-2/Bax ratio. These effects are potentiated upon combined treatment with VPA (Wang et al., 2015; Jiang et al., 2016).