Mexiletine is the only drug with proven effect for treatment of non-dystrophic myotonia, but mexiletine is expensive, has limited availability and several side effects. There is therefore a need to identify other pharmacological compounds that can alleviate myotonia in non-dystrophic myotonias. Like mexiletine, lamotrigine is a sodium channel blocker, but unlike mexiletine, lamotrigine is available, inexpensive, and well tolerated. We investigated the potential of using lamotrigine for treatment of myotonia in patients with non-dystrophic myotonias. In this, randomized double-blind, placebo-controlled, two-period cross-over study, we included adult outpatients recruited from all of Denmark with clinical myotonia and genetically confirmed myotonia congenita and paramyotonia congenita for investigation at the Copenhagen Neuromuscular Center. A pharmacy produced the medication and placebo, and randomized patients in blocks of 10. Participants and investigators were all blinded to treatment until the end of the trial. In two 8-week periods, oral lamotrigine or placebo capsules were provided once daily, with increasing doses (from 25 mg, 50 mg, 150 mg to 300 mg) every second week. The primary outcome was a severity score of myotonia, the Myotonic Behaviour Scale ranging from asymptomatic (score 1) to invalidating myotonia (score 6), reported by the participants during Weeks 0 and 8 in each treatment period. Clinical myotonia was also measured and side effects were monitored. The study was registered at ClinicalTrials.gov (NCT02159963) and EudraCT (2013-003309-24). We included 26 patients (10 females, 16 males, age: 19-74 years) from 13 November 2013 to 6 July 2015. Twenty-two completed the entire study. One patient withdrew due to an allergic reaction to lamotrigine. Three patients withdrew for reasons not related to the trial intervention. The Myotonic Behaviour Scale at baseline was 3.2 ± 1.1, which changed after treatment with lamotrigine by 1.3 ± 0.2 scores (P < 0.001), but not with placebo (0.2 ± 0.1 scores, P = 0.4). The estimated effect size was 1.0 ± 0.2 (95% confidence interval = 0.5-1.5, P < 0.001, n = 22). The standardized effect size of lamotrigine was 1.5 (confidence interval: 1.2-1.8). Number needed to treat was 2.6 (P = 0.006, n = 26). No adverse or unsuspected event occurred. Common side effects occurred in both treatment groups; number needed to harm was 5.2 (P = 0.11, n = 26). Lamotrigine effectively reduced myotonia, emphasized by consistency between effects on patient-related outcomes and objective outcomes. The frequency of side effects was acceptable. Considering this and the high availability and low cost of the drug, we suggest that lamotrigine should be used as the first line of treatment for myotonia in treatment-naive patients with non-dystrophic myotonias.