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• Patients with schizophrenia can manifest negative symptoms such as functional, verbal, and social performance loss. • Negative symptoms are usually resistant to monotherapy with currently available antipsychotics and require adjunctive treatments. • Anandamide, which is a major component of the endocannabinoid system, is associated with severity of schizophrenia symptoms. • N-palmitoylethanolamide (PEA) is an endogenous analogue of anandamide and has been conventionally used as a medication for its anti-inflammatory and analgesic properties. • In this 8-week, randomized, double-blind, placebo-controlled clinical trial, we investigated the efficacy and safety of adjuvant PEA with risperidone in treatment of chronic schizophrenia and found significant improvement in negative symptoms. Primary negative symptoms of schizophrenia are usually resistant to monotherapy with antipsychotics. The present study sought to assess the efficacy and tolerability of Palmitoylethanolamide (PEA) adjunctive therapy in treatment of negative symptoms in patients with stable schizophrenia. This 8-week (trial timepoints: baseline, week 4, week 8), double-blind, placebo-controlled clinical trial randomized patients with schizophrenia in a 1:1 ratio to compare the efficacy and safety of 600 mg twice a day of PEA and matched placebo alongside a stable dose of risperidone. Outcome measures were the positive and the negative syndrome scale (PANSS), the extrapyramidal symptom rating scale (ESRS), and the Hamilton depression rating scale (HDRS). The primary outcome was change in the negative subscale score during the trial period between the groups. Safety of interventions were controlled and addressed during the trial. A total of 50 participants completed the trial (25 in each group). Baseline characteristics of the groups were comparable (p >0.05). There was significant effect from time-treatment interaction on negative symptoms (p = 0.012) suggesting greater symptom improvement in the PEA group. In contrast, the longitudinal changes in positive symptoms and depressive symptoms were similar between groups (p values>0.05). Safety assessments showed no significant difference regarding extrapyramidal symptoms, measured by ESRS, and also frequency of other complications between PEA and placebo groups (p values>0.05). Adjunctive therapy with PEA and risperidone alleviates schizophrenia-related primary negative symptoms in a safe manner. [ABSTRACT FROM AUTHOR]