Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial

J Affect Disord. 2018 May;232:127-133. doi: 10.1016/j.jad.2018.02.057. Epub 2018 Feb 21.


Background: Experimental studies provide evidence for antidepressant effects of Palmitoylethanolamide (PEA) in animal models of depression. We aimed to evaluate the efficacy and tolerability of PEA add-on therapy in treatment of patients with major depressive disorder (MDD).

Methods: In a randomized double-blind, and placebo-controlled study, 58 patients with MDD (DSM-5) and Hamilton Depression Rating Scale (HAM-D) score ≥ 19 were randomized to receive either 600 mg twice daily Palmitoylethanolamide or placebo in addition to citalopram for six weeks. Patients were assessed using the HAM-D scale at baseline and weeks 2, 4, and 6.

Results: Fifty-four individuals completed the trial. At week 2, patients in the PEA group demonstrated significantly greater reduction in HAM-D scores compared to the placebo group (8.30 ± 2.41 vs. 5.81 ± 3.57, P = .004). The PEA group also demonstrated significantly greater improvement in depressive symptoms [F (3, 156) = 3.35, P = .021] compared to the placebo group throughout the trial period. The patients in the PEA group experienced more response rate (≥ 50% reduction in the HAM-D score) than the placebo group (100% vs. 74% respectively, P = .01) at the end of the trial. Baseline parameters and frequency of side effects were not significantly different between the two groups.

Limitations: The population size in this study was small and the follow-up period was relatively short.

Conclusions: Palmitoylethanolamide adjunctive therapy to citalopram can effectively improve symptoms of patients (predominantly male gender) with major depressive disorder. PEA showed rapid-onset antidepressant effects which need further investigation.

Keywords: Anti-inflammatory; Glutamate; Major Depressive Disorder (MDD); PPAR-α agonists; Palmitoylethanolamide (PEA).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amides
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Antidepressive Agents / therapeutic use*
  • Chemotherapy, Adjuvant
  • Citalopram / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology
  • Double-Blind Method
  • Drug Therapy, Combination
  • Ethanolamines / therapeutic use*
  • Female
  • Humans
  • Male
  • Palmitic Acids / therapeutic use*
  • Treatment Outcome


  • Amides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antidepressive Agents
  • Ethanolamines
  • Palmitic Acids
  • Citalopram
  • palmidrol

Associated data

  • IRCT/IRCT201508201556N97