Opioid use disorder (OUD) represents one of the most severe public health crises, with more than 2 million individuals affected in the United States. Existing treatments do not target and restore several key alterations triggering opioid craving and relapse, including increased response to stress, mood disturbances and greater sensitivity to pain, which are caused by prolonged exposure to opioids. This double-blind, randomized, placebo-controlled study will investigate the effects that palmitoylethanolamide (PEA), an endogenous molecule part of the endocannabinoid system available as a dietary supplement, exerts on these alterations and their underlying mechanisms, with the goal of identifying a novel therapeutic approach to reduce craving and prevent relapse in patients with OUD.

Inclusion Criteria:

• Age 18 to 65

• DSM-5 diagnosis of OUD

• English speaking

• Receiving either buprenorphine or methadone for treatment of opioid use disorder for at least 3 consecutive months prior to enrollment

• Receiving a stable dose of buprenorphine or methadone for the duration of the study

• Agreeable to abstaining from using any cannabis or CBD products two weeks prior to enrollment in the study, and for the duration of the trial

• For women of childbearing potential: agreeable to use one of the following:

  • hormonal methods, such as birth control pills, patches, injections, vaginal rings, or implants
  • barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm)
  • intrauterine device (IUD)
  • abstinence (no sex)

Exclusion Criteria:

• DSM-5 diagnosis of moderate-to-severe cannabis use disorder, alcohol use disorder, and/or psychostimulant use disorder [medical record review and health history form]
• Active, recurrent substance use within the last 3 months that will interfere with study participation and completion of study procedures [medical record review and health history form]
• History of psychotic, bipolar and schizoaffective disorders [medical record review and health history form]
• Lifetime psychiatric hospitalization or suicide attempt, as assessed by the health history form
• Recent history (within 2 years) of major depressive disorder [health history form and clinical interview]
• Currently pregnant or breastfeeding (female only) [pregnancy test/ self-reported]
• History of autoimmune or chronic inflammatory diseases [health history form] Current use of medications known to alter inflammatory and immune response [health history form] Raynaud's disease [health history form]
• BMI >45
• Hepatic liver enzymes greater than 3x upper normal limit
• Vital signs: HR ≤60 or ≥100, SBP ≤90 or ≥160, DBP ≤50 or ≥100, RR < 12 or > 20
• Recent history of clinically significant medical conditions including, but not limited to, malignancy (and treatment for malignancy), HIV, immunological, endocrine (including uncontrolled diabetes or thyroid disease), renal, GI, or hematological abnormalities that are uncontrolled* [health history form and medical record review]