Phytocannabinoids in the treatment of depression and opioid use disorder

• Grant number: 24/19611-4
• Support Opportunities: Generation Project Research Grant
• Start date: February 01, 2026
• End date: January 31, 2031
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Amanda Juliana Sales
• Grantee: Amanda Juliana Sales
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• City of the host institution: Ribeirão Preto
• Associated researchers: Fabricio de Araujo Moreira ; Felipe Villela Gomes ; Francisco Silveira Guimaraes ; João Francisco Cordeiro Pedrazzi ; José Alexandre de Souza Crippa ; Pedro Henrique Gobira Nunes ; Sâmia Regiane Lourenço Joca
• Associated scholarship(s): 26/04604-8 - Phytocannabinoids in the treatment of depression and opioid use disorder, BP.IC; 26/01267-0 - Phytocannabinoids in the treatment of depression and opioid use disorder, BP.GR

Abstract

The plant Cannabis sativa contains over 200 phytocannabinoids, including cannabidiol (CBD) and cannabigerol (CBG), which demonstrate therapeutic potentials in various psychiatric disorders such as depression and substance use disorder. Both disorders involve alterations in the reward system responsible for the reinforcing effects of substance abuse, enhancing feelings of reward and pleasure while reinforcing drug-seeking behavior. Depression is often characterized by anhedonia, which refers to a reduced ability to experience pleasure. This symptom is linked to dysfunctions in the brain's reward system, particularly involving the mesocorticolimbic dopaminergic system, which includes the ventral tegmental area (VTA) and its projections to the nucleus accumbens (NAc) and prefrontal cortex (PFC), crucial for the reward process.Our group's research has been pioneering in demonstrating the involvement of different mechanisms of action associated with various molecular targets, contributing to the beneficial in vivo effects of CBD, the main non-psychotomimetic constituent of cannabis. CBD shows promise in modulating the reward system, interacting with the serotonergic system and increasing serotonin release in the PFC, which is essential for its rapid antidepressant-like effect. In addition to improving mood, this increase in serotonin would facilitate signaling of brain-derived neurotrophic factor (BDNF) - tyrosine kinase B (TrkB), promoting neuroplasticity and synaptogenesis in the PFC, essential for the sustained antidepressant-like effect of CBD. Although there has been an exponential increase in the number of studies investigating these compounds, the pharmacological aspects related to the observed effects are not completely understood.Epigenetic mechanisms, such as DNA methylation and histone acetylation, play important roles in modulating psychiatric disorders and the action of phytocannabinoids. Our group's study was pioneering in demonstrating that CBD modulates methylation in vivo, affecting the transcription of genes involved in mood disorders. Additionally, the increase in histone acetylation, primarily associated with increased transcription of genes related to the endocannabinoid system (ECS, a possible target for direct or indirect action of phytocannabinoids), is linked to the development of psychiatric disorders. However, the involvement of epigenetic mechanisms in the effects of CBD remains underexplored.CBG, one of the most prevalent non-psychotomimetic constituents of cannabis, has garnered increasing interest in recent years; however, its effects on depression and substance abuse are poorly understood. CBG interacts with the ECS and modulates the release of neurotransmitters, including serotonin and norepinephrine, which have been associated with its antidepressant and anxiolytic effects. Thus, CBG may influence behaviors associated with substance abuse, but so far, there is no direct evidence of this effect. While in vitro studies suggest that CBG modulates epigenetic mechanisms, no in vivo studies have been conducted to date. Additionally, its potential interaction with CBD in these disorders has not been investigated.In light of this, this project aims to continue research on the pharmacological properties of phytocannabinoids, particularly CBD and CBG, seeking to investigate: 1) the effects of acute (rapid and sustained) and chronic use of CBD and CBG in animal models of depression and substance dependence, especially resulting from opioid use, given that the opioid crisis is a concerning situation requiring urgent control; and 2) the involvement of DNA methylation and histone acetylation in vivo in the effects of CBD and/or CBG in these contexts. (AU)