Functional interactions between cannabinoids, omega‐3 fatty acids, and peroxisome proliferator‐activated receptors: Implications for mental health pharmacotherapies

Abstract

Cannabis contains a plethora of phytochemical constituents with diverse neurobiological effects. Cannabidiol (CBD) is the main non-psychotropic component found in cannabis that is capable of modulating mesocorticolimbic DA transmission and may possess therapeutic potential for several neuropsychiatric disorders. Emerging evidence also suggests that, similar to CBD, omega-3 polyunsaturated fatty acids may regulate DA transmission and possess therapeutic potential for similar neuropsychiatric disorders. Although progress has been made to elucidate the mechanisms underlying the therapeutic properties of CBD and omega-3s, it remains unclear through which receptor mechanisms they may produce their purported effects. Peroxisome proliferator-activated receptors are a group of nuclear transcription factors with multiple isoforms. PPARγ is an isoform activated by both CBD and omega-3, whereas the PPARα isoform is activated by omega-3. Interestingly, the activation of PPARγ and PPARα with selective agonists has been shown to decrease mesocorticolimbic DA activity and block neuropsychiatric symptoms similar to CBD and omega-3s, raising the possibility that CBD and omega-3s produce their effects through PPAR signaling. This review will examine the relationship between CBD, omega-3s, and PPARs and how they may be implicated in the modulation of mesocorticolimbic DAergic abnormalities and associated neuropsychiatric symptoms.

Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement

“…For example, Murphy and colleagues found that CBD and THC co-administration in adolescent mice prevented deficits in working memory, anxiety, and compulsive-like behaviors [108] (Table 1). Although the mechanisms are not yet fully elucidated, CBD may either antagonize THC effects via negatively modulating an allosteric site of CBRs [109] or interacting with other molecular substrates [101,[110][111][112]. For instance, CBD has been found to exert its therapeutic properties by increasing serum levels of endogenous AEA, potentially through inhibition of the enzyme fatty acid amide hydrolase (FAAH) [113].…”

Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders

“…PPARα and PPARγ, which are members of an important class of nuclear hormone receptors (PPARs), are additional targets of endocannabinoids. 103,104 Although the data are more significant for some cannabinoids, such as N-oleoylethanolamine (OEA) and Npalmitoylethanolamine (PEA), neuroprotective, antiinflammatory and analgesic effects have been considered to be mediated, in part, by their activation of PPARs. However, there are a myriad of factors influencing the interactions between cannabinoids and PPARs that need to be elucidated.…”

Special issue editorial: Cannabinoid signalling in the brain: New vistas

“…Future research will confirm if this can also be the case in other neuropsychiatric conditions. Moreover, in relation with neuropsychiatric disorders, Jung et al (2020) reviewed the relevant literature on the potential link between cannabinoids (especially cannabidiol), omega‐3 fatty acids, and peroxisome proliferator‐activated receptors in the regulation of neuropsychiatric alterations. Specifically, they propose how this relationship might be involved in the modulation of dopaminergic abnormalities often associated with neuropsychiatric symptoms.…”