Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review

Abstract

Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as potential moderators of the neuropsychiatric effects and pharmacokinetics of CBD. In this case, 300 articles were screened, retrieved from searches in PubMed/Medline, Scopus, Google Scholar, PsycInfo and CINAHL, though only 12 met our eligibility criteria: eight studies in preclinical models and four studies in humans. Among the preclinical studies, three suggested that sex may influence long-term effects of gestational or adolescent exposure to CBD; two found no impact of sex on CBD modulation of addiction-relevant effects of Δ⁹-tetrahydrocannabinol (THC); two found antidepressant-like effects of CBD in males only; and one found greater plasma and liver CBD concentrations in females compared to males. Among the human studies, two found no sex difference in CBD pharmacokinetics in patient samples, one found greater plasma CBD concentrations in healthy females compared to males, and one found no evidence of sex differences in the effects of CBD on responses to trauma recall in patients with post-traumatic stress disorder (PTSD). No studies were identified that considered the role of gender in CBD treatment effects. We discuss potential implications and current limitations of the existing literature.

Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats

“…A major limitation of this study was that it was only performed in male rats. Sex differences have been reported in the pharmacokinetics of cannabidiol [ 45 , 46 ]. In addition, limited clinical data in humans indicated three female participants withdrew from study due to nausea and/or vomiting, which may indicate that females are more sensitive to kratom than males [ 8 , 10 ].…”

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors

“…Previous studies investigating CBD antinociceptive sex differences found either similar results ( Greene et al, 2018 ; Linher-Melville et al, 2020 ) or no significant sex differences ( Britch et al, 2017 , 2020 ). Conversely, pharmacokinetic analysis has revealed that females have higher CBD concentrations following acute or repeated dosing ( Matheson et al, 2022 ). Lacking further pharmacokinetic and pharmacodynamic studies, it is premature to speculate as to why CBD was more effective in male mice ( Lucas et al, 2018 ).…”

Decoding the Postulated Entourage Effect of Medicinal Cannabis: What It Is and What It Isn’t

“…Depending on study parameters, the compounds show differing, sometimes biphasic, affinities and effects at different targets, thus highlighting the contradictory and equivocal evidence state. For a more extensive review on cannabinoid mechanisms of action and pharmacological effects, see these extensive reviews on the subject: Morales et al [ 24 ], Stasiulewicz et al [ 196 ], Almeida et al [ 197 ], Oultram et al [ 198 ], Vitale et al [ 25 ], Peng et al [ 199 ], Matheson et al [ 200 ], Odieka et al [ 71 ], and Castillo-Arellano et al [ 26 ]. Abbreviations: 5-hydroxytryptamine receptor 1A (5-HT-1A); 5-hydroxytryptamine receptor 3A (5-HT-3A); adrenergic receptor alpha-1 (A1A); adrenergic receptor alpha-2 (A2A); anandamide endocannabinoid (AEA); cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2); delta-opioid receptor (DOR); dopamine D2 receptor (D2); fatty acid amide hydrolase enzyme (FAAH); gamma-aminobutyric acid type A receptor (GABA-A); glycine receptor (GlyR); glycine receptor type α 1 (GlyR-α1); glycine receptor type α 3 (GlyR-α3); G-protein-coupled receptor 2 (GPR2); G-protein-coupled receptor 3 (GPR3); G-protein-coupled receptor 6 (GPR6); G-protein-coupled receptor 12 (GPR12); G-protein-coupled receptor 18 (GPR18); G-protein-coupled receptor 55 (GPR55); Mu-opioid receptor (MOR); peroxisome proliferator-activated receptor gamma (PPAR-γ); transient receptor potential cation channel type A1 (TRPA1); transient receptor potential cation channel 8 (TRPM8); transient receptor potential vanilloid type 1 (TRPV1); transient receptor potential vanilloid type 2 (TRPV2); transient receptor potential vanilloid type 3 (TRPV3); transient receptor potential vanilloid type 4 (TRPV4).…”