Utilization of Cannabidiol in Post-Organ-Transplant Care

Abstract

Cannabidiol (CBD) is one of the major phytochemical constituents of cannabis, Cannabis sativa, widely recognized for its therapeutic potential. While cannabis has been utilized for medicinal purposes since ancient times, its psychoactive and addictive properties led to its prohibition in 1937, with only the medical use being reauthorized in 1998. Unlike tetrahydrocannabinol (THC), CBD lacks psychoactive and addictive properties, yet the name that suggests its association with cannabis has significantly contributed to its public visibility. CBD exhibits diverse pharmacological properties, most notably anti-inflammatory effects. Additionally, it interacts with key drug-metabolizing enzyme families, including cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT), which mediate phase I and phase II metabolism, respectively. By binding to these enzymes, CBD can inhibit the metabolism of co-administered drugs, which can potentially enhance their toxicity or therapeutic effects. Mild to moderate adverse events associated with CBD use have been reported. Advances in chemical formulation techniques have recently enabled strategies to minimize these effects. This review provides an overview of CBD, covering its historical background, recent clinical trials, adverse event profiles, and interactions with molecular targets such as receptors, channels, and enzymes. We particularly emphasize the mechanisms underlying its anti-inflammatory effects and interaction with drugs relevant to organ transplantation. Finally, we explore recent progress in the chemical formulation of CBD in order to enhance its bioavailability, which will enable decreasing the dose to use and increase its safety and efficacy.

Keywords: adverse events; cannabidiol; cannabis plant chemical constituent; chemical formulation; cytochrome P450; drug–drug interaction; inflammation; organ transplant; pharmacodynamics; pharmacokinetics.

Figure 1

Chemical structure of cannabidiol (CBD) (from PubChem website, PubChem CID: 644019; molecular formular C₂₁H₃₀O₂; MW: 314.5 g/mol).

Figure 2

Hypothetical mechanisms of action of anti-inflammatory effects by exposure to CBD through TRPV1. Activation of TRPV1 and desensitizing TRPV1 in neuronal and non-neuronal cells. Activation of the TRPV1 channel triggers Ca²⁺ influx, which leads to increased intracellular calcium concentration and initiation of secondary signaling pathways, stimulating PKC, PKA, and CaMKII. Overload of Ca²⁺ or prolonged influx of Ca²⁺, dephosphorylation of the channel takes place, and the channel becomes unable to respond to further stimulation, desensitizing the TRPV1 channel [80,103,104,105,106,107,108,109]. PKC: protein kinase C, PKA: protein kinase A, CaMKII: calmodulin-dependent protein kinase II.

Figure 3

Anti-inflammatory effect of CBD through activation of PPARγ. FABP (especially FABP5) serves as an intracellular transporter of CBD. CBD binds to the ligand-binding domain (LBD) of PPARγ, which initiates transrepression with a specific DNA region called the peroxisome proliferator hormone response element (PPRE) and produces transrepression effects, suppressing the transcription activities of NF-κB and the nuclear factor of activated T cells (NFAT), etc., and blocks the downstream signaling of them, suppressing the expression of, for example, IL-2, TNFα, IL-1β, IL-6, MMP9, and IFNγ [121,134,135,136]. Arrow in the grey box show the decrease in the amount. Other arrows show the process.

Figure 4

GPR55 is a seven-transmembrane receptor coupled to Gα12,13 proteins. It activates RhoA and ROCK and the PLC pathway, which causes an increase in intracellular Ca²⁺. Increase of Ca²⁺ triggers phosphorylation of ERK, activates p38 mitogen-activated protein kinase, and the downstream signaling of NFAT, NF-κB, CREB, ATF2.

Figure 5

Indirect influences of increasing the activation of CB1 and CB2 through competitive binding to FABP. CBD is an antagonist/inverse agonist and allosteric modulator of CB1 and CB2, and this can negatively affect other molecules’ binding affinity to CB1 and CB2 receptors [58]. However, CBD can indirectly activate CB1 and CB2 by binding to FABP, suppressing the binding of FABP to AEA (illustrated on top right), and increasing the levels of AEA, which binds and activates CB1 and CB2. FABP: fatty acid binding protein, AEA: anandamide, FAAH: fatty acid amide hydrolase. The arrow next to AEA show the increase in the amount and other arrows show the process.

Figure 6

Effects of CBD on adenosine receptors. Binding of CBD to the adenosine receptors increases the intracellular cAMP levels, the levels of PKA, and activation of CREB [163]. This will lead to the suppression of transcriptional activity of NF-κB/p65 and suppression of pro-inflammatory cytokine expression [163]. Thick arrows indicate the process, and thin arrows show increase/decrease in the amount.

Figure 7

Influence of CBD on molecular switch to produce anti-inflammatory M2-monocyte-derived-macrophages. CBD increases specialized pro-resolving mediators by stimulating phospholipase A2 enzyme-dependent polyunsaturated fatty acid release and by increasing 12/15-LOX. It also suppresses 5-LOX leukotriene production [16]. M2-MDM: M2-monocyte-derived macrophage, LOX: lipoxygenase. Thick arrows show the process, and thin arrows show increase/decrease in the amount.

Figure 8

Depending on the types of CYPs that metabolize CBD, the derivatives are different. Bioactive properties of them are not thoroughly determined yet, and some show contradictory results.

Figure 9

Chemical structure of tacrolimus (FK506) (from PubChem website, PubChem CID: 445643; molecular formula C₄₄H₆₉NO₁₂; MW: 804.0 g/mol). Inhibitors of CYP3A, such as ketoconazole, cyclosporin A, nifedipine [183], SKF525A, troleandomycin suppressed metabolism of tacrolimus (FK506) [185].

Figure 10

Possible effects of CBD on suppressing tacrolimus metabolism of post-organ transplant patients. (A) Post-kidney transplant patients have an elevated immune response caused by surgical injury and a foreign substance, the transplanted kidney. Antigens on antigen-presenting cells, such as major histocompatibility (MHC) molecules, are detected by T cell receptors (TCR), which stimulates calcium influx through CARC, which is sensed by calmodulin (CaM) and activates a calcineurin signaling cascade. Ca²⁺ binds to CaM and calcineurin, and calcineurin dephosphorylate nuclear factor of an activated T cell (NFAT), which translocates to the nucleus and initiates activation of lymphocytes. (B) When tacrolimus is present, it binds to calcineurin and blocks the calcineurin signaling cascade. (C) If tacrolimus is metabolized by CYP or UGT, calcineurin signaling cascades proceed. (D) If CBD is present, it interacts with CYP or UGT, and tacrolimus can block the calcineurin signaling cascade.

Figure 11

Chemical structure of cyclodextrin. (PubChem CID: 320760; image was retrieved from PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/320760; access date 8 January 2025).