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Pottosin, I. Cannabidiol (CBD). Encyclopedia. Available online: https://encyclopedia.pub/entry/20888 (accessed on 14 July 2025).
Pottosin I. Cannabidiol (CBD). Encyclopedia. Available at: https://encyclopedia.pub/entry/20888. Accessed July 14, 2025.
Pottosin, Igor. "Cannabidiol (CBD)" Encyclopedia, https://encyclopedia.pub/entry/20888 (accessed July 14, 2025).
Pottosin, I. (2022, March 22). Cannabidiol (CBD). In Encyclopedia. https://encyclopedia.pub/entry/20888
Pottosin, Igor. "Cannabidiol (CBD)." Encyclopedia. Web. 22 March, 2022.
Cannabidiol (CBD)
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This entry is adapted from the peer-reviewed paper 10.3390/ph15030366

Cannabidiol (CBD), a major non-psychotropic component of cannabis, is receiving growing attention as a potential anticancer agent. CBD suppresses the development of cancer in both in vitro (cancer cell culture) and in vivo (xenografts in immunodeficient mice) models. There is utterly need for the development of novel CBD formulations in a combination with synergic traditional anticancer drugs, using nanocarriers to improve the CBD biavailability in preclinicala and clinical trials.  

anticancer activity anticancer treatment adverse effects cannabidiol

1. Introduction

Cannabidiol (CBD) is the most abundant natural cannabinoid found in cannabis plants. The advantage of CBD is the apparent lack of any intoxicating effect. CBD has been proposed for the treatment of pain, insomnia, several psychological conditions, graft-versus-host disease, inflammatory diseases, and cancer [1][2][3][4][5][6][7]. The wide spectrum of biological effects seems to be related to numerous molecular targets for CBD, which include various G-protein-coupled receptors, ion channels and ionotropic receptors, transporter proteins, nuclear receptors, and numerous enzymes involved in lipid, xenobiotic/drug, and mitochondrial metabolism [7][8]. The anticancer properties of CBD are mostly reported in studies in vitro, and to a lesser extent in vivo, whereas clinical studies including cancer patients are still scarce. 

2. CBD Tolerability, Toxicity, and Adverse Effects

CBD’s toxicity against numerous cancer cell lines has been identified, as previously discussed. Although healthy cells have been reported to be less sensitive, the causes and mechanisms of the differential sensitivity of cancer and healthy cells to CBD toxicity are still unclear. Moreover, CBD may target a variety of surface and intracellular molecules (receptors, ion channels/transporters, enzymes) and triggers multiple signaling pathways present in both cancer and healthy cells. Taken together, these facts raise safety and side effect issues. According to traditional protocols, drug toxicity is first tested in pre-clinical animal models. Pre-clinical studies, carried out on animal models, reported acute and chronic adverse effects of CBD on different organs and systems [9][10][11][12][13][14][15][16][17][18][19]. There are several highly recommended comprehensive reviews, which critically analyzed the CBD safety and toxicity experiments carried out in animal pre-clinical and human clinical trials [20][21][22][23][24][25]. The following important observations should be mentioned: (1) regarding the administration route, in most human trials, CBD was administrated orally or by inhalation, whereas predominantly intraperitoneal (i.p.) and intravenous (i.v.) injections and sometimes the oral route were used in animals; (2) CBD pharmacokinetics and molecular targets seem to differ between humans and rodents; these differences should be taken into consideration when extrapolating results obtained in pre-clinical models to humans; (3) regarding the composition, in numerous CBD toxicity reports in humans, patients consumed not pure CBD but different preparations of CBD of unknown concentration and uncertain composition. Many preparations marketed as CBD contain also variable quantities of THC [26]. Since the toxicity profile and side effects caused by THC and CBD are different and THC seems to be more toxic [24], the data obtained in these studies are misleading, reporting the net effect of THC, CBD, and their interaction. Drug–drug interactions represent a very important issue in the case of CBD, because it targets enzymes implicated in drug metabolism and excretion [8]. Thus, it may prolong the presence and increase the toxicity of co-administrated drugs. Taking all the aforementioned factors into consideration, we will restrict ourselves to the most prominent and reliable data concerning the toxicity and adverse effects of CBD.
Obviously, CBD’s tolerability depends on the doses, frequency, routes of administration, and treatment duration. CBD is usually well tolerable during acute and short-lasting treatment in moderate doses. At a range of 3–30 mg/kg (i.p.) or 0.1–30 mg/kg (i.v.), CBD did not change the heart rate, blood pressure, gastrointestinal (GI) transit, respiration, biochemical blood parameters, and hematocrit in rodents [20]. In piglets, CBD doses of 10 mg/kg (i.v.) were well tolerated, whereas higher doses (50 mg/kg) in some cases caused hypotension and cardiac arrest [13][23]. In rhesus monkeys, high CBD doses of 150–300 mg/kg (i.v.) caused acute CNS toxicity (tremor, sedation, and prostration) within 30 min of injection, whereas prolonged treatment for 9 days elicited bradycardia, hypopnea, cardiac failure, liver weight increase, and inhibition of spermatogenesis [10][23]. For the same model (rhesus monkeys), chronic oral CBD application (30–300 mg/kg/day, 90 days) caused systemic negative effects on the liver, heart, kidneys, and thyroids, and inhibited spermatogenesis [10][22][23]. Negative effects of chronic CBD on embryonic development were reported in rats when relatively high doses (75–250 mg/kg/day) were administrated orally during pregnancy, which included developmental toxicity, decreased fetal body weight, increased fetal structural variations, and embryofetal mortality [23].
Clinical reports in humans are scarce, and, obviously, are limited to low and moderate doses. No disturbances in physiological parameters or psychomotor functions were observed in clinical CBD trials after oral administration (15–160 mg), i.v. injection (5–30 mg), or inhalation (0.15 mg/kg) [20]. No side effects were observed during the prolonged CBD treatment of cancer patients (up to 60 mg daily, orally, up to 6 months) [27].
Most of the reliable clinical trials (i.e., double-blind, randomized, placebo-controlled) were performed on patients (children and adults) suffering from treatment-resistant epilepsy or schizophrenia, or related neurologic and psychotic disorders. The CBD dose range utilized in these trials was usually from 0.5 to 50 mg/kg/day or from 200 to 1000 mg/day for psychiatric studies. When CBD was administrated orally (25–50 mg/kg/day) for an extended period (weeks), moderate adverse effects included somnolence and fatigue, sleep disorders, diarrhea and GI intolerance, and respiratory complications, and pneumonia, thrombocytopenia, and liver and blood abnormalities were reported [23][28][29][30][31]. Pyrexia was relatively common in children with Dravet’s or Lennox-Gastaut syndrome during 3- or 4-week treatment trials with doses of 5–20 mg/kg/day administered orally [23][28][29].
Since CBD is suggested to be included in combined anticancer chemotherapy protocols, CBD’s hepatotoxicity, which can cause changes in drug metabolism, is an issue of special importance. A hepatotoxic effect was documented in pre-clinical and clinical studies when relatively high CBD doses were administrated for a prolonged time [20][21][22][23][24][25]. As was revealed by a randomized, double-blind trial that included 171 patients, hepatocellular injury represents the most frequent adverse effect, so it was recommended to test serum transaminases and total bilirubin levels in all patients prior to starting the treatment with Epidiolex®, which is CBD in an oral solution [32][33]. Importantly, CBD targets the cytochrome P450 system and is metabolized by CYP3A4 and CYP2C1 in human liver microsomes (HLMs), giving rise to 6α-OH-, 6β-OH-, 7-OH-, and 4″-OH-CBDs [34]. A female patient, treated for 6 years with tamoxifen, and, additionally, by CBD, which inhibited CYP3A4/5 and CYP2D6, presented a consequent reduction in N-desmethyltamoxifen and active metabolite endoxifen [35]. In cancer patients, especially if they have liver diseases or a poor metabolic profile, possible effects of CBD on cytochromes P450, which in turn can affect the pharmacokinetics of conventional anticancer drugs, need to be considered.

3. Concerning Better CBD Delivery for Cancer Therapy

Satisfactory delivery of anticancer therapeuticals should provide its efficient accumulation in the target cancer tissue, with minimal side systemic effects on other organs. CBD is a highly lipophilic compound, which is poorly soluble in aqueous solutions and highly sensitive to light, temperature, and oxidation, which underlies its relatively low bioavailability [36]. CBD, when administrated orally, can precipitate in the GI tract, resulting in poor GI permeability. It undergoes then the first step of metabolism by liver and gut enzymes and is predominantly excreted through the kidneys [36][37]. As a result of the first step of metabolism, the oral CBD bioavailability is estimated to be between 5% and 19% [36][37]. Variable pharmacokinetics profiles were reported, depending on the means of CBD administration. These include more traditional and better-studied oral/mucosal, inhalation, and smoking, and less explored intravenous routes [38].

3.1. Free CBD Delivery

To date, the only CBD formulation approved by the FDA for the treatment of rare forms of epilepsy is Epidiolex®, CBD in an oral solution (100 mg/mL), with maximum recommended doses of 20 mg/kg/daily. Currently, there are numerous clinical trials of CBD for the treatment of different disorders, including palliative care in cancers, where CBD is delivered predominantly as an oil solution, orally, or via inhalations (https://clinicaltrials.gov/ct2/results?cond=&term=cannabidiol&cntry=&state=&city=&dist=, accessed on 14 February 2022).
Intravenous CBD injection is an alternative delivery method, which prevents GI degradation and has demonstrated better bioavailability. It was tested and compared with other delivery methods in studies in humans and mice (Table 1) [39][40][41]. Intravenous administration caused higher CBD plasma levels than oral administration [41], smoking [39], or inhalation [40] (Table 1). In healthy volunteers, the injection of a 20 mg/kg dose resulted in a rapid rise in the plasma concentration, ranging from 358 to 972 ng/mL (1–3 μM), which was approximately five times higher than by smoking [39]. Although these concentrations are close to the cytotoxicity range reported for some tumors, plasma CBD levels had dropped drastically within 1 h of administration [39]. Similar results were obtained in a murine model, with an immediate plasmatic concentration rise to 3000 ng/mL (approx. 10 μM), when 10 mg/kg was injected, followed by a rapid (within 1 h) tenfold drop [41].
Table 1. Comparative studies of alternative routes of free CBD administration.
Participants Delivery Method
Doses		 Plasma Concentration, ng/mL Reference
Young healthy male volunteers (n = 5) Smoking
20 mg		 Max at 3 min: 110 ± 55
Max at 1 h: 10.2 ± 6.6		 [39]
i.v.
20 mg		 Max at 3 min: 686 ± 239
Max at 1 h: 48.4 ± 10.7
Male ICR mice (n = 3) p.o.
20 mg/kg		 Max at 2 h: 111 ± 52
Max at 4 h: 60 ± 58		 [41]
i.v.
10 mg/kg		 Max at 10 min: 3343 ± 1048
Max at 1 h: 376 ± 229
Healthy male/female volunteers (n = 8/8) p.o.
25 mg		 Max at 3 h: 3.05: range: 1.57–4.54
Max at 8 h: 1		 [42]
p.o., SEDDS
25 mg		 Max at 1 h: 13.53, range: 7.9–19.1
4 h: 2.5
Healthy male/female volunteers inhalation,
THC/CBD
20/20 mg		 5 min (max): 2–17 [40]
i.v.,
THC/CBD
10/10 mg		 Max at 5 min: 14–26
Healthy male/female volunteers p.o., single dose
1500 mg
3000 mg
6000 mg		 Max at 5 h:
292.4 ± 87.9
533.0 ± 35.1
782.0 ± 83.0		 [43]
p.o., multiple dose
2 × 750 mg or
2 × 1500 mg daily		 Max at 7 d:
330
541
Thus, any administration route of free CBD resulted in a transient rise in the plasmatic drug level, where only the maximal levels are comparable to cytotoxic concentrations. Importantly, bioavailability in cancer tissue is expected to be significantly lower than in plasma and highly variable, depending on the cancer type, tumor size, geometry, and vascularization. On the other hand, achieved plasma concentrations are sufficient to cause undesirable side effects. Thus, increasing the dose of pure CBD by any administration method should not be considered as an appropriate strategy for CBD delivery for cancer treatment. Instead, alternative formulations, aimed to increase CBD’s stability and its specific targeting to the cancer tissue, should be developed.

3.2. Nanotechnology May Improve CBD Delivery for Cancer Therapy: General Considerations and Experimental Evidence

Multiple nanoformulations have been proposed to overcome the delivery challenges of hydrophobic unstable drugs such as CBD. There are several excellent comprehensive reviews discussing in detail the best approaches to design nanocarriers (NC) for cancer therapeutics [44][45][46]. There are various important criteria that should be taken into consideration. NC should be composed of biocompatible nontoxic and non-immunogenic materials. According to their chemical structure, NP can be categorized into different groups, such as inorganic, polymeric, liposomas, nanomicelles, etc. In inorganic nanoparticles, the core is composed of metal or metal oxide (silver or gold are frequently used). Polymeric NC are produced using a conjugation of several polymers with desirable characteristics. Liposomes are nanoparticles with an aqueous interior part, surrounded by one or more concentric bilayers of amphipathic lipids (e.g., phospholipids). The design of such NC can be developed according to therapeutic requirements. Their diameter ranges normally from 1 nm to several μM. Consequently, such liposomes can be distributed in the bloodstream (smallest capillary diameter is approximately 5–6 μM) and accumulated in the target tumors. The ultra-filterable range of less than 200 nm provides the possibility for sterilization. Covalent linkage of NC to polyethylene glycol (PEG), so-called PEGylation, decreased significantly their immunogenicity. Moreover, such a modification changes the physicochemical and hydrodynamic properties, which results in a prolonged circulation time and reduced renal clearance [47]. NC easily incorporate drug molecules and form a barrier around therapeutic agents, preventing the premature drug interaction with body fluids and immune cells before their delivery to the target site. A precise design, which takes into consideration the material, size, and shape of NC, may provide drug release in a controlled and predictable fashion. This approach is also useful for the delivery of two or more drugs simultaneously, which can be very useful for cancer treatment, considering multi-drug chemotherapeutic protocols. Moreover, the nature of the core molecules may provide the possibility to combine both hydrophobic and hydrophilic drugs at the same time. In liposomes, hydrophobic drugs are incorporated into the lipid membrane, whereas hydrophilic compounds are present within the central aqueous cavity.
Target-specific drug delivery can significantly decrease side effects and increase the therapeutic index of encapsulated drugs. Passive and active targeting of nanoparticles can be used for cancer therapy. Passive targeting is possible due to the phenomenon known as the enhanced permeability and retention (EPR) effect in solid tumors [45][48][49][50][51]. In rapidly growing tumor tissue, characterized by the overexpression of vascular endothelial growth factor (VEGF), the microvasculature is characterized by a chaotic ramification with enhanced endothelial porosity or fenestration, in contrast to the tighter endothelial structures of normal capillaries. As a result of the changed cytoarchitecture, the blood flow is slower, and, due to the high porosity, tumor capillaries are leaky. Both these factors ensure the retention of enlarged particles, such as NC, in tumors. In hematological malignances, the bone marrow (BM) leukemic niche is the target tissue. Blood vessels supplying BM (sinusoids) possess the fenestrations and are semipermeable, providing favorable conditions for the accumulation of NC [52]. At the same time, the EPR effect was reported to provide a relatively modest, twofold enhancement of the nanodrug retention in tumor tissues, when compared with healthy organs [53].
The surface of NC can be modified to improve their targeting to tumors. A variety of ligands/antibodies to specific antigens, expressed by cancer cells, can be proposed for NC surface engineering [44]. Dual-action CXCR4-targeting liposomes were developed and proposed for drug delivery and the simultaneous blockage of the CXCR4/CXCL12 axis for leukemia treatment [54]. HER2-targeted liposomes were accumulated in the tumor tissue of patients with HER2-positive breast cancer [55]. The RGD (arginyl/glycyl/aspartic acid) motif was proposed to target integrins to tumor cells [56]. Anionic liposomes were shown to accumulate in BM and were then predominantly adsorbed by leukemic cells [52]. Hyaluronic acid, which shows a high binding affinity for the CD44 adhesion molecule, is present at enhanced concentrations in a variety of tumors and was also proposed for NC modification [57][58]. Experimental trials of novel delivery methods for CBD in cancer therapy are still scarce but have demonstrated promising results (Table 2) [59][60][61][62][63][64][65][66].
Table 2. Novel formulations proposed for cannabinoid delivery.
Carrier System Structural Details Models Tested Administration Route Advantages Concerns and Limitations Reference
Inorganic nanoparticles Gold drones loaded with CBD In vivo: transgenic mouse model bearing lung adenocarcinoma Inhalation
i.v.		 Improved:
Stability
Bioavailability
Retention in tumors		 Loading concentration
Drone size for EPR		 [59]
Nano-micelles Poly(styrene-co-maleic anhydride), cumene-terminated (SMA) micelles loaded with WIN In vitro: breast cancer cell lines Added to growth medium Improved:
Stability
Bioavailability
Retention in tumors		 Loading concentration
Micelle size for EPR		 [60]
In vivo:
Female Balb/c mice bearing 4T1 mammary carcinoma		 i.v.
Polymeric microparticles CBD-loaded poly-ε-caprolactone microparticles In vivo:
murine xenograft (glioblastoma) model		 Local delivery Long-lasting CBD delivery Optimal particle size for better drug delivery [61]
CBD-loaded PLGA microparticles (25 μM) In vitro and in ovo: breast or ovarian cancer cell lines Added to growth medium or inoculated in chicken embryos PLGA is FDA-approved
Long-lasting delivery
Possibility for multi-drug codelivery		 Particle sterilization caused polymer erosion
Particle size should be optimized to be suitable for bloodstream circulation		 [62][63]
Lipid nanoparticles CBD-loaded and CBD-decorated (functionalized) lipid nanoparticles In vitro:
glioma cell lines		 Added to growth medium Enhanced targeting and crossing of BBB
Enhanced tumor targeting
Biocompatible
Biodegradable		 Nanoparticle stability in organism [64][65]
In vivo:
murine xenograft (glioma) model		 i.v.
Proteinoid nanoparticles CBD-loaded Poly(RGD) proteinoid nanoparticles In vitro:
Colon carcinoma and breast cancer Cell lines		 Added to growth medium Cancer tissue targeting   [66]
In vivo:
Athymic mice bearing colon and breast cancer xenografts		 i.v.
Gold PEGylated nanodrones were proposed recently to target lung cancer with cannabinoids and radiosensitizers [59]. The efficiency of two administration routes, inhalation and intravenous, was tested in transgenic mouse models bearing lung adenocarcinoma. The particle size (100 nm) was optimized to ensure an increased circulation time and efficient tumor uptake. Additionally, drones were functionalized with the RGD (arginyl/glycyl/aspartic acid) motif to target integrin receptors on the lung tumor cells’ surface. Both administration routes provided efficient nanodrone penetration into the tumor tissue, but the inhalation route was more promising for this tumor type. CBD was proposed to be conjugated to the amine groups present on the PEG. However, CBD-conjugated drones have not been tested yet.
The efficiency of a micellar delivery system for targeting cannabinoids to cancer tissue was tested in a murine model of triple-negative breast cancer [60]. In this case, micelles were loaded with the synthetic cannabinoid WIN55,212-2. The average micelle size was 152 nm, ensuring their accumulation in the tumor by the EPR. WIN, being conjugated with the micellar system, efficiently inhibited tumor growth. Remarkably, predominant micelle accumulation in the tumor was demonstrated, indicating the viability of the micellar system for its use with cannabinoids.
CBD-loaded poly-ε-caprolactone microparticles, as an alternative delivery system for long-term CBD administration, demonstrated their efficiency in inhibiting glioblastoma growth and tumor angiogenesis in a murine xenograft model [61].
More recently, poly-(lactic-co-glycolic acid), PLGA, microparticles, loaded with CBD, were tested for their potential to improve the conventional chemotherapy of breast and ovarian cancers [62][63]. PLGA is approved by the FDA for use in parenteral release systems. The mean particle size was around 25 μM, with a high entrapment efficiency in the tumor tissue. Particles were sterilized by gamma irradiation (25 kGy). Since sterilization accelerates the polymer erosion, a CBD:polymer ratio (10:100) was selected to ensure a durable release profile. Remarkably, a single administration of this formulation ensures the antitumor activity in vitro for at least 10 days. CBD-loaded microparticles were effective as a monotherapy, but synergism with DEX (breast cancer) and paclitaxel (breast and ovarian cancer) allowed a more pronounced effect at a single administration. However, a particle size in the μM range is not suitable for intravenous injections, because only particles smaller than 5 μM can freely circulate in the bloodstream and reach the tumor site. Afterwards, PLGA CBD-loaded nanocarriers for i.p. administration in ovarian cancer treatment were developed, which demonstrated improved CBD stability, its long-lasting release, internalization by cancer cells, and anticancer efficiency [63].
Drug delivery to brain malignancies such as glioma/glioblastoma is restricted by the blood–brain barrier (BBB). Aparicio-Blanco and colleagues proposed the original strategy of non-immunologic BBB targeting using NC decorated (functionalized) with CBD [64][65]. They elaborated small lipid nanoparticles with a size range of 10–100 nm, carrying CBD on their surface, which were able to pass through the BBB. CBD-decorated particles were suggested to target the brain endothelium, which expresses different surface molecules able to bind CBD, namely the CB1 receptor, the G-protein-coupled receptor 55 (GPR55), and serotonin receptor 5-HT. After the brain endothelium transcytosis, these particles were expected to target glioma cells overexpressing CB1/2 receptors. As far as CBD was reported to be cytotoxic for glioma, lipid nanoparticles were loaded with CBD and tested as prolonged-release carriers for glioma therapy [64][65]. This strategy was demonstrated to enhance the glioma targeting, and a combination of CBD loading with CBD functionalization significantly reduced the IC50 values. CBD decoration was confirmed to enhance the passage of lipid nanoparticles across the BBB both in vitro (human brain endothelial hCMEC/D3 cells) and in vivo (mouse glioma xenograft models).
An RGD proteinoid polymer was synthesized and used to encapsulate CBD [66]. Resulting nanoparticles inhibited tumor growth in xenograft mouse models of colorectal and breast cancer and were proposed for further trials.
The possibility of the delivery of two or more drugs simultaneously by nanocarriers is of special interest for the inclusion of CBD into chemotherapeutic protocols, taking into the account the fact that CBD improves the effect of various anticancer drugs. Importantly, there are several anticancer drugs that are already clinically used in liposomal formulations for chemotherapeutic protocols [67]. Among them are doxorubicin (Doxil®, 1995 and Myocet®, 2000), danourobicin (DaunoXome®, 1996), cytarabine (Depocyt®, 1999), mifamurtide (Mepact®, 2004), vincristine (Marquibo®, 2012), and irinotecan (OnivydeTM, 2015). Recently, pure CBD, encapsulated in a lipid bilayer for enhanced CBD delivery (liposomal CBD), was developed by InnoCanFarma (https://www.newsfilecorp.com/release/72614/Innocan-Pharma-Announces-Successful-Production-of-CBD-Loaded-Liposomes-under-Aseptic-Conditions, accessed on 14 February 2022).

References

  1. Zuardi, A.W.; Crippa, J.A.; Hallak, J.E.; Bhattacharyya, S.; Atakan, Z.; Martin-Santos, R.; McGuire, P.K.; Guimarães, F.S. A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Curr. Pharm. Des. 2012, 18, 5131–5140.
  2. Massi, P.; Solinas, M.; Cinquina, V.; Parolaro, D. Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 2012, 75, 303–312.
  3. Yeshurun, M.; Shpilberg, O.; Herscovici, C.; Shargian, L.; Dreyer, J.; Peck, A.; Israeli, M.; Levy-Assaraf, M.; Gruenewald, T.; Mechoulam, R.; et al. Cannabidiol for the prevention of graft-versus-host-disease after allogeneic hematopoietic cell transplantation: Results of a phase II Study. Biol. Blood Marrow Transplant. 2015, 21, 1770–1775.
  4. Christensen, A.; Pruskowski, J. The role of cannabidiol in palliative care #370. J. Palliat. Med. 2019, 22, 337–338.
  5. Sunda, F.; Arowolo, A. A molecular basis for the anti-inflammatory and anti-fibrosis properties of cannabidiol. FASEB J. 2020, 34, 14083–14092.
  6. Seltzer, E.S.; Watters, A.K.; MacKenzie, D., Jr.; Granat, L.M.; Zhang, D. Cannabidiol (CBD) as a promising anti-cancer drug. Cancers 2020, 12, 3203.
  7. Mangal, N.; Erridge, S.; Habib, N.; Sadanandam, A.; Reebye, V.; Sodergren, M.H. Cannabinoids in the landscape of cancer. J. Cancer Res. Clin. Oncol. 2021, 147, 2507–2534.
  8. Mlost, J.; Bryk, M.; Starowicz, K. Cannabidiol for pain treatment: Focus on pharmacology and mechanism of action. Int. J. Mol. Sci. 2020, 21, 8870.
  9. Rosenkrantz, H.; Hayden, D.W. Acute and subacute inhalation toxicity of Turkish marihuana, cannabichromene, and cannabidiol in rats. Toxicol. Appl. Pharmacol. 1979, 48, 375–386.
  10. Rosenkrantz, H.; Fleischman, R.W.; Grant, R.J. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicol. Appl. Pharmacol. 1981, 58, 118–131.
  11. Hložek, T.; Uttl, L.; Kadeřábek, L.; Balíková, M.; Lhotková, E.; Horsley, R.R.; Nováková, P.; Šíchová, K.; Štefková, K.; Tylš, F.; et al. Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of con- version in vivo of CBD to THC. Eur. Neuropsychopharmacol. 2017, 27, 1223–1237.
  12. Center for Drug Evaluation and Research. Non-Clinical Reviews. US FDA Report. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000PharmR.pdf (accessed on 24 January 2022).
  13. Garberg, H.T.; Solberg, R.; Barlinn, J.; Martinez-Orgado, J.; Løberg, E.M.; Saugstad, O.D. High-dose cannabidiol induced hypotension after global hypoxia-ischemia in piglets. Neonatology 2017, 112, 143–149.
  14. ElBatsh, M.M.; Assareh, N.; Marsden, C.A.; Kendall, D.A. Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology 2012, 221, 239–247.
  15. Schiavon, A.P.; Bonato, J.M.; Milani, H.; Guimarães, F.S.; Weffort de Oliveira, R.M. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016, 64, 27–34.
  16. Schuel, H.; Schuel, R.; Zimmerman, A.M.; Zimmerman, S. Cannabinoids reduce fertility of sea urchin sperm. Biochem. Cell Biol. 1987, 65, 130–136.
  17. Schuel, H.; Berkery, D.; Schuel, R.; Chang, M.C.; Zimmerman, A.M.; Zimmerman, S. Reduction of the fertilizing capacity of sea urchin sperm by cannabinoids derived from marihuana. I. Inhibition of the acrosome reaction induced by egg jelly. Mol. Reprod. Dev. 1991, 29, 51–59.
  18. Narimatsu, S.; Watanabe, K.; Matsunaga, T.; Yamamoto, I.; Imaoka, S.; Funae, Y.; Yoshimura, H. Inhibition of hepatic microsomal cytochrome P450 by cannabidiol in adult male rats. Chem. Pharm. Bull. 1990, 38, 1365–1368.
  19. Carvalho, R.K.; Santos, M.L.; Souza, M.R.; Rocha, T.L.; Guimarães, F.S.; Anselmo-Franci, J.A.; Mazaro-Costa, R. Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice. J. Appl. Toxicol. 2018, 38, 1545.
  20. Bergamaschi, M.M.; Queiroz, R.H.C.; Zuardi, A.W.; Crippa, J.A.S. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr. Drug Saf. 2011, 6, 237–249.
  21. Iffland, K.; Grotenhermen, F. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis Cannabinoid Res. 2017, 2, 139–154.
  22. Carvalho, R.K.; Andersen, M.L.; Mazaro-Costa, R. The effects of cannabidiol on male reproductive system: A literature review. J. Appl. Toxicol. 2020, 40, 132–150.
  23. Huestis, M.A.; Solimini, R.; Pichini, S.; Pacifici, R.; Carlier, J.; Busardò, F.P. Cannabidiol adverse effects and toxicity. Curr. Neuropharmacol. 2019, 17, 974–989.
  24. Černe, K. Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol. Arch. Ind. Hyg. Toxicol. 2020, 71, 1–11.
  25. Nelson, K.M.; Bisson, J.; Singh, G.; Graham, J.G.; Chen, S.N.; Friesen, J.B.; Dahlin, J.L.; Niemitz, M.; Walters, M.A.; Pauli, G.F. The essential medicinal chemistry of cannabidiol (CBD). J. Med. Chem. 2020, 63, 12137–12155.
  26. Bonn-Miller, M.O.; Loflin, M.J.E.; Thomas, B.F.; Marcu, J.P.; Hyke, T.; Vandrey, R. Labeling accuracy of cannabidiol extracts sold online. JAMA 2017, 318, 1708–1709.
  27. Kenyon, J.; Liu, W.; Dalgleish, A. Report of objective clinical responses of cancer patients to pharmaceutical-grade synthetic cannabidiol. Anticancer Res. 2018, 38, 5831–5835.
  28. Devinsky, O.; Marsh, E.; Friedman, D.; Thiele, E.; Laux, L.; Sullivan, J.; Miller, I.; Flamini, R.; Wilfong, A.; Filloux, F.; et al. Cannabidiol in patients with treatment-resistant epilepsy: An open-label interventional trial. Lancet Neurol. 2016, 15, 270–278.
  29. Devinsky, O.; Cross, J.H.; Laux, L.; Marsh, E.; Miller, I.; Nabbout, R.; Scheffer, I.E.; Thiele, E.A.; Wright, S.; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 2017, 376, 2011–2020.
  30. Koo, C.M.; Kang, H.C. Could cannabidiol be a treatment option for intractable childhood and adolescent epilepsy? J. Epilepsy Res. 2017, 7, 16–20.
  31. Neale, M. Efficacy and safety of cannabis for treating children with refractory epilepsy. Nurs. Child. Young People 2017, 29, 32–37.
  32. Greenwich Biosciences Inc. Epidiolex . U.S. Food and Drug Administration Website. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (accessed on 11 June 2021).
  33. Thiele, E.A.; Marsh, E.D.; French, J.A.; Mazurkiewicz-Beldzinska, M.; Benbadis, S.R.; Joshi, C.; Lyons, P.D.; Taylor, A.; Roberts, C.; Sommerville, K.; et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018, 391, 1085–1096.
  34. Jiang, R.; Yamaori, S.; Takeda, S.; Yamamoto, I.; Watanabe, K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011, 89, 165–170.
  35. Parihar, V.; Rogers, A.; Blain, A.M.; Zacharias, S.R.K.; Patterson, L.L.; Siyam, M.A.M. Reduction in tamoxifen metabolites endoxifen and N-desmethyltamoxifen with chronic administration of low dose cannabidiol: A CYP3A4 and CYP2D6 drug interaction. J. Pharm. Pract. 2020, 897190020972208.
  36. Millar, S.A.; Stone, N.L.; Yates, A.S.; O’Sullivan, S.E. A systematic review on the pharmacokinetics of cannabidiol in humans. Front. Pharmacol. 2018, 9, 1365.
  37. Millar, S.A.; Maguire, R.F.; Yates, A.S.; O’Sullivan, S.E. Towards better delivery of cannabidiol (CBD). Pharmaceuticals 2020, 13, 219.
  38. Bruni, N.; Della Pepa, C.; Oliaro-Bosso, S.; Pessione, E.; Gastaldi, D.; Dosio, F. Cannabinoid delivery systems for pain and inflammation treatment. Molecules 2018, 23, 2478.
  39. Ohlsson, A.; Lindgren, J.E.; Andersson, S.; Agurell, S.; Gillespie, H.; Hollister, L.E. Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration. Biomed. Environ. Mass Spectrom. 1986, 13, 77–83.
  40. Meyer, P.; Langos, M.; Brenneisen, R. Human pharmacokinetics and adverse effects of pulmonary and intravenous THC-CBD formulations. Med. Cannabis Cannabinoids 2018, 1, 36–43.
  41. Xu, C.; Chang, T.; Du, Y.; Yu, C.; Tan, X.; Li, X. Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model. Environ. Toxicol. Pharmacol. 2019, 70, 103202.
  42. Knaub, K.; Sartorius, T.; Dharsono, T.; Wacker, R.; Wilhelm, M.; Schön, C. A novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology improving the oral bioavailability of cannabidiol in healthy subjects. Molecules 2019, 24, 2967.
  43. Taylor, L.; Gidal, B.; Blakey, G.; Tayo, B.; Morrison, G.A. A phase I, Randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs 2018, 32, 1053–1067.
  44. Rosenblum, D.; Joshi, N.; Tao, W.; Karp, J.M.; Peer, D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat. Commun. 2018, 9, 1410.
  45. Alavi, M.; Hamidi, M. Passive and active targeting in cancer therapy by liposomes and lipid nanoparticles. Drug Metab. Pers. Ther. 2019, 34, 20180032.
  46. Morales-Cruz, M.; Delgado, Y.; Castillo, B.; Figueroa, C.M.; Molina, A.M.; Torres, A.; Milián, M.; Griebenow, K. Smart targeting to improve cancer therapeutics. Drug Des. Devel. Ther. 2019, 13, 3753–3772.
  47. Bulbake, U.; Doppalapudi, S.; Kommineni, N.; Khan, W. Liposomal formulations in clinical use: An updated review. Pharmaceutics 2017, 9, 12.
  48. Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986, 46, 6387–6392.
  49. He, C.; Hu, Y.; Yin, L.; Tang, C.; Yin, C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 2010, 31, 3657–3666.
  50. Choi, I.K.; Strauss, R.; Richter, M.; Yun, C.O.; Lieber, A. Strategies to increase drug penetration in solid tumors. Front. Oncol. 2013, 3, 193.
  51. Maeda, H.; Tsukigawa, K.; Fang, J. A retrospective 30 years after discovery of the enhanced permeability and retention effect of solid tumors: Next-generation chemotherapeutics and photodynamic therapy: Problems, solutions, and prospects. Microcirculation 2016, 23, 173–182.
  52. Tardi, P.; Wan, C.P.L.; Mayer, L.J. Passive and semi-active targeting of bone marrow and leukemia cells using anionic low cholesterol liposomes. J. Drug Target 2016, 24, 797–804.
  53. Nakamura, Y.; Mochida, A.; Choyke, P.L.; Kobayashi, H. Nanodrug delivery: Is the enhanced permeability and retention effect sufficient for curing cancer? Bioconjug. Chem. 2016, 27, 2225–2238.
  54. McCallion, C.; Peters, A.D.; Booth, A.; Rees-Unwin, K.; Adams, J.; Rahi, R.; Pluen, A.; Hutchinson, C.V.; Webb, S.J.; Burthem, J. Dual-action CXCR4-targeting liposomes in leukemia: Function blocking and drug delivery. Blood Adv. 2019, 3, 2069–2081.
  55. Lee, H.; Shields, A.F.; Siegel, B.A.; Miller, K.D.; Krop, I.; Ma, C.X.; LoRusso, P.M.; Munster, P.N.; Campbell, K.; Gaddy, D.F.; et al. 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin. Cancer Res. 2017, 23, 4190–4202.
  56. Schleich, N.; Po, C.; Jacobs, D.; Ucakar, B.; Gallez, B.; Danhier, F.; Préat, V. Comparison of active, passive and magnetic targeting to tumors of multifunctional paclitaxel/SPIO-loaded nanoparticles for tumor imaging and therapy. J. Control. Release 2014, 194, 82–91.
  57. Ravar, F.; Saadat, E.; Gholami, M.; Dehghankelishadi, P.; Mahdavi, M.; Azami, S.; Dorkoosh, F.A. Hyaluronic acid-coated liposomes for targeted delivery of paclitaxel, in-vitro characterization and in-vivo evaluation. J. Control. Release 2016, 229, 10–22.
  58. Yu, T.; Li, Y.; Gu, X.; Li, Q. Development of a hyaluronic acid-based nanocarrier incorporating doxorubicin and cisplatin as a pH-sensitive and CD44-targeted anti-breast cancer drug delivery system. Front. Pharmacol. 2020, 11, 532457.
  59. Ngwa, W.; Kumar, R.; Moreau, M.; Dabney, R.; Herman, A. Nanoparticle drones to target lung cancer with radiosensitizers and cannabinoids. Front. Oncol. 2017, 7, 208.
  60. Greish, K.; Mathur, A.; Al Zahrani, R.; Elkaissi, S.; Al Jishi, M.; Nazzal, O.; Taha, S.; Pittalà, V.; Taurin, S. Synthetic cannabinoids nano-micelles for the management of triple negative breast cancer. J. Control. Release 2018, 291, 184–195.
  61. Hernán Pérez de la Ossa, D.; Lorente, M.; Gil-Alegre, M.E.; Torres, S.; García-Taboada, E.; Aberturas, M.; Molpeceres, J.; Velasco, G.; Torres-Suárez, A.I. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme. PLoS ONE 2013, 8, e54795.
  62. Fraguas-Sánchez, A.I.; Fernández-Carballido, A.; Delie, F.; Cohen, M.; Martin-Sabroso, C.; Mezzanzanica, D.; Figini, M.; Satta, A.; Torres-Suárez, A.I. Enhancing ovarian cancer conventional chemotherapy through the combination with cannabidiol loaded microparticles. Eur. J. Pharm. Biopharm. 2020, 154, 246–258.
  63. Fraguas-Sánchez, A.I.; Torres-Suárez, A.I.; Cohen, M.; Delie, F.; Bastida-Ruiz, D.; Yart, L.; Martin-Sabroso, C.; Fernández-Carballido, A. PLGA nanoparticles for the intraperitoneal administration of CBD in the treatment of ovarian cancer: In vitro and in ovo assessment. Pharmaceutics 2020, 12, 439.
  64. Aparicio-Blanco, J.; Romero, I.A.; Male, D.K.; Slowing, K.; García-García, L.; Torres-Suárez, A.I. Cannabidiol enhances the passage of lipid nanocapsules across the blood-brain barrier both in vitro and in vivo. Mol. Pharm. 2019, 16, 1999–2010.
  65. Aparicio-Blanco, J.; Sebastián, V.; Benoit, J.P.; Torres-Suárez, A.I. Lipid nanocapsules decorated and loaded with cannabidiol as targeted prolonged release carriers for glioma therapy: In vitro screening of critical parameters. Eur. J. Pharm. Biopharm. 2019, 134, 126–137.
  66. Lugasi, L.; Grinberg, I.; Margel, S. Targeted delivery of CBD-targeted poly (RGD) protenoid nanoparticles for antitumor therapy. J. Nanomed. Nanotechnol. 2020, 11, 552.
  67. Moosavian, S.A.; Bianconi, V.; Pirro, M.; Sahebkar, A. Challenges and pitfalls in the development of liposomal delivery systems for cancer therapy. Semin. Cancer Biol. 2021, 69, 337–348.
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Igor Pottosin
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