Table 3.

Summary of the drug–drug interactions of CBD with microtubule-targeting agents.

Microtubule-Targeting Agents
CT	Aim	Model	Administration	CBD c	CT c	Evaluation Time	Special Condition	Results of Combined Treatment	References
VBT	Viability	CCRF-CEM, CEM/ VLB100		10 µM	0.1 nM to 10 µM	72 h		Increased toxicity	Holland et al. (2006) [25]
	Viability, combination index, apoptosis	AXA, Orig, and SH cell lines		0.03–300 μM; IC50: 5.77; 5.30, and 5.48μM (and derived concentration series)	0.01–10 μM; IC50: 2.51; 2.23; and 3.09 μM (and derived concertation series)	24 h	0.1% FBS	Increased toxicity	Inkol et al. (2021) [81]
PTX	Cold and mechanical allodynia	C57Bl/6 mice female and male	IP	5 or 10 mg/kg daily on days 1–14	1, 2, 4 or 8 mg/kg on days 1, 3, 5, and 7	Testing every 3–10 day (for 66 days)	Cold allodynia—acetone; mechanical allodynia—von Frey filaments	Attenuation of cold and mechanical allodynia	Ward et al. (2011) [89]
	Mechanical allodynia	female C57Bl/6 mice	IP	2.5–10 mg/kg 15 min before PTX	4, 8 mg/kg on days 1, 3, 5 and 7	Weekly for 10 weeks	von Frey monofilaments	Attenuation of mechanical allodynia	Ward et al. (2014) [90]
	Viability	LN 231, 4T1		1–4 µM	2,5–35 µM	48 h		Increased toxicity
	Mechanical allodynia	Male C57Bl/6 mice	IP	0.625–20 mg/kg 15 min before PTX	8 mg/kg on days 1, 3, 5, and 7	Reassessed on days 9, 14, and 21		attenuation of mechanical allodynia	King et al. (2017) [74]
	CBD-mediated protection against PTX	Dissociated DRG from embryonic rats		10 µM	3 µM	5 h		Knockdown of Mncx-1 attenuated CBD-mediated protection against PTX	Brenneman et al. (2019) [92]
	Viability, pre-administration strategy	MCF-7, MDA-MB-231		2.5, 5 and 10 µM (MCF-7); 1.25, 2.5 and 5 µM (MDA-MB-231) 24 h before PTX	10–500 nM	24 + 48 h		Increased toxicity	Fraguas-Sánches et al. (2020) [94]
	Viability, co-treatment strategy	MCF-7, MDA-MB-231		10, 15 and 20 µM (MCF-7); 5, 7.5 and 10 µM (MDA-MB-231)	10–500 nM	48 h		Increased toxicity
	Viability, combination studies	MCF-7, MDA-MB-231		CBD in solution 5 or 10 µM daily; CBD-Mps (single administration), started 24 h before PTX	10–500 nM	24 + 48 h		Increased toxicity with both formulations
	Tumour growth	MDA-MB-231 grafted onto CAM membrane	Topically	CBD in solution 100 µM daily, CBD-Mps ones (single administration) 24 h before PTX	100 µM	24 + 48 h		Reduced tumour growth
	Viability, pre-administration study	SKOV-3		1 and 10 µM for 24 h before PTX	10–500 nM	24 + 48 h		Increased toxicity with 10 µM CBD	Fraguas-Sánches et al. (2020) [70]
	Viability, coadministration study	SKOV-3		10, 15, and 20 µM	10–500 nM	48 h		Increased toxicity
	Viability, pre- and coadministration study	SKOV-3		CBD in solution 10 µM daily; CBD-Mps (single administration), started 24 h before paclitaxel	10–500 nM	24 + 48 h		Increased toxicity (Mps are more effective)
	Tumour growth	SKOV-3	Topically	CBD in solution 100 µM daily, CBD-Mps once (single administration) 24 before PTX	100 µM	24 + 36 h		Reduced tumour growth
	Viability	PANC-1 and MiaPaCa-2		6.25, 12.5, 25 µM	1.75, 3.5, 7 µM	72 h		Increased toxicity	Luongo et al. (2020) [39]
	Viability and synergy study	MCF7		CBD:PTX (1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, and 9:1, v/v)		72 h		Found the most synergistic ration	Alsherbiny et al. (2021) [95]
	Apoptosis and necrosis	MCF7		64.6 µM	0.1 µM	24 h		Enhanced cell deaths (CBD toxic itself)
	Viability, DNA synthesis	HT29		0.5–10 µM	10 nM	72 h		No effect	Sainz-Cort et al. (2020) [96]
	Viability, DNA synthesis	AGS, SW480		0.5–10 µM	2 and 10 nM	72 h		No effect at viability, increased inhibition of DNA synthesis
	Viability	Ishikawa		3.92 µg/ml	0.0015 and 0.003 µg/ml	72 h		Increased toxicity	Marinelli et al. (2020) [69]
	Mechanical sensitivity	Male C57Bl/6	IP	2.5 mg/kg on days 1, 3, 5 and 7; 15 min before PTX	8 mg/kg on days 1, 3, 5 and 7	Days −3, −2, −1, and 14	von Frey monofilaments	Prevention against the development of mechanical sensitivity	Foss et al. (2021) [93]
	Mechanical sensitivity	Male C57Bl/6	PO, IP	0.25, 2.5, 25 mg/kg on days 1, 3, 5 and 7; 15 min before PTX	8 mg/kg on days 1, 3, 5 and 7	Days −3, −2, −1, and 14	von Frey monofilaments	Prevention against the development of mechanical sensitivity
	Mechanical sensitivity	Male C57Bl/6	IP	20 mg/kg on days 12, 13 and 14	8 mg/kg on days 1, 3, 5 and 7	Days −3, −2, −1, 11, and 14	von Frey monofilaments	CBD did not reverse mechanical sensitivity
DTX	Xenograft growth	Male MF-1 nude mice	IP+IV	100 mg/kg CBD-BDS daily	5 mg/kg once weekly	4–5 weeks observation		Different results according to xenograft origin	De Petrocellis et al. (2013) [99]
	Viability and proliferation	LNCaP, DU-145		1–25 µM	increasing concentration	72 h		Effect modulated by CBD concentration and sera presence
	Viability and synergy study	MCF7		CBD:DTX (1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, and 9:1, v/v)		72 h		Found the most synergistic ration	Alsherbiny et al. (2021) [95]
	Apoptosis, necrosis	MCF7		39.75 µM	0.5 µM	24 h		Increased apoptosis and necrosis
VCT	Mechanical allodynia	Male C57Bl6 mice	IP	1.25–10 mg/kg 15 min before VCT	0.1 mg/kg daily for 7 days	Days 5, 10, 15, and 22		No effect	King et al. (2017) [74]
	VCT accumulation	Hu ovarian carcinoma cell line 2008/MRP1		2–100 µM 30 min before VCT	100 nM	30 + 90 min	Absence of serum	Increased VCT intracellular concentration	Holland et al. (2008) [102]
	Viability	Canine neoplastic cell lines		0.34, 0.67, 1.25, 2.5, 5, 10, 20 g/ml	0.25–6.6 nM	48 h		Reduced cell proliferation	Henry et al. (2021) [103]
	Disease progression	Patients with high-grade glioma		100–450 mg/day	Standard PCV therapy		Surgical resection + radiotherapy	Improved health condition	Dall’Stella et al. (2018) [104]

c: concentration; CAM: chicken chorioallantoic membrane; CBD: cannabidiol; CT: chemotherapeutics; DRG: dorsal root ganglion; DTX: docetaxel; Hu: human; IP: intraperitoneal; IV: intravenous; Mps: microparticles; PO: per os; PTX: paclitaxel; VBT: vinblastine; VCT: vincristine.