Table 3.

The most important findings in preclinical studies on major cannabinoids and their related compounds.

Class	Compound	Experimental Model	Findings	Reference
CBG	CBG	Mouse model of intestinal inflammation induced with the intracolonic administration of DNBS	Anti-inflammatory effect associated with the downregulation of inflammatory cytokines interleukin-1β, interleukin-10, and interferon-γ and reduction in iNOS expression.	[77]
	CBG CBGA CBGV	In vitro HEK-293 cells stably overexpressing rat recombinant TRPV3 or TRPV4	CBGV and CBGA desensitize TRPV3 to the action of carvacrol at concentrations of EC50 = 0.8 and 7.4 µM. CBGV, CBGA, and CBG desensitize TRPV4 to the action of 4α-phorbol-12,13-didecanoate(4α-PDD) with EC50 values of 1.3–5.4 µM. These compounds desensitize TRPV3 and TRPV4 channels at lower doses than those at which they stimulate these channels.	[76]
	CBG CBGV	HEK-293 cells stably overexpressing human TRPV1	CBG and CBGV stimulated and desensitized human TRPV1.	[72]
	CBG CBGA	COX-1 enzyme, purified from ram seminal vesicles and COX-2 enzyme, purified from sheep placental cotyledons	Inhibition of more than 30% of COX -1 and 292 COX -2 in a concentration-dependent manner.	[78]
	CBG	Computational model of α2A, α2B, and α2C isoforms of murine and human 304 adrenoceptors	Affinity for the receptor appeared higher than that of the α2-adrenergic receptor agonist clonidine.	[152]
CBG	CBG	Mouse skin melanoma cells	Significant antitumor activity (inhibitory concentration (ICs0) = 31.31 gg/mL) in in vitro assay.	[117]
	CBG	Human oral epithelioid carcinoma 308 cell lines (KB) and NIH 3T3 fibroblasts	CBG exhibited the highest growth inhibitory activity against the cancer cell lines.	[118]
	CBG	HEK-293 encoding the rat TRPM8 and overexpressing high levels of TRPM8	Potent TRPM8 antagonist (IC50 = 0.16 ± 0.02).	[72]
CBG	CBG	Two human colon adenocarcinoma cell lines (Caco-2 and HCT 116, ATCC); Mouse azoxymethane (AOM) model of colon carcinogenesis	CBG inhibits the growth of CRC cells mainly via a pro-apoptotic mechanism and hinders the development and the growth of colon carcinogenesis in vivo.	[111]
		Mouse brain membranes	CBG activates α2-adrenoreceptors and blocks 5-HT1A receptors, antagonizing the 5-HT1A receptor agonist R-(+)-8-hydroxy-2-(di-n-propylamino) tetralin.	[86]
	CBG	TMEV (Thaler’s murine encephalomyelitis virus)-induced demyelinating disease (TMEV-IDD) in SJL/J mice	Anti-inflammatory and neuroprotective effects through the inhibition of IL-1β and IL-6 cytokines, and downregulation of PGE2 synthesis. CBG and CBG-quinone inhibited the microglia inflammatory response, protected neurons from toxic insults.	[124]
CBG	CBG	Mouse model of Huntington’s disease (HD), created using 3-Nitropropionate i.p. repeated administration	Neuroprotective effects by downregulating the proinflammatory markers COX-2, 367 iNOS, IL-6, and TNF-α, by preventing neuronal degradation, downregulating disease-associated genes SgKL and CD44, and normalizing specific protein-1 levels.	[125]
	CBG	In vitro model of neuro inflammation on NSC-34 motor neurons	Pretreatment with CBG (7.5 μM) improved viability in treated cells through the inhibition of cell apoptosis, reduction in IL-1β, TNF-α, IFN-γ, and PPAR-γ proinflammatory protein levels, reduction in oxidative stress, and upregulation of Nrf-2 levels.	[74]
	CBG	MC65 human neuron-like cell lines treated to induce intra-neuronal Alzheimer’s disease cell alterations	CBG blocked cell death, reduced oxidative damage, and prevented neurons from accumulating toxic β-amyloid protein.	[126]
	CBG	Male Lister hooded rats	Doses between 120 and 140 mg/ kg of CBG induced a dose-dependent increase in food intake, increased the number of meals taken, decreased the latency until the first meal, and improved locomotor activity.	[128]
	CBG	Standard S. aureus strain (ATCC 25923) and a clinical isolate (XU212) MRSA strain	Antibacterial properties.	[110]
		Methicillin-resistant S. aureus 404 (MRSA) strain; murine systemic infection model caused by MRSA	In vitro disruption of the cytoplasmatic membrane of MRSA. In vivo efficacy against MRSA.	[129]
	CBG	Keratinocyte proliferation assay	CBG had an inhibitory action on keratinocyte proliferation in a CB1/CB2 receptor-independent manner.	[130]
		Human keratinocytes (HaCaT cells)	CBG acted as a transcriptional repressor controlling cell proliferation and differentiation through a mechanism that involved increasing DNA methylation on the keratin-10 gene.	[131]
	CBG CBGA	Human recombinant and pig kidney aldose reductase	Both compounds showed statistically significant ALR2 inhibitory activity by being able to interact with the major active site of the enzyme.	[79]
CBG	CBG	HEK-293 cells stably overexpressing human TRPV1	Stimulates and desensitizes TRPV1 channels with an of EC50 = 21.0 ± 1.25.	[72]
		Colon cancer cells and normal colon cell lines	Cytotoxic activity on colon cancer cells, but reduced activity on normal colon cell lines.	[120]
	CBGV	HEK-293 cells encoding the rat TRPV2 and expressing high levels of TRPV2	Antagonizes TRPV2 channels with an EC50 = 1.7 μM.	[72]
CBD	CBD	Murine (mouse) model of depression	CBD reduced immobility time in mice undergoing forced swimming test, the effect being similar to that produced by antidepressants such as imipramine.	[85]
	CBD	Mouse model of autism spectrum disorders	10–20 mg/kg acute administration of CBD determined an improvement in social behavior.	[89]
	CBD	Alzheimer’s disease mouse model	20 mg/kg sub-chronic administration of CBD reversed cognitive deficits in object recognition memory and social recognition memory.	[153]
	CBD	PTSD determined by yohimbine HCl (Tocris) administration in Wistar rats	10 mg/kg acute administration came with therapeutic benefits for post-traumatic stress disorder symptoms.	[154]
	CBD	Human breast cancer cell lines MDA-MB231 and MDA-MB436	Significantly decreased Id-1 expression in metastatic breast cancer cells, leading to the downregulation of tumor aggressiveness.	[155]
CBD	CBDV	HEK-293 cells stably overexpressing human TRPV1 HEK-293 cells encoding the rat TRPV2 and expressing high levels of TRPV2 HEK-293 cells over- expressingTRPA1 HEK-293 encoding the rat TRPM8 and overexpressing high levels of TRPM8	Stimulates TRPV1 channels. Stimulates TRPV2 channels. Stimulates TRPA1 channels. Antagonizes TRPM8 channels.	[72]
		hGPR55-HEK293 cells	Antagonizes GPR55 channels.	[148]
	CBD	43-day-old rats received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the conditioned place preference (CPP) paradigm (8 days), when each experimental group was re-assigned to receive CBD at two different doses (5 or 10 mg/kg, i.p) or control, for 5 days	CBD treatment prevented amphetamine relapse behavior in rats that had previously exhibited amphetamine-conditioned place preference, modulated immunoreactivity of dopaminergic targets in the prefrontal cortex and ventral striatum, areas with major involvement in drug dependence. CBD maintains dopamine transport levels.	[27]
	CBD	Mouse genetic model of Dravet syndrome (DS)	CBD reduced the frequency, severity, and duration of spontaneous seizures through the antagonization of GPR55 receptors.	[89]
		Mecp2 mutant mice, a model of Rett syndrome (RTT)	CBDV rescues recognition memory deficits in Mecp2 mutant mice and delays the appearance of neurological defects.	[149]
		Mouse model for Rett syndrome, caused by mutations in the MECP2 gene	CBDV proved to attenuate brain alterations, restore the compromised general status, increase sociability, and partially restore motor coordination in treated mice. Molecularly, CBDV has antagonistic properties on GPR55.	[144]
	CBD	Double AD transgenic mouse model (APP/PS1)	CBD inhibited tau hyperphosphorylation and reduced Aβ production.	[26]
CBD	CBD	Wistar rat model of neuropathic pain (Bennet and Xie’s NP model (1988))	CBD modulates chronic neuropathic pain and depression-specific behavior by activating 5-HT1A and CB1 receptors in the prefrontal cortex.	[83]
	CBDV	Autism-like behavior models through prenatal valproic acid exposure in rats	CBDV ameliorated behavioral abnormalities, restored hippocampal endocannabinoid signaling, and decreased neuroinflammation.	[149]
	CBDV	In vitro model of ischemic stroke obtained by exposing cells to ischemic conditions through oxygen–glucose deprivation	CBDV has neuroprotective and anti-inflammatory properties.	[151]
	CBDV	IBD mouse model of DNBS- and DSS-induced colitis	CBDV (orally or intraperitoneally) reduced the specific signs of colon inflammation–neutrophil infiltration, and increased colon weight and intestinal permeability.	[91]
		Human colonic tissues from children with active ulcerative colitis	In vitro treatment with CBGV produced a significant reduction in the proinflammatory cytokine levels (IL-1β).
	CBDA	Mouse model of Dravet syndrome (Scn1aRX/+ mice)	CBDA exhibited significant anticonvulsant properties through a mechanism that could involve the 5-HT1A, GPR55, or TRPV1 receptors.	[136]
		Rodent models of carrageenan-induced inflammatory pain	I.p. administration of CBDA at 60 min before carrageenan produced anti-inflammatory and anti-hyperalgesia effects.	[135]
		MDA-MB-231 breast cancer cell model	CBDA inhibited cell migration through a mechanism that is supposed to involve the activation of RhoA and through the inhibition of cAMP-dependent protein kinase A.	[94]
		Rat models of acute lithium chloride-induced nausea	CBDA suppresses nausea and vomiting in rats through the activation of the serotonin 1A receptor (5-HT1A).	[92,93]
THC	Δ9-THC	Murine model of concanavalin A (ConA)-induced hepatitis	Intraperitoneal administration of THC inhibited hepatitis by significant decrease in liver enzymes and reduced liver tissue injury. THC treatment significantly suppressed inflammatory cytokines in ConA-induced hepatitis.	[156]
	Δ9-THC	Splenocytes of C57BL/6 mice	In vitro THC treatment significantly reduced proliferative response to mitogens, including anti-CD3 monoclonal antibodies (mAbs), concanavalin A (Con A), and lipopolysaccharide (LPS).	[157]
	Δ9-THC	Sprague Dawley male rats	Δ9-THC therapy inhibited acetylcholinesterase, reduced amyloid-β levels and hippocampal neurogenesis, and induced brain-derived neurotrophic factor release through mixed CB1 and CB2 modulation.	[9,117]
	Δ9-THC	Genes encoding human, mouse, and rat TRPV2	Δ9-THC is a potent TRPV2 agonist.	[101]
	Δ8-THC	Water-deprived albino rats	Groups treated with 5.0 and 10.0 mg/kg of Δ8-THC reduced intake of food at 1 day post-injection.	[158]
	THCV	Rat recombinant TRPV3- and TRPV4-expressing HEK-293 cells	Stimulates TRPV3 with high efficacy (50–70% of the effect of ionomycin) and potency (EC50 = 3.7 μM) and TRPV4 with moderate-high efficacy (30–60% of the effect of ionomycin) and potency (EC50 = 0.9–6.4 μM) [76].	[76]
	Δ9-THCA	HEK-293T, Neuro-2a (N2a), STHdh Q7/Q7, and STHdh Q111/Q111 cells, which express either a wild-type or a mutated form of the huntingtin protein	Δ9-THCA activated PPARγ and increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdh Q111/Q111 cells and by mutHtt-q94 in N2a cells. Δ9-THCA showed potent neuroprotective activity, worth consideration for the treatment of Huntington’s disease and possibly other neurodegenerative and neuroinflammatory diseases.	[104]
	Δ9-THCA-A	Mouse model of HFD significantly induced obesity	Administration of Δ9-THCA-A reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis, and macrophage infiltration in fat tissues.	[159]

CBG, cannabigerol; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 1; TRPM8, Transient Receptor Potential Melastatin-8; TRPV1, vanilloid receptor 1; α2-Adrenoceptor, alpha-2-Adrenoceptor; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon gamma; PPAR-γ, peroxisome proliferator-activated receptor gamma; Nrf-2 levels, nuclear factor E2-related factor 2; TRPA1, transient receptor potential ankyrin 1; TRPV3, transient receptor potential vanilloid-3; TRPV4, transient receptor potential vanilloid-type 4; iNOS expression, inducible nitric oxide synthase expression; CBGV, cannabigerovarin; CBGA, cannabigerolic acid; CBD, cannabidiol; CBDV, cannabidivarin; CBDA, cannabidiolic acid; COX-1, COX-2, Cyclooxygenase-1, Cyclooxygenase-2; SOD, superoxide dismutase; PLA2, Phospholipase A2; MAGL, monoacylglycerol lipase; PPARα/γ, peroxisome proliferator-activated receptors α/γ; GPR55, G protein-coupled receptor 55; CBDV, cannabidivarin; TRPV2, transient receptor potential vanilloid 2; GPR6, G Protein-Coupled Receptor 6; DAGLα, diacylglycerol lipase-alpha; AEA, N-arachidonoylethanolamine (anandamide); 5HT1A, 5-hydroxytryptamine receptor 1A; cAMP protein kinase A, cyclic adenosine monophosphate protein kinase A; THC, tetrahydrocannabinol; Δ9-THC, Δ9-trans-tetrahydrocannabinol; MDSCs, myeloid-derived suppressor cells; AchE, acetylcholinesterase; Δ8-THC, Δ8-trans-tetrahydrocannabinol; THCA-A, tetrahydrocannabinolic acid; IBD, inflammatory bowel disease; ConA, concanavalin A; mAbs, monoclonal antibodies; LPS, lipopolysaccharide; i.p., intraperitoneal; DNBS, dinitrobenzene sulphonic acid; DSS, dextran sulfate sodium; AD, Alzheimer’s disease.