Molecular Targets of Cannabidiol in Neurological Disorders.

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Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ

Molecular Targets of Cannabidiol in Neurological Disorders.

Neurotherapeutics. 2015 Oct;12(4):699-730. doi: 10.1007/s13311-015-0377-3.

PubMed ID

26264914 [ View in PubMed

]

Abstract

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD's effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD's therapeutic mechanism of action.

DrugBank Data that Cites this Article

Drugs

Cannabidiol

Medical Cannabis

Nabiximols

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cannabidiol	3-hydroxy-3-methylglutaryl-coenzyme A reductase	Protein	Humans	Unknown	Stimulator	Details
Cannabidiol	5-hydroxytryptamine receptor 1A	Protein	Humans	Unknown	Agonist	Details
Cannabidiol	5-hydroxytryptamine receptor 2A	Protein	Humans	Unknown	Agonist	Details
Cannabidiol	Acetyl-CoA acetyltransferase, mitochondrial	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Catalase	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Cytochrome P450 1A2	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Cytochrome P450 1B1	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Cytochrome P450 2D6	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Cytochrome P450 3A5	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Cytochrome P450 3A7	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Delta-type opioid receptor	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	G-protein coupled receptor 55	Protein	Humans	Unknown	Antagonist	Details
Cannabidiol	Glutathione peroxidase 1	Protein	Humans	Unknown	Stimulator	Details
Cannabidiol	Glutathione reductase, mitochondrial	Protein	Humans	Unknown	Stimulator	Details
Cannabidiol	Glycine receptor (alpha-1/beta) (Protein Group)	Protein group	Humans	Unknown	Allosteric modulator	Details
Cannabidiol	Glycine receptor subunit alpha-1	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	Glycine receptor subunit alpha-3	Protein	Humans	Unknown	Potentiator	Details
Cannabidiol	Indoleamine 2,3-dioxygenase 1	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Mu-type opioid receptor	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	N-acylethanolamine-hydrolyzing acid amidase	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	N-arachidonyl glycine receptor	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	NAD(P)H dehydrogenase [quinone] 1	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Neuronal acetylcholine receptor subunit alpha-7	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	Peroxisome proliferator-activated receptor gamma	Protein	Humans	Unknown	Activator	Details
Cannabidiol	Prostaglandin G/H synthase 1	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Prostaglandin G/H synthase 2	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Serotonin N-acetyltransferase	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Steroid 17-alpha-hydroxylase/17,20 lyase	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Transient receptor potential cation channel subfamily A member 1	Protein	Humans	Unknown	Agonist	Details
Cannabidiol	Transient receptor potential cation channel subfamily M member 8	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	Transient receptor potential cation channel subfamily V member 1	Protein	Humans	Unknown	Activator	Details
Cannabidiol	Transient receptor potential cation channel subfamily V member 2	Protein	Humans	Unknown	Activator	Details
Cannabidiol	Transient receptor potential cation channel subfamily V member 3	Protein	Humans	Unknown	Activator	Details
Cannabidiol	Voltage-dependent anion-selective channel protein 1	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	Voltage-dependent T-type calcium channel subunit alpha-1G	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	Voltage-dependent T-type calcium channel subunit alpha-1H	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	Voltage-dependent T-type calcium channel subunit alpha-1I	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	3-hydroxy-3-methylglutaryl-coenzyme A reductase	Protein	Humans	Unknown	Inducer	Details
Medical Cannabis	5-hydroxytryptamine receptor 1A	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	5-hydroxytryptamine receptor 2A	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Acetyl-CoA acetyltransferase, mitochondrial	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Cannabinoid receptor 1	Protein	Humans	Yes	Negative modulator	Details
Medical Cannabis	Catalase	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Delta-type opioid receptor	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Fatty-acid amide hydrolase 1	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	G-protein coupled receptor 55	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Glutathione peroxidase 1	Protein	Humans	Unknown	Inducer	Details
Medical Cannabis	Glutathione reductase, mitochondrial	Protein	Humans	Unknown	Inducer	Details
Medical Cannabis	Glycine receptor (alpha-1/beta) (Protein Group)	Protein group	Humans	Unknown	Not Available	Details
Medical Cannabis	Glycine receptor subunit alpha-1	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Glycine receptor subunit alpha-3	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Indoleamine 2,3-dioxygenase 1	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Mu-type opioid receptor	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	N-acylethanolamine-hydrolyzing acid amidase	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	N-arachidonyl glycine receptor	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Neuronal acetylcholine receptor subunit alpha-7	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Peroxisome proliferator-activated receptor gamma	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Phospholipase A2	Protein	Humans	Unknown	Inhibitor Inducer	Details
Medical Cannabis	Prostaglandin G/H synthase 1	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Prostaglandin G/H synthase 2	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Quinone oxidoreductase	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Serotonin N-acetyltransferase	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Sphingomyelin phosphodiesterase	Protein	Humans	Unknown	Inducer	Details
Medical Cannabis	Steroid 17-alpha-hydroxylase/17,20 lyase	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Transient receptor potential cation channel subfamily A member 1	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Transient receptor potential cation channel subfamily M member 8	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Transient receptor potential cation channel subfamily V member 1	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Transient receptor potential cation channel subfamily V member 2	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Transient receptor potential cation channel subfamily V member 3	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Voltage-dependent anion-selective channel protein 1	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Voltage-dependent T-type calcium channel subunit alpha-1G	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Voltage-dependent T-type calcium channel subunit alpha-1H	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Voltage-dependent T-type calcium channel subunit alpha-1I	Protein	Humans	Unknown	Not Available	Details
Nabiximols	3-hydroxy-3-methylglutaryl-coenzyme A reductase	Protein	Humans	Unknown	Stimulator	Details
Nabiximols	5-hydroxytryptamine receptor 1A	Protein	Humans	Unknown	Not Available	Details
Nabiximols	5-hydroxytryptamine receptor 2A	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Acetyl-CoA acetyltransferase, mitochondrial	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Catalase	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Cytochrome P450 1A1	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Cytochrome P450 1A2	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Cytochrome P450 1B1	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details
Nabiximols	Cytochrome P450 3A5	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Cytochrome P450 3A7	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Delta-type opioid receptor	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Fatty-acid amide hydrolase 1	Protein	Humans	Unknown	Inhibitor Inducer	Details
Nabiximols	G-protein coupled receptor 55	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Glutathione peroxidase 1	Protein	Humans	Unknown	Stimulator	Details
Nabiximols	Glutathione reductase, mitochondrial	Protein	Humans	Unknown	Stimulator	Details
Nabiximols	Glycine receptor (alpha-1/beta) (Protein Group)	Protein group	Humans	Unknown	Not Available	Details
Nabiximols	Glycine receptor subunit alpha-1	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Glycine receptor subunit alpha-3	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Indoleamine 2,3-dioxygenase 1	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Mu-type opioid receptor	Protein	Humans	Unknown	Not Available	Details
Nabiximols	N-acylethanolamine-hydrolyzing acid amidase	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	N-arachidonyl glycine receptor	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Neuronal acetylcholine receptor subunit alpha-7	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Peroxisome proliferator-activated receptor gamma	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Prostaglandin G/H synthase 1	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Prostaglandin G/H synthase 2	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Quinone oxidoreductase	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Serotonin N-acetyltransferase	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Transient receptor potential cation channel subfamily A member 1	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Transient receptor potential cation channel subfamily M member 8	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Transient receptor potential cation channel subfamily V member 1	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Transient receptor potential cation channel subfamily V member 2	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Transient receptor potential cation channel subfamily V member 3	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Voltage-dependent anion-selective channel protein 1	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Voltage-dependent T-type calcium channel subunit alpha-1G	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Voltage-dependent T-type calcium channel subunit alpha-1H	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Voltage-dependent T-type calcium channel subunit alpha-1I	Protein	Humans	Unknown	Not Available	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Cannabidiol	Arachidonate 15-lipoxygenase	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Arachidonate 5-lipoxygenase	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Cytochrome P450 1A1	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details
Cannabidiol	Cytochrome P450 2C9	Protein	Humans	No	Substrate Inhibitor	Details
Cannabidiol	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details
Cannabidiol	Fatty-acid amide hydrolase 1	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Quinone oxidoreductase	Protein	Humans	Unknown	Not Available	Details
Cannabidiol	Serotonin N-acetyltransferase	Protein	Humans	Unknown	Not Available	Details
Medical Cannabis	Arachidonate 15-lipoxygenase	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Arachidonate 5-lipoxygenase	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Cytochrome P450 1A1	Protein	Humans	Unknown	Inhibitor Inducer	Details
Medical Cannabis	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details
Medical Cannabis	Cytochrome P450 1B1	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details
Medical Cannabis	Cytochrome P450 2C9	Protein	Humans	No	Substrate Inhibitor Inducer	Details
Medical Cannabis	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details
Medical Cannabis	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details
Medical Cannabis	Cytochrome P450 3A5	Protein	Humans	Unknown	Substrate Inhibitor	Details
Medical Cannabis	Cytochrome P450 3A7	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Superoxide dismutase [Cu-Zn]	Protein	Humans	Unknown	Not Available	Details
Nabiximols	Arachidonate 15-lipoxygenase	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Arachidonate 5-lipoxygenase	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate	Details
Nabiximols	Cytochrome P450 2C9	Protein	Humans	No	Substrate	Details
Nabiximols	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cannabidiol	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Equilibrative nucleoside transporter 1	Protein	Humans	Unknown	Inhibitor	Details
Cannabidiol	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Equilibrative nucleoside transporter 1	Protein	Humans	Unknown	Inhibitor	Details
Medical Cannabis	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Equilibrative nucleoside transporter 1	Protein	Humans	Unknown	Inhibitor	Details
Nabiximols	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details