Molecular Targets of Cannabidiol in Neurological Disorders.

Article Details

Citation

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
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Cannabidiol3-hydroxy-3-methylglutaryl-coenzyme A reductaseProteinHumans
Unknown
Stimulator
Details
Cannabidiol5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Agonist
Details
Cannabidiol5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Agonist
Details
CannabidiolAcetyl-CoA acetyltransferase, mitochondrialProteinHumans
Unknown
Inhibitor
Details
CannabidiolArylalkylamine N-acetyltransferaseProteinHumans
Unknown
Inhibitor
Details
CannabidiolCatalaseProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 1A2ProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 1B1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 3A5ProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 3A7ProteinHumans
Unknown
Inhibitor
Details
CannabidiolDelta-type opioid receptorProteinHumans
Unknown
Not AvailableDetails
CannabidiolG-protein coupled receptor 55ProteinHumans
Unknown
Antagonist
Details
CannabidiolGlutathione peroxidase 1ProteinHumans
Unknown
Stimulator
Details
CannabidiolGlutathione reductase, mitochondrialProteinHumans
Unknown
Stimulator
Details
CannabidiolGlycine receptor (alpha-1/beta) (Protein Group)Protein groupHumans
Unknown
Allosteric modulator
Details
CannabidiolGlycine receptor subunit alpha-1ProteinHumans
Unknown
Not AvailableDetails
CannabidiolGlycine receptor subunit alpha-3ProteinHumans
Unknown
Potentiator
Details
CannabidiolIndoleamine 2,3-dioxygenase 1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolMu-type opioid receptorProteinHumans
Unknown
Not AvailableDetails
CannabidiolN-acylethanolamine-hydrolyzing acid amidaseProteinHumans
Unknown
Inhibitor
Details
CannabidiolN-arachidonyl glycine receptorProteinHumans
Unknown
Not AvailableDetails
CannabidiolNAD(P)H dehydrogenase [quinone] 1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolNeuronal acetylcholine receptor subunit alpha-7ProteinHumans
Unknown
Not AvailableDetails
CannabidiolPeroxisome proliferator-activated receptor gammaProteinHumans
Unknown
Activator
Details
CannabidiolProstaglandin G/H synthase 1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolProstaglandin G/H synthase 2ProteinHumans
Unknown
Inhibitor
Details
CannabidiolSteroid 17-alpha-hydroxylase/17,20 lyaseProteinHumans
Unknown
Inhibitor
Details
CannabidiolSuperoxide dismutase [Cu-Zn]ProteinHumans
Unknown
Inhibitor
Details
CannabidiolTransient receptor potential cation channel subfamily A member 1ProteinHumans
Unknown
Agonist
Details
CannabidiolTransient receptor potential cation channel subfamily M member 8ProteinHumans
Unknown
Not AvailableDetails
CannabidiolTransient receptor potential cation channel subfamily V member 1ProteinHumans
Unknown
Activator
Details
CannabidiolTransient receptor potential cation channel subfamily V member 2ProteinHumans
Unknown
Activator
Details
CannabidiolTransient receptor potential cation channel subfamily V member 3ProteinHumans
Unknown
Activator
Details
CannabidiolVoltage-dependent anion-selective channel protein 1ProteinHumans
Unknown
Not AvailableDetails
CannabidiolVoltage-dependent T-type calcium channel subunit alpha-1GProteinHumans
Unknown
Not AvailableDetails
CannabidiolVoltage-dependent T-type calcium channel subunit alpha-1HProteinHumans
Unknown
Not AvailableDetails
CannabidiolVoltage-dependent T-type calcium channel subunit alpha-1IProteinHumans
Unknown
Not AvailableDetails
Medical Cannabis3-hydroxy-3-methylglutaryl-coenzyme A reductaseProteinHumans
Unknown
Inducer
Details
Medical Cannabis5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Not AvailableDetails
Medical Cannabis5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Not AvailableDetails
Medical CannabisAcetyl-CoA acetyltransferase, mitochondrialProteinHumans
Unknown
Inhibitor
Details
Medical CannabisArylalkylamine N-acetyltransferaseProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCannabinoid receptor 1ProteinHumans
Yes
Negative modulator
Details
Medical CannabisCatalaseProteinHumans
Unknown
Inhibitor
Details
Medical CannabisDelta-type opioid receptorProteinHumans
Unknown
Not AvailableDetails
Medical CannabisFatty-acid amide hydrolase 1ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisG-protein coupled receptor 55ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisGlutathione peroxidase 1ProteinHumans
Unknown
Inducer
Details
Medical CannabisGlutathione reductase, mitochondrialProteinHumans
Unknown
Inducer
Details
Medical CannabisGlycine receptor (alpha-1/beta) (Protein Group)Protein groupHumans
Unknown
Not AvailableDetails
Medical CannabisGlycine receptor subunit alpha-1ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisGlycine receptor subunit alpha-3ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisIndoleamine 2,3-dioxygenase 1ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisMu-type opioid receptorProteinHumans
Unknown
Not AvailableDetails
Medical CannabisN-acyl-phosphatidylethanolamine-hydrolyzing phospholipase DProteinHumans
Unknown
Inhibitor
Details
Medical CannabisN-acylethanolamine-hydrolyzing acid amidaseProteinHumans
Unknown
Inhibitor
Details
Medical CannabisN-arachidonyl glycine receptorProteinHumans
Unknown
Not AvailableDetails
Medical CannabisNeuronal acetylcholine receptor subunit alpha-7ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisPeroxisome proliferator-activated receptor gammaProteinHumans
Unknown
Not AvailableDetails
Medical CannabisPhospholipase A2ProteinHumans
Unknown
Inhibitor
Inducer
Details
Medical CannabisProstaglandin G/H synthase 1ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisProstaglandin G/H synthase 2ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisQuinone oxidoreductaseProteinHumans
Unknown
Inhibitor
Details
Medical CannabisSphingomyelin phosphodiesteraseProteinHumans
Unknown
Inducer
Details
Medical CannabisSteroid 17-alpha-hydroxylase/17,20 lyaseProteinHumans
Unknown
Inhibitor
Details
Medical CannabisSuperoxide dismutase [Cu-Zn]ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisTransient receptor potential cation channel subfamily A member 1ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisTransient receptor potential cation channel subfamily M member 8ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisTransient receptor potential cation channel subfamily V member 1ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisTransient receptor potential cation channel subfamily V member 2ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisTransient receptor potential cation channel subfamily V member 3ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisVoltage-dependent anion-selective channel protein 1ProteinHumans
Unknown
Not AvailableDetails
Medical CannabisVoltage-dependent T-type calcium channel subunit alpha-1GProteinHumans
Unknown
Not AvailableDetails
Medical CannabisVoltage-dependent T-type calcium channel subunit alpha-1HProteinHumans
Unknown
Not AvailableDetails
Medical CannabisVoltage-dependent T-type calcium channel subunit alpha-1IProteinHumans
Unknown
Not AvailableDetails
Nabiximols3-hydroxy-3-methylglutaryl-coenzyme A reductaseProteinHumans
Unknown
Stimulator
Details
Nabiximols5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Not AvailableDetails
Nabiximols5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Not AvailableDetails
NabiximolsAcetyl-CoA acetyltransferase, mitochondrialProteinHumans
Unknown
Inhibitor
Details
NabiximolsArylalkylamine N-acetyltransferaseProteinHumans
Unknown
Inhibitor
Details
NabiximolsCatalaseProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 1A1ProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 1A2ProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 1B1ProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 2D6ProteinHumans
Unknown
Substrate
Inhibitor
Details
NabiximolsCytochrome P450 3A5ProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 3A7ProteinHumans
Unknown
Inhibitor
Details
NabiximolsDelta-type opioid receptorProteinHumans
Unknown
Not AvailableDetails
NabiximolsFatty-acid amide hydrolase 1ProteinHumans
Unknown
Inhibitor
Inducer
Details
NabiximolsG-protein coupled receptor 55ProteinHumans
Unknown
Not AvailableDetails
NabiximolsGlutathione peroxidase 1ProteinHumans
Unknown
Stimulator
Details
NabiximolsGlutathione reductase, mitochondrialProteinHumans
Unknown
Stimulator
Details
NabiximolsGlycine receptor (alpha-1/beta) (Protein Group)Protein groupHumans
Unknown
Not AvailableDetails
NabiximolsGlycine receptor subunit alpha-1ProteinHumans
Unknown
Not AvailableDetails
NabiximolsGlycine receptor subunit alpha-3ProteinHumans
Unknown
Not AvailableDetails
NabiximolsIndoleamine 2,3-dioxygenase 1ProteinHumans
Unknown
Inhibitor
Details
NabiximolsMu-type opioid receptorProteinHumans
Unknown
Not AvailableDetails
NabiximolsN-acylethanolamine-hydrolyzing acid amidaseProteinHumans
Unknown
Inhibitor
Details
NabiximolsN-arachidonyl glycine receptorProteinHumans
Unknown
Not AvailableDetails
NabiximolsNeuronal acetylcholine receptor subunit alpha-7ProteinHumans
Unknown
Not AvailableDetails
NabiximolsPeroxisome proliferator-activated receptor gammaProteinHumans
Unknown
Not AvailableDetails
NabiximolsProstaglandin G/H synthase 1ProteinHumans
Unknown
Inhibitor
Details
NabiximolsProstaglandin G/H synthase 2ProteinHumans
Unknown
Inhibitor
Details
NabiximolsQuinone oxidoreductaseProteinHumans
Unknown
Inhibitor
Details
NabiximolsSuperoxide dismutase [Cu-Zn]ProteinHumans
Unknown
Inhibitor
Details
NabiximolsTransient receptor potential cation channel subfamily A member 1ProteinHumans
Unknown
Not AvailableDetails
NabiximolsTransient receptor potential cation channel subfamily M member 8ProteinHumans
Unknown
Not AvailableDetails
NabiximolsTransient receptor potential cation channel subfamily V member 1ProteinHumans
Unknown
Not AvailableDetails
NabiximolsTransient receptor potential cation channel subfamily V member 2ProteinHumans
Unknown
Not AvailableDetails
NabiximolsTransient receptor potential cation channel subfamily V member 3ProteinHumans
Unknown
Not AvailableDetails
NabiximolsVoltage-dependent anion-selective channel protein 1ProteinHumans
Unknown
Not AvailableDetails
NabiximolsVoltage-dependent T-type calcium channel subunit alpha-1GProteinHumans
Unknown
Not AvailableDetails
NabiximolsVoltage-dependent T-type calcium channel subunit alpha-1HProteinHumans
Unknown
Not AvailableDetails
NabiximolsVoltage-dependent T-type calcium channel subunit alpha-1IProteinHumans
Unknown
Not AvailableDetails
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
CannabidiolArachidonate 15-lipoxygenaseProteinHumans
Unknown
Inhibitor
Details
CannabidiolArachidonate 5-lipoxygenaseProteinHumans
Unknown
Inhibitor
Details
CannabidiolArylalkylamine N-acetyltransferaseProteinHumans
Unknown
Not AvailableDetails
CannabidiolCytochrome P450 1A1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details
CannabidiolCytochrome P450 2C9ProteinHumans
No
Substrate
Details
CannabidiolCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details
CannabidiolFatty-acid amide hydrolase 1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolQuinone oxidoreductaseProteinHumans
Unknown
Not AvailableDetails
Medical CannabisArachidonate 15-lipoxygenaseProteinHumans
Unknown
Inhibitor
Details
Medical CannabisArachidonate 5-lipoxygenaseProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCytochrome P450 1A1ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCytochrome P450 1A2ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCytochrome P450 1B1ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details
Medical CannabisCytochrome P450 2C9ProteinHumans
No
Substrate
Inhibitor
Details
Medical CannabisCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCytochrome P450 3A5ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisCytochrome P450 3A7ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisSuperoxide dismutase [Cu-Zn]ProteinHumans
Unknown
Not AvailableDetails
NabiximolsArachidonate 15-lipoxygenaseProteinHumans
Unknown
Inhibitor
Details
NabiximolsArachidonate 5-lipoxygenaseProteinHumans
Unknown
Inhibitor
Details
NabiximolsCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details
NabiximolsCytochrome P450 2C9ProteinHumans
No
Substrate
Details
NabiximolsCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
CannabidiolATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Inhibitor
Details
CannabidiolEquilibrative nucleoside transporter 1ProteinHumans
Unknown
Inhibitor
Details
CannabidiolMultidrug resistance-associated protein 1ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisEquilibrative nucleoside transporter 1ProteinHumans
Unknown
Inhibitor
Details
Medical CannabisMultidrug resistance-associated protein 1ProteinHumans
Unknown
Inhibitor
Details
NabiximolsATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Inhibitor
Details
NabiximolsEquilibrative nucleoside transporter 1ProteinHumans
Unknown
Inhibitor
Details
NabiximolsMultidrug resistance-associated protein 1ProteinHumans
Unknown
Inhibitor
Details