(−)-Trans-Δ9-Tetrahydrocannabinol-Like Discriminative-Stimulus Effects of Gabapentin in Cannabis Users

A recent study by Dr. Joshua Lile and his colleagues demonstrated the capability of gabapentin to produce marijuana-like effects in humans. The finding is unexpected since the primary binding site of gabapentin is not thought to be any of the cannabinoid receptor subtypes. Gabapentin (Neurontin®) (Figure 1) is an FDA-approved medication for the treatment of epilepsy and neuropathic pain and several cases of its off-label use are also known. Several case reports have indicated gabapentin misuse/abuse [1-4] but the in vivo pharmacology and abuse potential of gabapentin have not yet been directly characterized. Thus, there is a clear need to characterize the in vivo pharmacology of gabapentin including its abuse potential.


Editorial
A recent study by Dr. Joshua Lile and his colleagues demonstrated the capability of gabapentin to produce marijuana-like effects in humans. The finding is unexpected since the primary binding site of gabapentin is not thought to be any of the cannabinoid receptor subtypes. Gabapentin (Neurontin ® ) ( Figure 1) is an FDA-approved medication for the treatment of epilepsy and neuropathic pain and several cases of its off-label use are also known. Several case reports have indicated gabapentin misuse/abuse [1][2][3][4] but the in vivo pharmacology and abuse potential of gabapentin have not yet been directly characterized. Thus, there is a clear need to characterize the in vivo pharmacology of gabapentin including its abuse potential.
Drug discrimination procedures have high human predictive validity with respect to the subjective effects of various test articles across pharmacological classes and have served as the gold standards for characterizing drug pharmacology in vivo because of their high pharmacological specificity [14][15][16][17]. Assessment of the capacity of gabapentin to induce a discriminative-stimulus (DS) in drug naïve subjects has not been reported. Interestingly, several L-VDCC blockers (nifedipine and verapamil) by themselves have been demonstrated to condition place preference in drug naïve rats using a placeconditioning procedure [18]. Considering the potential of gabapentin to serve as a functional L-VDCC antagonist [13,19,20], gabapentin alone at an appropriate dose and treatment time may exert an in vivo action indicative of its abuse potential.
Several studies using drug discrimination procedures have assessed the capacity of gabapentin or pregabalin to substitute for various psychoactive compounds from different pharmacological classes [21][22][23][24][25][26]. Among them is a double-blind, placebo-controlled, clinical study that found gabapentin capable of full substitution for the cannabinoid CB 1/2 receptor (CB 1/2 R) partial agonist (−)-trans-Δ 9tetrahydrocannabinol (Δ 9 -THC) in Cannabis users trained to discriminate ingestion of Δ 9 -THC from ingestion of placebo [26]. However, this clinical result is inconsistent with preclinical findings that indicate a lack of cannabinoid-like DS effects for gabapentin in rats trained to discriminate another cannabinoid CB 1/2 R partial agonist, BAY 59-3074 [23]. There is currently no literature on the assessment of the binding affinity of gabapentin and other high-affinity ligands at the [ 3 H] gabapentin-binding site for any cannabinoid receptor subtypes or endocannabinoid [e.g. anandamide and 2arachidonoylglycerol (2-AG)] uptake enzymes. Δ 9 -THC [27,28] and BAY 59-3074 [29] have been reported to have substantial, high affinity for cannabinoid CB 1 and CB 2 receptor subtypes (Ki values: 15.3-55.4 nM). Δ 9 -THC also is known to exert potent action that is mediated through non-CB1/2R, cannabinoid G protein-coupled receptor 55 (GPR55) [30,31] that is expressed in human [32] and rat [33,34] brains while it is unknown whether BAY 59-3074 has actions at the cannabinoid GPR55. Importantly, cannabinoid GPR55 has been found to increase intracellular Ca 2+ levels [31] and a recent in vitro study demonstrated that cannabinoid GPR55 can form a heteromer with cannabinoid CB1R [34] in the rat striatum. In addition, another study identified a heteromer consisting of cannabinoid CB 2 R and GPR55 [35]. Considering the well-characterized effect of cannabinoid CB1R agonists as L-VDCC blockers [36][37][38][39][40][41][42] and the potential of gabapentin to serve as a functional L-VDCC blocker [13,19,20], the full Δ 9 -THClike DS effects of gabapentin in Cannabis users [26] might result from a blocking action of gabapentin and Δ 9 -THC at L-VDCCs.
In summary, it does appear pharmacologically important comprehensively to assess the L-VDCC-blocker-and cannabinoid-like DS effects of gabapentin and pregabalin for regulatory purposes. Further it may be important to assess whether gabapentin and pregabalin can enhance reinforcing and toxic effects of Δ 9 -THC and cannabinoid products. Given the clinical use of L-VDCC blockers against hypertension, such studies would also have significant impact on their safer use.

Acknowledgement
The The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152: 1092-1101.