Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence

Cannabis use disorders are a significant public health concern and the absence of effective medications is a critical barrier to overcome. A recent pilot clinical trial indicated that gabapentin, a drug approved to manage seizures and neuropathic pain, reduced cannabis use dependent, treatment-seeking adults. Gabapentin is a ligand at ƒÑ2ƒÔ-1 subunit containing voltage-dependent calcium channels (VDCCs), and also increases brain GABA levels. Based on the initial promising findings with gabapentin and its neurochemical actions, the present proposal will evaluate the ability of outpatient maintenance on pregabalin, a ¡§next generation¡¨ VDCC ligand and tiagabine, a GABA reuptake inhibitor, to reduce cannabis use in the laboratory and the natural environment. Pregabalin will be tested because, although their mechanism of action is the same, the pharmacokinetic profile of pregabalin is improved compared to gabapentin, and clinical results suggest that this translates into improved therapeutic benefit and cost effectiveness. Tiagabine will be tested because its therapeutic effects overlap with gabapentin and pregabalin, GABA elevation is a possible mechanism for gabapentin¡¦s effects on cannabis use, and our recent data demonstrated that tiagabine produced a similar profile of effects to gabapentin when tested with ƒ´9-THC. Outpatient maintenance dosing will be tested because it more closely resembles the clinical treatment situation. Cannabis self-administration using a concurrent drug-money choice procedure was chosen as the primary outcome for this project because the reinforcing effects of cannabis are central to its continued use and drug self-administration procedures are predictive of therapeutic efficacy. Cannabis use in the natural environment will also be monitored during drug maintenance as a secondary outcome to optimize resource management and quicken the pace of intervention development. The assembled research team is highly qualified and the environment will significantly contribute to the success of the research. The proposed project is highly innovative because it compares previously untested compounds to a drug with known therapeutic efficacy and employs a novel hybrid procedure to study the impact of medication maintenance on direct cannabis effects in the laboratory as well as cannabis use in the natural environment. Positive findings will exert an immediate and sustained impact by rapidly advancing currently available medications for the treatment of cannabis-use disorders, promoting novel pharmacological targets for further medications development and providing valuable basic science information about the mechanisms underlying cannabis reinforcement.