Separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC

Abstract

Background The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ9-tetrahydrocannabinol (Δ9-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC using more pharmacologically specific drug-discrimination procedures. Methods Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received tiagabine (6 and 12 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Results Δ9-THC produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on psychomotor performance tasks. The higher tiagabine dose substituted for the Δ9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ9-THC when administered alone. In combination, tiagabine shifted the discriminative-stimulus effects of Δ9-THC leftward/upward and enhanced Δ9-THC effects on other outcomes. Conclusions These results indicate that GABA is involved in the clinical effects of Δ9-THC, and by extension, cannabis. Future studies should test selective GABAergic compounds to determine which receptor subtype(s) are responsible for the effects observed when combined with cannabinoids.

Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ9-THC in humans discriminating Δ9-THC

“…Limitations of the present methodology have been described in detail previously (Lile et al, 2012a) and include the use of illicit drugs having short durations of action that might have been missed by toxicology screening and variability in cannabis use during outpatient participation. In addition, the present study used a staggered dosing procedure to account for anticipated differences in the onset of peak effects for Δ 9 -THC and diazepam.…”

“…Subjects rated 20 items (see Lile et al, 2012a) that assessed general “positive” (e.g., Good Effects, Like Drug) and “negative” (e.g., Bad Effects, Nauseated) drug effects, as well as items specific to cannabis intoxication (e.g., Stoned). Items were presented individually on the computer by marking a 100-unit line anchored on the extremes by “Not At All” and “Extremely”.…”

“…In an initial study we probed the involvement of GABA in the interoceptive effects of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) in humans by administering the GABA reuptake inhibitor tiagabine alone and in combination with Δ 9 -THC in subjects trained to discriminate oral Δ 9 -THC from placebo (Lile et al, 2012a). Tiagabine alone occasioned Δ 9 -THC-appropriate responding, and when combined with Δ 9 -THC, produced leftward/upward shifts in the dose response curves for drug-appropriate responding, subjective response and performance impairment.…”

Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol

“…Subjects rated 20 items (see Lile et al, 2012) that assessed general “positive” (e.g., Good Effects, Like Drug) and “negative” (e.g., Bad Effects, Nauseated) drug effects, as well as items specific to cannabis intoxication (e.g., Stoned). Items were presented individually on the computer by marking a 100-unit line anchored on the extremes by “Not At All” and “Extremely”.…”

“…To further investigate potential similarities, particularly as they relate to the abuse-related interoceptive effects of cannabis, the present study determined the separate and combined effects of gabapentin and Δ 9 -tetrahydrocananbinol (i.e., Δ 9 -THC, the primary active constituent of cannabis) using pharmacologically selective drug-discrimination procedures (Lile et al, 2009, 2010, 2012, 2014). Gabapentin was hypothesized to occasion Δ 9 -THC-like discriminative-stimulus alone and shift the discriminative-stimulus effects of Δ 9 -THC leftward/upward when administered concurrently.…”