Acute and chronic effects of cannabidiol on Δ⁹-tetrahydrocannabinol (Δ⁹-THC)-induced disruption in stop signal task performance

Abstract

Recent clinical and preclinical research has suggested that cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have interactive effects on measures of cognition; however, the nature of these interactions is not yet fully characterized. To address this, we investigated the effects of Δ9-THC and CBD independently and in combination with proposed therapeutic dose ratios of 1:1 and 1:3 Δ9-THC:CBD in adult rhesus monkeys (n = 6) performing a stop signal task (SST). Additionally, the development of tolerance to the effects of Δ9-THC on SST performance was evaluated by determining the effects of acutely administered Δ9-THC (0.1-3.2 mg/kg), during a 24-day chronic Δ9-THC treatment period with Δ9-THC alone or in combination with CBD. Results indicate that Δ9-THC (0.032-0.32 mg/kg) dose-dependently decreased go success but did not alter go reaction time (RT) or stop signal RT (SSRT); CBD (0.1-1.0 mg/kg) was without effect on all measures and, when coadministered in a 1:1 dose ratio, did not exacerbate or attenuate the effects of Δ9-THC. When coadministered in a 1:3 dose ratio, CBD (1.0 mg/kg) attenuated the disruptive effects of 0.32 mg/kg Δ9-THC but did not alter the effects of other Δ9-THC doses. Increases in ED50 values for the effects of Δ9-THC on SST performance were apparent during chronic Δ9-THC treatment, with little evidence for modification of changes in sensitivity by CBD. These results indicate that CBD, when combined with Δ9-THC in clinically available dose ratios, does not exacerbate and, under restricted conditions may even attenuate, Δ9-THC's behavioral effects. (PsycINFO Database Record

Figure 1. ‘Go’ trial success (±SEM) and reaction time change (±SEM) during pre-chronic tests with Δ9-THC and CBD (Left Panels), or 1 Δ9-THC: 1 CBD, and 1 Δ9-THC: 3 CBD (Right Panels)

Abscissa: cumulative drug dose in mg/kg. Top ordinates: ‘Go’ trial success percentage for all ‘go’ trials; Bottom ordinates: ‘Go’ trial reaction time for responding completed within 1 second of stimulus onset as change from control. As indicated, some subjects were excluded in go reaction time analysis with numbers in parentheses indicating sample size when data was excluded, otherwise n=6. *p<0.05 vs. vehicle. *p<0.05, **p<0.01, ***p<0.001 from control tests; ^#p<0.05 THC alone vs THC 1:3

Figure 2. ‘Go’ trial success (±SEM) in training sessions before and during chronic treatment with and corresponding drug treatment regimens

Data are presented for the last 4 consecutive training sessions for each Phase per group. Abscissa: Corresponding Phase. Ordinates: ‘Go’ trial success percentage for all ‘go’ trials. Bottom: Daily drug treatment administered. All subjects received treatments at 0600 in Phase 1 (Days 1-4), and at 0600 & 1800 in Phases 2 (Days 6-11) and 3 (Days 13-23). All Phases were separated by one day, during which the effects of cumulative doses of Δ9-THC (0.1-3.2 mg/kg) in the SST were determined. In Phase 3 of chronic treatment, the limited hold was increased for two subjects (see methods), after which group ‘go’ success returned to pre-chronic levels.

Figure 3. Individual and Group ‘go’ trial success during pre-chronic Δ9-THC tests and Δ9-THC tests after chronic dosing with Δ9-THC (Top Panels) or Δ9-THC + CBD (Bottom Panels)

Abscissa: cumulative drug dose in mg/kg. Ordinates: ‘Go’ trial success percentage for all ‘go’ trials. Chronic Test 1 – 0.32 mg/kg/day Δ9-THC both groups; Chronic Test 2 – 1.0 mg/kg/day Δ9-THC both groups and 1.0 mg/kg/day CBD for Δ9-THC:CBD group (n=2); Chronic Test 3 - Chronic Test 2 – 1.0 mg/kg/day Δ9-THC both groups and 3.0 mg/kg/day CBD for Δ9-THC:CBD group. Subject Mm 066 (Top Middle, Right) did not respond after 0.1 mg/kg during Chronic Test 2. Subject Mm 8189 (Bottom Middle, Right) did not respond during Chronic Test 2 (see text for details).