Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle

Abstract

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the "anti-relapse" potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity. Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen. CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history. The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.

Fig. 1

Experimental design. Effects of CBD were established on recovery of extinguished drug seeking on treatment days 1, 4, and 7. Testing then continued without further CBD or vehicle (VEH) treatment at early (day 3), intermediate (days 18, 48), and late (day 138) post-treatment stages. Additionally, one test of experimental anxiety (EPM) was conducted on post-treatment day 2. The diagram illustrates the design and sequence of CBD vs vehicle (VEH) treatments and behavioral tests across experimental phases. PreTx:VEH daily VEH gel.T:CBD/VEHdaily CBD or VEH gel. To evaluate the drug specificity of its effects, CBD was probed at some time points for interference with context and stress-induced reinstatement motivated by a sweet solution in separate groups of drug-naive rats. PostTx no treatment. Symbols denote ethanol (●), cocaine (○), or sweet solution (□) self-administration history, and sampling days for plasma (∆) and brain (▲) CBD levels

Fig. 2

Reinstatement of ethanol seeking. a Contextual reinstatement. PreTx:VEH: extinction (EXT) and “Baseline Reinstatement” performance during the VEH pretreatment phase. Note: Data represent behavior in rats assigned to CBD or VEH treatment (N = 12/group) as matched pairs after completion of the baseline reinstatement test. Tx:CBD/VEH: reinstatement during CBD or VEH treatment. PostTx: reinstatement after termination of CBD treatment. ^&&&p < 0.01 vs extinction (EXT); *p < 0.05, **p < 0.01 vs VEH. b Stress-induced reinstatement. PreTx:VEH: yohimbine-induced “baseline” reinstatement. Tx:CBD/VEH: reinstatement during CBD or VEH treatment (N = 12/group). PostTx: Reinstatement across the CBD-free test phase. ^&p < 0.05 vs EXT; *p < 0.05 vs VEH. Inset: Footshock-induced reinstatement. *p < 0.05 vs VEH; ^#p < 0.05, ^###p < 0.001 vs EXT (N = 11/group). Note: Ordinate scales are standardized across drugs for context and stress-induced reinstatement respectively  in Figs. 2 and 3, but differ within each figure for context and stress effects for the sake of clarity

Fig. 3

Reinstatement of cocaine seeking. a Contextual reinstatement (N = 11/group). b Yohimbine-induced reinstatement (N = 12/group). For both contextual and stress-induced reinstatement, the same profile of effects was observed as in rats with an ethanol history across all three experimental phases (Fig. 2). ^&&p < 0.01 vs EXT; *p < 0.05, **p < 0.01 vs VEH. Note: EXT and “Baseline Reinstatement” data represent behavior of rats assigned to either CBD or VEH treatment as matched pairs after completion of the baseline reinstatement test

Fig. 4

Effects on experimental anxiety. Effects on experimental (EPM open arm time) in rats with a an alcohol (N = 12/group) or b cocaine (CBD: N = 9, VEH: N = 12) history. In both drug history groups CBD significantly reduced anxiety-like behavior, reflected by increased EPM open arm time as measured on PostTx day 2. c Dose dependence of the CBD effects on EPM open arm time measured in drug-naive rats on PostTx day 2 (N = 10/group). *p < 0.05 vs VEH.

Fig. 5

Tests for nonspecific CBD effects. a Reward seeking motivated by palatable sweet solution. Left panel: Effects of CBD on reinstatement induced by contextual cues conditioned to availability of sweet solution reward (N = 6/group). Right panel: Effects of CBD on yohimbine-induced reinstatement of sweet solution seeking (N = 6/group). No statistical differences were found between VEH and CBD treatment on contextual or yohimbine-induced behavior. **p < 0.01, ***p < 0.001 vs EXT. b Effects of CBD on spontaneous locomotor activity in rats with an alcohol (left panel; N = 12/group) or cocaine (right panel; N = 11/group) history

Fig. 6

Preference for delayed large over small immediate reward as a function of delay time. Preference for delayed large reward was significantly lower in rats with an EtOH dependence history (DEP-VEH) than nondependent controls (NDEP-VEH) and nondependent CBD-treated (NDEP-CBD) rats. This effect was fully reversed by CBD (DEP-CBD). *p < 0.05 DEP-VEH (N = 7) vs DEP-CBD (N = 6), DEP-VEH (N = 7), and NDEP-CBD (N = 7)

Fig. 7

Plasma and brain CBD concentrations. a Plasma levels differed significantly by dose on Tx day 7 and PostTx day 3. *p < 0.05, **p < 0.01; ***p < 0.001 vs 15 mg/kg. (ND not detectable; in Fig. 7b not collected). b Brain CBD concentrations in CBD-treated (left bars: 15 mg/kg) rats differed from untreated controls (right bars: “ND”) on Tx day 7 and PostTx day 3 (N = 10/dose). Brain CBD in untreated controls was below detection limits, as was CBD in CBD-treated rats on PostTx days 18–138 (N = 4/group)