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.

Vapor inhalation of cannabidiol (CBD) in rats

“…The observed plasma concentrations were also comparable to plasma CBD observed in rats four hours after dermal gel application, which was the same time post-application that CBD reduced alcohol and cocaine seeking (Gonzalez-Cuevas et al, 2018). We have shown previously that 30 minutes of inhalation of vapor generated from CBD (100, 400 mg/mL) reduces the body temperature of male and female Wistar rats in a concentration-dependent manner, and here it was confirmed that inhalation of vapor from CBD also reduces body temperature of Sprague-Dawley male rats in a concentration-dependent manner.…”

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

“…Similarly, Mahmud et al (2017) did not find that CBD (5, 10 mg/kg) reduced cocaine seeking in the first withdrawal session. However, transdermal CBD (15 mg/kg) induced an effect similar to what we report (Gonzalez-Cuevas et al, 2018). After the first exposure to CBD, cocaine seeking was found decreased.…”

“…Such a protective role of CBD in similar experimental conditions has been previously reported using rats. A transdermal preparation of CBD (15 mg/kg, 7 days) implanted after the first reinstatement of cocaine seeking attenuated subsequent measures of motivation to pursue cocaine, and alcohol, when related cues (context) were presented (Gonzalez-Cuevas et al, 2018). In a non-operant model of cocaine reinforcement, CBD was also reported able to impair the reconsolidation of cocaine-induced conditioning place preference (de Carvalho and Takahashi, 2016).…”

“…Such an adverse consequence of CBD has not been reported before. Instead, Gonzalez-Cuevas et al (2018) reported that CBD (15 mg/kg) attenuated cocaine pursue after yohimbine priming. Yohimbine (a pharmacological alpha 2 blocker that increases peripheral and central effects of stress) is considered equivalent to stress (Bossert et al, 2013), but evidence suggests that its effects are not the same that those induced by a footshock presentation (Chen et al, 2015).…”

“…So far, two studies have suggested that CBD administration can reduce cocaine intake in mice (Luján et al, 2018) and rats . A single report by Gonzalez-Cuevas et al (2018) supported the treatment potential of CBD in reducing cue-and stress-induced retrieval of cocaine seeking behavior in rats. In contrast, it was also reported that CBD had no effect on cocaine seeking behavior (Mahmud et al, 2017).…”