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

Gustavo Gonzalez-Cuevas, Remi Martin-Fardon, Tony M. Kerr, David G. Stouffer, Loren H. Parsons, Dana C. Hammell, Stan L. Banks, Audra L. Stinchcomb and Friedbert Weiss

Neuropsychopharmacology, 2018, 43, 2036–2045.

Doi : 10.1038/s41386-018-0050-8

 

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.

 

INTRODUCTION

There is debate as to the legitimate medical use of marijuana and cannabinoids. Various medical benefits of cannabinoids have been described (e.g., [1]). Nonetheless, prescription of Cannabis sativa for medical use faces major challenges (e.g., [1, 2]). However, C. sativa contains distinct non-psychoactive, non-addictive constituents that offer medical benefit and may be more readily amenable for use as therapeutics. Among these, cannabidiol (CBD) is a major candidate [2, 3]. CBD (Epidiolex®) is under clinical investigation for the treatment of childhood seizures related to Dravet Syndrome, and a CBD containing formulation (Sativex®) is currently in use to treat spasticity and neuropathic pain in multiple sclerosis [4, 5].

Recently, CBD has received attention for potential in treating drug and alcohol addiction [2]. But, to date, both clinical [6, 7] and preclinical [8–11] studies yielded mixed results such that the promise of CBD as an intervention for addictive disorders requires further scrutiny [12]. Leads exist in literature pointing toward pharmacotherapeutic potential of CBD, particularly for a spectrum of indications relevant for the prevention of relapse to drug use. Drug addiction is a chronic, relapsing brain disease [13, 14], and drug addicts remain at risk for relapse for multiple reasons. Prominent among these are susceptibility to stress, craving induced by drug contexts, heightened anxiety, and impaired impulse control. Several findings suggest that CBD may be effective for targeting these risk states. First, many of CBD’s reported general pharmacological effects imply therapeutic benefit also for affective changes and the compulsive nature of drug seeking in addicted individuals. These include effects consistent with anxiolytic [15, 16], stress-reducing [15, 17, 18], antidepressant [19], and anti-compulsive [20] activity. Second, CBD exerts many of its neurobiological effects [21–23] within the brain circuitry that mediates drug craving and seeking elicited by drugrelated environmental contexts and stress [24]. Third, CBD has neuroprotective actions [25] that extend to attenuation of alcoholinduced neurodegeneration [26], the latter likely contributing to impulse control deficits in alcoholics [27]. Considering this profile of behavioral and neuropharmacological effects as well as CBD’s actions within the addiction neuro-circuitry, we predicted that CBD has therapeutic potential relevant for multiple conditions that underlie relapse risk, including craving induced by drug-related environmental contexts, susceptibility to stress, heightened anxiety and, possibly, impaired impulse control. Guided by this hypothesis we sought to establish preclinical proof of principle toward a large-spectrum potential of CBD in relapse prevention. To this end, we used rats with histories of alcohol or cocaine selfadministration to determine (a) whether CBD attenuates the capacity of both drug-related contextual stimuli and stress to elicit drug seeking in animal models of relapse, (b) reduces experimental anxiety during abstinence, and (c) reverses impaired impulse control associated with a history of alcohol dependence.

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