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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    119—Addiction Treatment and Genetics: Translational Studies

    Sunday, November 10, 2013, 8:00 am - 11:30 am

    119.06: Multi-therapeutic potential of transdermal cannabidiol in relapse

    Location: 24A

    *G. GONZALEZ-CUEVAS1, R. MARTIN-FARDON1, D. HAMMEL2, S. BANKS2, R. SINHA3, A. STINCHCOMB2,4, F. WEISS1;
    1Mol. and Cell. Neurosci. Dept., The Scripps Res. Inst., La Jolla, CA; 2AllTranz Inc, Lexington, KY; 3Yale Univ. Sch. of Med., New Haven, CT; 4Univ. of Maryland Sch. of Pharm., Baltimore, MD

    Abstract Body: Several processes have been implicated in vulnerability to relapse, a major factor impeding recovery from addiction. These include conditioning factors responsible for drug urges and drug seeking upon exposure to drug-related cues, drug-induced neuroadaptation precipitating heightened anxiety and hypersensitivity to stress challenges, as well as cognitive deficits associated with drug-induced neurodegeneration that can lead to impaired impulse control as a risk factor for relapse. Evidence is emerging that cannabidiol, the main non-psychoactive and non-addictive component of the cannabis sativa plant, may have significant potential to prevent drug seeking associated with various risk factors for relapse. We examined the effects of a transdermal CBD preparation (tCBD) on both EtOH- and cocaine-seeking in reinstatement models of cue- and stress-induced relapse. Additionally, we evaluated tCBD actions on two vulnerability states for relapse: negative affect as measured by anxiety-like behavior (elevated plus maze test) and impulsivity associated with a history of EtOH dependence, as measured by a delay discounting task. Male Wistar rats with a history of EtOH or cocaine self-administration were subjected to a 7-day tCBD treatment phase during which they were treated at 24h intervals with tCBD (15 mg/kg) or vehicle. Reinstatement tests were conducted during the treatment phase as well as a 5-month post-treatment phase. tCBD attenuated cue- and stress-induced reinstatement of both EtOH- and cocaine-seeking over the 7-day tCBD treatment phase. Particularly striking was the observation that cue- and stress-induced drug seeking remained significantly reduced as late as ≈5 months after termination of tCBD treatment. Furthermore, tCBD reduced anxiety-like behavior without producing motor impairment and reversed the high impulsivity profile of rats with a dependence history. These findings suggest that CBD may have treatment potential for multiple vulnerability states associated with relapse. The interpretation of positive treatment drug potential is particularly compelling in view of the long-lasting post-treatment effects of tCBD, an observation that suggests that CBD may reverse drug-induced neuroplasticity underlying susceptibility to relapse.

    Lay Language Summary: A major challenge for the successful treatment of drug and alcohol addiction is long-lasting susceptibility to relapse. The pervasive risk of relapse during abstinence is linked to multiple vulnerability states. These include (a) drug craving produced by exposure to drug-related environmental cues or contexts, (b) drug-induced neuroadaptation resulting in anxiety and hypersensitivity to stress that motivates resumption of drug use in a self-medication sense, and (3) cognitive deficits induced by chronic drug use that can lead to impaired impulse control. While various medications are currently in use for relapse prevention, success rates achieved with these agents are typically unimpressive. Moreover, drugs currently FDA approved for the treatment of alcohol abuse and relapse prevention target only motivational properties of alcohol (i.e., reward and craving) and none addresses protracted withdrawal symptoms such as heightened anxiety and stress sensitivity, or impulse control deficits. Presently, there are no FDA-approved medications to treat cocaine addiction. Thus, developing medications for the treatment of cocaine addiction and relapse prevention remains a top research priority.
    Considering that drug addicts enter vulnerability states for several reasons, treatment drugs that concurrently target multiple precipitating factors are likely to provide greatly improved therapeutic efficacy. Our findings in rats suggest that cannabidiol, the main non-psychoactive and non-addictive component of the cannabis sativa plant, may provide such a profile of actions. Cannabidiol reduced cocaine and alcohol-seeking behavior induced by drug-related environmental stimuli and stress in animal models of relapse, attenuated anxiety-like behavior following cocaine and alcohol withdrawal, and reversed impulsive behavior following chronic alcohol intoxication. Cannabidiol produced these actions without non-specific behavioral suppression or tolerance to the drug’s “therapeutic” effects with repeated treatment. Indeed, of particular significance was the finding that the reduction of drug seeking in animal models of relapse outlasted a brief 7-day cannabidiol treatment period and remained undiminished after nearly five months of testing. Together, these observations suggest that cannabiol restores normal function to neural mechanisms regulating incentive motivation, stress and anxiety and, thus, may have unique treatment drug potential beyond mere transient pharmacotherapeutic amelioration of vulnerability states. Additionally, since cocaine and alcohol addiction often go hand in hand, cannabidiol may provide a particularly effective strategy for the treatment of these substance use disorders.