Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats

Abstract

Background: Methamphetamine is an addictive stimulant that can cause many adverse physical, psychological and psychosocial effects. Preliminary evidence shows cannabidiol, a non-intoxicating constituent of the cannabis plant, may have efficacy in treating opioid and nicotine dependence. However, no study has yet examined whether cannabidiol treatment might impact on methamphetamine addiction. Aims: The current study investigated whether cannabidiol administration reduces the motivation to self-administer methamphetamine and relapse to methamphetamine-seeking behavior following abstinence. Methods: Thirty-two male Sprague Dawley rats with implanted jugular vein catheters were initially trained to self-administer methamphetamine via lever press during two-hour sessions on a fixed ratio 1 schedule of reinforcement. Rats in experiment 1 (n=16) then advanced to a progressive ratio reinforcement schedule to examine the effects of cannabidiol (0, 20, 40, and 80 mg/kg intraperitoneal) on motivation to self-administer methamphetamine. Rats in experiment 2 (n=16) were tested for cannabidiol effects on methamphetamine-primed reinstatement following extinction. Results: Cannabidiol (80 mg/kg, but not 40 mg/kg, or 20 mg/kg) reduced the motivation to self-administer methamphetamine and attenuated methamphetamine-primed relapse to methamphetamine-seeking behavior after extinction. Conclusion: This is the first demonstration that cannabidiol can reduce the motivation to seek and consume methamphetamine, and suggests that cannabidiol might be worth trialing as a novel pharmacotherapy for methamphetamine dependence.

Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

“…The evidence of CBD’s role in regulating emotional memory is further supported by the blockade of stress-induced reinstatement of cocaine seeking [59]. CBD was also able to block priming-induced reinstatement of METH seeking but this effect was observed only with high doses [58] or icv administration [61,98]. In comparison to other drugs of abuse, CBD seems to have a relatively weaker efficacy in disrupting the rewarding and reinstating effects of psychostimulant drugs.…”

“…These apparent opposite results probably indicated that high doses of CBD are needed to reduce cocaine self-administration. In support of this idea, motivation of rats to self-administer METH in a progressive ratio reinforcement schedule was also reduced by a high dose of CBD (80 mg/kg), but not by lower doses (20 and 40 mg/kg) [58]. In addition, the effectiveness of CBD to reduce the reinforcing properties of cocaine in the self-administration paradigm apparently contrasts with its lack of effect in the ICSS, but again this apparent discrepancy may be due to the fact that a low dose of CBD was employed to test its effects on cocaine reward in the ICSS paradigm.…”

“…It is important to note that following the cessation of treatment with CBD, reinstatement remained attenuated for a long time (≈5 months) despite plasma and brain CBD levels remaining detectable only for 3 days [59]. CBD administration (80 mg/kg, but not with lower doses) attenuated priming-induced reinstatement of METH self-administration following extinction [58].…”

One Is Not Enough: Understanding and Modeling Polysubstance Use

“…Interestingly, CBD has no effect on cocaine self-administration, motivation, or cue-induced reinstatement of cocaine-seeking (Mahmud et al, 2017), suggesting the effects of cannabis on cocaine craving are likely due to THC, rather than CBD. However, CBD treatment has been found to reduce motivation to self-administer methamphetamine on a progressive ratio schedule and to reduce methamphetamine-primed reinstatement of drug-seeking (Hay et al, 2018). The additive effects of cannabinoid and psychostimulant polydrug use appear to be dependent on both the amount of drug consumed and the age range during use.…”

The Endocannabinoid System and Cannabidiol's Promise for the Treatment of Substance Use Disorder

“…Further studies on relapse are similarly mixed with one demonstrating CBD's ability to attenuate reconsolidation of CPP (1 week post-CPP acquisition) for cocaine in mice (71), and effectively reduce cue and stress-induced reinstatement of cocaine seeking up to 48 days post-CBD treatment (140), whilst another suggested no effect of CBD on drug-primed reinstatement post-extinction (122). Dose dependency may explain contradictory findings, as Hay et al (134) demonstrated that 80 mg/kg (and not less) of CBD was needed to significantly reduce motivation to self-administer methamphetamine and reinstatement post-extinction. While evidence for CBD use for stimulant addiction in animals is weak, a longitudinal observational study of 122 participants did find cocaine users who self-report using cannabis to control their cocaine use, to have reduced their cocaine use over a 3 years period (147).…”