Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation

ABSTRACT

Introduction

Tobacco use disorder (TUD) is a chronic relapsing condition. Existing pharmacotherapy can assist smokers to initiate smoking cessation, but relapse rates remain high. Novel therapeutics are required to help people quit and also to prevent relapse. The endocannabinoid system has been increasingly implicated in reward and addiction processes and the cannabinoid CB1 receptor inverse agonist rimonabant has been shown to be effective at promoting smoking cessation but has been associated with adverse psychiatric side effects.

Areas covered

Multiple converging factors likely contribute to the maintenance of smoking and cause relapse including nicotine reinforcement, propensity to reinstate drug seeking (induced by nicotine priming, nicotine-associated cues, and stress), the severity of withdrawal signs and executive function status. Studies assessing the impact of endocannabinoid (CB1 receptor, CB2 receptor, anandamide, and 2-arachidonoylglycerol) modulation on these addiction-related factors are reviewed. Future research avenues are also discussed.

Expert opinion

Endocannabinoid research in TUD is at a relatively early stage. Based on current evidence, CB1 receptor neutral antagonists and fatty acid amide hydrolase inhibitors demonstrate positive effects in studies assessing several addiction-related factors. This suggests they offer the greatest promise as novel cessation and anti-relapse agents.

KEYWORDS:

• Anandamide
• cannabinoid receptor
• endocannabinoid
• executive function
• FAAH inhibition
• nicotine reinforcement
• reinstatement
• tobacco use disorder
• withdrawal
• 2-Arachidonoylglycerol

Article highlights

• Multiple factors likely contribute to continued smoking and relapse including nicotine reinforcement, propensity to reinstate drug seeking (induced by nicotine priming, nicotine-associated cues, and stress), the severity of withdrawal signs and executive function status. We review the impact of endocannabinoid modulation on these factors.

• Inverse agonism and neutral antagonism at CB1 receptors reduces nicotine self-administration, reinstatement of nicotine seeking, as well as some withdrawal signs and may improve executive dysfunction.

• Inhibitors of fatty acid amide hydrolase (FAAH) attenuate reinstatement of nicotine seeking, reduce nicotine self-administration in some animals, and may reduce some withdrawal symptoms. There is mixed evidence for effects on executive function.

• CB1 receptor inverse antagonism is associated with adverse psychiatric effects. Neutral antagonism at this receptor may have an improved psychiatric side effect profile. FAAH inhibitors have anxiolytic and antidepressant effects.

• Research examining the impact of endocannabinoid modulation on addiction-relevant factors is at a relatively early stage. There is currently limited or mixed evidence for effects of alternative endocannabinoid modulating mechanisms on these addiction-relevant factors.

• Preclinical evidence suggests that CB1 receptor neutral antagonists and FAAH inhibitors hold promise as novel smoking cessation and anti-relapse agents. These findings need to be validated in human smokers.

This box summarizes key points contained in the article.

Declaration of interest

K Butler’s postdoctoral research fellowship at the Centre for Addiction and Mental Health (CAMH) is supported, in part, by Mitacs and Canopy Health Innovations Inc. B Le Foll has obtained funding from Pfizer (GRAND awards, including salary support) for investigator-initiated projects. He has/will receive some in-kind donation of cannabis product from Canopy and Aurora, medication donations from Pfizer and Bioproject and was provided a TMS coil from Brainsway. Dr Le Foll has or will perform research with industry funding obtained from Canopy (through research grants handled by the CAMH or the University of Toronto), Aphria, (through research grants handled by the CAMH or the University of Toronto), Bioprojet, ACS, and Alkermes. Dr Le Foll has also received in kind donations of nabiximols from GW Pharma for past studies funded by the CIHR and NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.