Publications by authors named "Bernard Le Foll"

221 Publications

Reviewing pharmacogenetics to advance precision medicine for opioids.

Biomed Pharmacother 2021 Oct 12;142:112060. Epub 2021 Sep 12.

Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Institute of Medical Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Toronto, ON, Canada. Electronic address:

Background: Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved with risk of accidental lethal overdosing. With the emergence of accumulating evidence linking genetic variation to opioid response, pharmacogenetic based treatment recommendations have been proposed.

Objective: The aim of this review is to evaluate pharmacogenetic evidence and provide an overview on genes involved in the pharmacokinetics and pharmacodynamics of opioids.

Methods: For this review, a systematic literature search of published articles was used in PubMed®, with no language restriction and between the time period of January 2000 to December 2020. We reviewed randomized clinical studies, study cohorts and case reports that investigated the influence of genetic variants on selected opioid pharmacokinetics and pharmacodynamics. In addition, we reviewed current CPIC clinical recommendations for pharmacogenetic testing.

Results: Results of this review indicate consistent evidence supporting the association between selected genetic variants of CYP2D6 for opioid metabolism. CPIC guidelines include recommendations that indicate the avoidance of tramadol use, in addition to codeine, in CYP2D6 poor metabolizers and ultrarapid metabolizers, and to monitor intermediate metabolizers for less-than-optimal response. While there is consistent evidence for OPRM1 suggesting increased postoperative morphine dosing requirements in A118G G-allele carriers, the clinical relevance remains limited.

Conclusion: There is emerging evidence of clinical relevance of CYP2D6 and, to a lesser extent, OPRM1 polymorphism in personalized opioid drug dosing. As a result, first clinics have started to implement pharmacogenetic guidelines for CYP2D6 and codeine.
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http://dx.doi.org/10.1016/j.biopha.2021.112060DOI Listing
October 2021

The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics.

Braz J Psychiatry 2021 Aug 30. Epub 2021 Aug 30.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Social anxiety disorder (SAD) is a highly prevalent psychiatric disorder that presents with an early age of onset, chronic disease course, and increased risk of psychiatric comorbidity. Current treatment options for SAD are associated with low response rates, suboptimal efficacy, and possible risk of adverse effects. Investigation of new neurobiological mechanisms may aid in the identification of more specific therapeutic targets for the treatment of this disorder. Emerging evidence suggests that the endogenous cannabinoid system, also referred to as the endocannabinoid system (ECS), could play a potential role in the pathophysiology of SAD. This review discusses the known pathophysiological mechanisms of SAD, the potential role of the ECS in this disorder, current drugs targeting the ECS, and the potential of these novel compounds to enhance the therapeutic armamentarium for SAD. Further investigational efforts, specifically in human populations, are warranted to improve our knowledge of the ECS in SAD.
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http://dx.doi.org/10.1590/1516-4446-2021-1926DOI Listing
August 2021

Preliminary Eye-Tracking Data as a Nonintrusive Marker for Blood Δ-9-Tetrahydrocannabinol Concentration and Drugged Driving.

Cannabis Cannabinoid Res 2021 Aug 24. Epub 2021 Aug 24.

Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, Canada.

Cannabis is one of the drugs most often found in drivers involved in serious motor vehicle collisions. Validity and reliability of roadside cannabis detection strategies are questioned. This pilot study aimed to investigate the relationship between eye characteristics and cannabis effects in simulated driving to inform potential development of an alternative detection strategy. Multimodal data, including blood samples, eye-tracking recordings, and driving performance data, were acquired from 10 participants during a prolonged single-session driving simulator experiment. The study session included a baseline driving trial before cannabis exposure and seven trials at various times over ∼5 h after exposure. The multidimensional eye-tracking recording from each driving trial for each participant was segmented into nonoverlapping epochs (time windows); 34 features were extracted from each epoch. Blood Δ-9-tetrahydrocannabinol (THC) concentration, standard deviation of lateral position (SDLP), and mean vehicle speed were target variables. The cross-correlation between the temporal profile of each eye-tracking feature and target variable was assessed and a nonlinear regression analysis evaluated temporal trend of features following cannabis exposure. Mean pupil diameter (=0.81-0.86) and gaze pitch angle standard deviation (=0.79-0.87) were significantly correlated with blood THC concentration (<0.01) for all epoch lengths. For driving performance variables, saccade-related features were among those showing the most significant correlation (=0.61-0.83, <0.05). Epoch length significantly affected correlations between eye-tracking features and speed (<0.05), but not SDLP or blood THC concentration (>0.1). Temporal trend analysis of eye-tracking features after cannabis also showed a significant increasing trend (<0.01) in saccade-related features, including velocity, scanpath, and duration, as the influence of cannabis decreased by time. A decreasing trend was observed for fixation percentage and mean pupil diameter. Due to the lack of placebo control in this study, these results are considered preliminary. Specific eye characteristics could potentially be used as nonintrusive markers of THC presence and driving-related effects of cannabis. clinicaltrials.gov (NCT03813602).
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http://dx.doi.org/10.1089/can.2020.0141DOI Listing
August 2021

Exploring regulation and function of dopamine D3 receptors in alcohol use disorder. A PET [C]-(+)-PHNO study.

Neuropsychopharmacology 2021 Aug 4. Epub 2021 Aug 4.

Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.

Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n = 17; 6.59 ± 4.14 days of abstinence) and healthy controls (n = 18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk's Λ = .58, F(6,28) =3.33, p = 0.013, η = 0.42), however there were no region-specific differences. Binding values demonstrate -12.3% and -16.1% lower [C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r = 0.66, p = 0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.
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http://dx.doi.org/10.1038/s41386-021-01095-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336665PMC
August 2021

Survival Probabilities and Predictors of Major Depressive Episode Incidence Among Individuals With Various Types of Substance Use Disorders.

J Clin Psychiatry 2021 Jul 27;82(5). Epub 2021 Jul 27.

Addictions Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

This study aimed to estimate the survival probabilities related to the occurrence of major depressive episodes (MDEs) after the onset of substance use disorders (SUDs) using data from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III.

The Alcohol Use Disorder and Associated Disabilities Interview Schedule-5 was used to diagnose SUD, and psychiatric diagnoses were based on the , Fifth Edition. Individuals with incidents of various SUDs with no prior history of MDEs (n = 5,987 with alcohol use disorder [AUD], 1,353 with cannabis use disorder [CUD], 351 with opioid use disorder [OUD], 827 with stimulant use disorder [STUD], and 5,363 with nicotine use disorder [NUD]) were included. The survival probabilities of these groups were compared to those of a control group without an SUD (n = 20,034). Outcome measures included the number of years from the age at SUD onset until MDE occurrence or the time of the interview.

The probabilities of experiencing MDEs after 1 year were 3.56%, 4.80%, 7.78%, 8.46%, and 5.31% for AUD, CUD, OUD, STUD, and NUD, respectively. The groups differed statistically significantly from each other and from the control group ( < .0001). Individuals with AUD and STUD, respectively, had a lower and higher probability of having an MDE compared to those with other SUDs. Young age, family history of depression, anxiety disorder presence, and failure to achieve full remission consistently predicted an MDE for all substances.

The findings highlight that users of all studied substances have an increased probability of having an MDE over the lifespan.
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http://dx.doi.org/10.4088/JCP.20m13637DOI Listing
July 2021

Influence of Cannabinoid Receptor 1 Genetic Variants on the Subjective Effects of Smoked Cannabis.

Int J Mol Sci 2021 Jul 9;22(14). Epub 2021 Jul 9.

Centre for Addiction and Mental Health, Translational Addiction Research Laboratory, University of Toronto, 33 Ursula Franklin Street, Toronto, ON M5S 2S1, Canada.

As many jurisdictions consider relaxing cannabis legislation and usage is increasing in North America and other parts of the world, there is a need to explore the possible genetic differences underlying the subjective effects of cannabis. This pilot study investigated specific genetic variations within the cannabinoid receptor 1 () gene for association with the subjective effects of smoked cannabis. Data were obtained from a double-blinded, placebo-controlled clinical trial studying the impact of cannabis intoxication on driving performance. Participants randomized to the active cannabis group who consented to secondary genetic analysis ( = 52) were genotyped at the rs1049353 and rs2023239 polymorphic areas. Maximum value and area under the curve (AUC) analyses were performed on subjective measures data. Analysis of subjective effects by genotype uncovered a global trend towards greater subjective effects for rs1049353 T-allele- and rs2023239 C-allele-carrying subjects. However, significant differences attributed to allelic identity were only documented for a subset of subjective effects. Our findings suggest that rs1049353 and rs2023239 minor allele carriers experience augmented subjective effects during acute cannabis intoxication.
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http://dx.doi.org/10.3390/ijms22147388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307475PMC
July 2021

Influence of personality on acute smoked cannabis effects on simulated driving.

Exp Clin Psychopharmacol 2021 Jul 22. Epub 2021 Jul 22.

Department of Pharmacology and Toxicology.

A recent study of the impact of smoked cannabis on simulated driver behavior demonstrated a reduction in mean speed after smoked cannabis. Previous research identified an association between personality and individual differences and acute drug effects. The present study examined the impact of personality on the reduction in mean speed after smoking cannabis under single- and dual-task driving conditions originally reported by Brands et al. (2019). Sixty-one participants randomly assigned to the active drug condition completed a battery of self-report questionnaires measuring various personality constructs and subsequently operated a driving simulator before and 30 min after smoking a 12.5% Δ9-tetrahydrocannabinol (THC) cigarette. Linear regression modeling tested the influence of self-reported driving errors, lapses, and violations, driver vengeance, psychological distress, impulsivity, and sensation seeking on the reduction in speed after smoking cannabis. After adjusting for the influence of sex, blood THC concentration, and predrug mean speed, impulsivity was a significant predictor of change in speed under both single- (β = -.45, = -3.94, < .001) and dual- (β = -.35, = -2.74, = .008) task driving conditions after cannabis. Higher trait impulsivity was significantly associated with greater reductions in driving speed after cannabis use, which may reflect greater sensitivity to drug effects and a stronger compensatory response. Further multidisciplinary study, including neurochemical, genetic, and psychological components, would be beneficial in helping to better understand how impulsivity and other personality or individual differences may impact the effects of cannabis on driver behavior and performance. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pha0000505DOI Listing
July 2021

The influence of conditioned stimuli on [C]-(+)-PHNO PET binding in tobacco smokers after a one week abstinence.

Sci Rep 2021 Jun 3;11(1):11667. Epub 2021 Jun 3.

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada.

Stimuli previously paired with drugs of dependence can produce cravings that are associated with increased dopamine (DA) levels in limbic and striatal brain areas. Positron Emission Tomography (PET) imaging with [C]-(+)-PHNO allows for a sensitive measurement of changes in DA levels. The purpose of the present study was to investigate changes in DA levels, measured with PET imaging with [C]-(+)-PHNO, in regions of interest in smokers who had maintained abstinence for 7-10 days. Participants (N = 10) underwent two PET scans on separate days, during which they viewed either smoking-related or neutral images, in counterbalanced order. Craving was measured with the 12-item Tobacco Craving Questionnaire (TCQ) and the Questionnaire on Smoking Urges-Brief (QSU-B). Compared to neutral cues, smoking cues did not increase craving. There were no changes in [C]-(+)-PHNO binding in the cue condition compared to the neutral condition for most regions of interest (ventral pallidum, globus pallidus, limbic striatum, associative striatum, sensorimotor striatum). However, binding potential in the substantia nigra was greater in the smoking-cue condition, indicating decreased synaptic dopamine. There is a potential change of DA level occurring in midbrain following the presentation of smoking-related cues. However, this preliminary finding would need to be validated with a larger sample.
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http://dx.doi.org/10.1038/s41598-021-90915-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175373PMC
June 2021

Sex differences in the acute pharmacological and subjective effects of smoked cannabis combined with alcohol in young adults.

Psychol Addict Behav 2021 Aug 3;35(5):536-552. Epub 2021 Jun 3.

Department of Pharmacology and Toxicology.

The prevalence of co-use of alcohol and cannabis is increasing, particularly among young adults. Sex differences in the effects of alcohol alone and cannabis alone have been observed in animals and humans. However, sex differences in the acute pharmacological effects of cannabis combined with alcohol have not yet been studied. In young adults, aged 19-29 years, we aimed to examine sex differences following an intoxicating dose of alcohol (target 0.08% breath alcohol content) combined with a moderate dose of cannabis (12.5% Δ⁹-tetrahydrocannabinol; THC) using an ad libitum smoking procedure. Using a within-subjects design, 28 regular cannabis users (16 males; 12 females) received in random order: (a) placebo alcohol and placebo cannabis, (b) active alcohol and placebo cannabis, (c) placebo alcohol and active cannabis, and (d) active alcohol and active cannabis. Blood samples for THC were collected and measures of vital signs, subjective drug effects, and cognition were collected. In the alcohol-cannabis combined condition, females smoked significantly less of the cannabis cigarette compared to males ( < .001), although both sexes smoked similar amounts in the other conditions. There was minimal evidence that females and males differed in THC blood concentrations, vitals, subjective effects, or cognitive measures. In the alcohol-cannabis combined condition, females experienced the same acute pharmacological and subjective effects of alcohol and cannabis as males, after smoking less cannabis, which has potential implications for informing education and policy. Further research is warranted on sex differences in cannabis pharmacology, as well as the combined effects of alcohol and cannabis. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/adb0000749DOI Listing
August 2021

Impact of CYP2A6 Activity on Nicotine Reinforcement and Cue-Reactivity in Daily Smokers.

Nicotine Tob Res 2021 Aug;23(10):1735-1743

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.

Introduction: Variation in CYP2A6, the primary enzyme responsible for nicotine metabolism, is associated with nicotine dependence, cigarette consumption, and abstinence outcomes in smokers. The impact of CYP2A6 activity on nicotine reinforcement and tobacco cue-reactivity, mechanisms that may contribute to these previous associations, has not been fully evaluated.

Aims And Methods: CYP2A6 activity was indexed using 3 genetic approaches in 104 daily smokers completing forced-choice and cue-induced craving tasks assessing nicotine reinforcement and tobacco cue-reactivity, respectively. First, smokers were stratified by the presence or absence of reduced/loss-of-function CYP2A6 gene variants (normal vs. reduced metabolizers). As nicotine metabolite ratio (NMR) is a reliable biomarker of CYP2A6 activity, our second and third approaches used additional genetic variants identified in genome-wide association studies of NMR to create a weighted genetic risk score (wGRS) to stratify smokers (fast vs. slow metabolizers) and calculate a wGRS-derived NMR.

Results: Controlling for race and sex, normal metabolizers (vs. reduced) selected a greater proportion of puffs from nicotine-containing cigarettes (vs. denicotinized) on the forced-choice task (p = .031). In confirmatory analyses, wGRS-based stratification (fast vs. slow metabolizers) produced similar findings. Additionally, wGRS-derived NMR, which correlated with actual NMR assessed in a subset of participants (n = 55), was positively associated with the proportion of puffs from nicotine-containing cigarettes controlling for race and sex (p = .015). None of the CYP2A6 indices were associated with tobacco cue-reactivity in minimally deprived smokers.

Conclusions: Findings suggest increased nicotine reinforcement is exhibited by smokers with high CYP2A6 activity, which may contribute to heavier smoking and poorer cessation outcomes previously reported in faster metabolizers.

Implications: CYP2A6 activity is a key determinant of smoking behavior and outcomes. Therefore, these findings support the targeting of CYP2A6 activity, either therapeutically or as a clinically relevant biomarker in a precision medicine approach, for tobacco use disorder treatment.
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http://dx.doi.org/10.1093/ntr/ntab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403244PMC
August 2021

Integrating a brief alcohol intervention with tobacco addiction treatment in primary care: qualitative study of health care practitioner perceptions.

Addict Sci Clin Pract 2021 03 16;16(1):17. Epub 2021 Mar 16.

Nicotine Dependence Service, Centre for Addiction and Mental Health, 1025 Queen Street W, Toronto, ON, M6J 1H4, Canada.

Background: Randomized trials of complex interventions are increasingly including qualitative components to further understand factors that contribute to their success. In this paper, we explore the experiences of health care practitioners in a province wide smoking cessation program (the Smoking Treatment for Ontario Patients program) who participated in the COMBAT trial. This trial examined if the addition of an electronic prompt embedded in a Clinical Decision Support System (CDSS)-designed to prompt practitioners to Screen, provide a Brief intervention and Referral to Treatment (SBIRT) to patients who drank alcohol above the amounts recommended by the Canadian Cancer Society guidelines-influenced the proportion of practitioners delivering a brief intervention to their eligible patients. We wanted to understand the factors influencing implementation and acceptability of delivering a brief alcohol intervention for treatment-seeking smokers for health care providers who had access to the CDSS (intervention arm) and those who did not (control arm).

Methods: Twenty-three health care practitioners were selected for a qualitative interview using stratified purposeful sampling (12 from the control arm and 11 from the intervention arm). Interviews were 45 to 90 min in length and conducted by phone using an interview guide that was informed by the National Implementation Research Network's Hexagon tool. Interview recordings were transcribed and coded iteratively between three researchers to achieve consensus on emerging themes. The preliminary coding structure was developed using the National Implementation Research Network's Hexagon Tool framework and data was analyzed using the framework analysis approach.

Results: Seventy eight percent (18/23) of the health care practitioners interviewed recognized the need to simultaneously address alcohol and tobacco use. Seventy four percent (17/23), were knowledgeable about the evidence of health risks associated with dual alcohol and tobacco use but 57% (13/23) expressed concerns with using the Canadian Cancer Society guidelines to screen for alcohol use. Practitioners acknowledged the value of adding a validated screening tool to the STOP program's baseline questionnaire (19/23); however, following through with a brief intervention and referral to treatment proved challenging due to lack of training, limited time, and fear of stigmatizing patients. Practitioners in the intervention arm (5/11; 45%) might not follow the recommendations from CDSS if these recommendations are not perceived as beneficial to the patients.

Conclusions: The results of the study show that practitioners' beliefs were reflective of the current social norms around alcohol use and this influenced their decision to offer a brief alcohol intervention. Future interventions need to emphasize both organizational and sociocultural factors as part of the design. The results of this study point to the need to change social norms regarding alcohol in order to effectively implement interventions that target both alcohol and tobacco use in primary care clinics. Trial registration ClinicalTrials.gov NCT03108144. Retrospectively registered 11 April 2017, https://www.clinicaltrials.gov/ct2/show/NCT03108144.
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http://dx.doi.org/10.1186/s13722-021-00225-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968293PMC
March 2021

Significant association of nicotine reinforcement and cue reactivity: a translational study in humans and rats.

Behav Pharmacol 2021 04;32(2&3):212-219

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada.

Relapse is common amongst smokers attempting to quit and tobacco cue-induced craving is an important relapse mechanism. Preclinical studies commonly use cue-induced reinstatement of nicotine seeking to investigate relapse neurobiology. Previous research suggests dependence severity and nicotine intake history affect smoking resumption and cue-induced reinstatement of nicotine seeking. However, behavioural data may be interpreted in terms of nicotine reinforcement. This translational study investigated if individual differences in objectively assessed nicotine reinforcement strength were associated with cue-reactivity in both rats and human smokers, which to our knowledge has not been investigated before. Rats (n = 16) were trained to self-administer nicotine and were tested on a progressive ratio schedule of nicotine reinforcement, to assess reinforcer strength, and on a test of cue-induced reinstatement of nicotine seeking. Nicotine reinforcement strength was assessed in human smokers (n = 104) using a forced choice task (nicotine containing vs. denicotinised cigarettes) and self-reported cue-induced craving was assessed following exposure to smoking and neutral cues. Responding for nicotine under progressive ratio was strongly positively correlated with cue-induced reinstatement of nicotine seeking in rats. Nicotine choices in human smokers were significantly associated with cue-induced craving controlling for dependence severity, years of smoking, and urge to smoke following neutral cues. Findings suggest nicotine reinforcement strength is associated with both types of cue-induced behaviour, implying some translational commonality between cue-induced craving in human smokers and cue-induced reinstatement of nicotine seeking in rats. Findings are discussed in relation to clinical implications and whether these laboratory tasks assess drug 'wanting'.
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http://dx.doi.org/10.1097/FBP.0000000000000607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965230PMC
April 2021

3-Year Follow-up of Lower Risk Cannabis Use Patterns: Evidence from a Longitudinal Survey: Suivi de 3 Ans Des Modèles D'usage du Cannabis à Faible Risque : Données Probantes D'une Enquête Longitudinale.

Can J Psychiatry 2021 Mar 4:706743721996118. Epub 2021 Mar 4.

Translational Addiction Research Laboratory, 7978Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Objectives: Following recommendations from the Lower Risk Cannabis Use Guidelines, we evaluated how lower risk cannabis use (late initiation and low use frequency) was associated with the risk of developing cannabis abuse/dependence over a 3-year follow-up period compared to 12-month abstinence (controls) or higher risk cannabis use (early initiation and higher use frequency). We also explored the effect of cannabis quantity.

Methods: Data were obtained from the U.S. nationally representative survey, National Epidemiologic Survey on Alcohol and Related Conditions wave I (2001 to 2002) and wave II (2004 to 2005), which included 31,464 respondents with no lifetime history of cannabis abuse/dependence at the first interview. We applied multiple logistic regression and propensity score matching analyses to examine the association between different use patterns at wave I and cannabis abuse/dependence at wave II, adjusting for covariates. Lower risk cannabis use and the transition to higher use frequency were also assessed.

Results: For propensity score analysis, lower risk cannabis use at wave I was associated with higher risk of cannabis use/dependence at wave II compared to controls (odds ratio []: 4.27; 95% confidence interval [95% CI], 1.57 to 11.61); however, there was no association with use frequency increase (: 2.52; 95% CI, 0.88 to 7.17). Higher risk use had a greater risk of cannabis use/dependence than controls (: 6.27; 95% CI, 2.56 to 15.38) and lower risk use (: 2.69; 95% CI, 1.12 to 6.47). Logistic regression analyses showed similar results, except that lower risk use was significantly associated with use frequency increase (: 2.49; 95% CI, 1.22 to 5.08). For the lower risk use group, 1 to 3 joints/day of use was significantly associated with cannabis abuse/dependence.

Conclusions: We found that following recommended use patterns can significantly lower one's risk of cannabis abuse/dependence. However, risk of cannabis abuse/dependence is still 4 times higher than staying abstinent. Updated recommendations on safe cannabis exposure levels are needed to guide cannabis use in the general population after cannabis legalization.
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http://dx.doi.org/10.1177/0706743721996118DOI Listing
March 2021

Cannabis use and cannabis use disorder.

Nat Rev Dis Primers 2021 02 25;7(1):16. Epub 2021 Feb 25.

National Centre for Youth Substance Use Research, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia.

Cannabis use disorder (CUD) is an underappreciated risk of using cannabis that affects ~10% of the 193 million cannabis users worldwide. The individual and public health burdens are less than those of other forms of drug use, but CUD accounts for a substantial proportion of persons seeking treatment for drug use disorders owing to the high global prevalence of cannabis use. Cognitive behavioural therapy, motivational enhancement therapy and contingency management can substantially reduce cannabis use and cannabis-related problems, but enduring abstinence is not a common outcome. No pharmacotherapies have been approved for cannabis use or CUD, although a number of drug classes (such as cannabinoid agonists) have shown promise and require more rigorous evaluation. Treatment of cannabis use and CUD is often complicated by comorbid mental health and other substance use disorders. The legalization of non-medical cannabis use in some high-income countries may increase the prevalence of CUD by making more potent cannabis products more readily available at a lower price. States that legalize medical and non-medical cannabis use should inform users about the risks of CUD and provide information on how to obtain assistance if they develop cannabis-related mental and/or physical health problems.
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http://dx.doi.org/10.1038/s41572-021-00247-4DOI Listing
February 2021

Service delivery models for injectable opioid agonist treatment in Canada: 2 sequential environmental scans.

CMAJ Open 2021 Jan-Mar;9(1):E115-E124. Epub 2021 Feb 23.

British Columbia Centre on Substance Use (Eydt, Glegg, Sutherland, Fairbairn); Department of Medicine (Glegg, Fairbairn), University of British Columbia, St. Paul's Hospital; Department of Family Medicine (Sutherland), University of British Columbia; PHS Community Services Society (Sutherland), Vancouver, BC; Alberta Health Services (Meador), Royal Alexandra Hospital; Department of Family Medicine (Meador), University of Alberta, Edmonton, Alta.; Alberta Health Services (Trew), Foothills Medical Centre; Department of Psychiatry (Trew), University of Calgary, Calgary, Alta.; Department of Psychiatry (Perreault), McGill University; Douglas Hospital Research Centre (Perreault); Department of Family Medicine (Goyer), University of Montreal, Montréal, Que.; Centre for Addiction and Mental Health (Le Foll), Toronto, Ont.; Ottawa Inner City Health (Turnbull), Ottawa, Ont.

Background: Injectable opioid agonist treatment (iOAT) is an emerging evidence-based option in the continuum of care for opioid use disorder in parts of Canada. Our study objective was to identify and describe iOAT programs operating during the ongoing opioid overdose crisis.

Methods: We conducted 2 sequential environmental scans. Programs were eligible to participate if they were in operation as of Sept. 1, 2018, and Mar. 1, 2019. Information was collected over 2-3 months for each scan (September-October 2018, March-May 2019). Programs that participated in the first scan and newly established programs were invited to participate in the second scan. The scans included questions about location, service delivery model, clinical and operational characteristics, numbers and demographic characteristics of clients, and program barriers and facilitators. Descriptive analysis was performed.

Results: We identified 14 unique programs across the 2 scans. Eleven programs located in urban centres in British Columbia and Ontario participated in the first scan. At the time of the second scan, 2 of these programs were on hold and 2 of 3 newly established programs were in Alberta. The total capacity of all participating programs was 420 clients at most. Four service delivery models were identified; iOAT was most commonly integrated within existing health and social services. All programs offered hydromorphone, and 1 program also offered diacetylmorphine. In the first scan, 73% of clients (133/183) were male; the mean age of clients was 47 years. Limited capacity, pharmacy operations and lack of diacetylmorphine access were among the most frequently reported barriers. The most commonly reported facilitators included client-centred care, client relationships and access to other health and social support.

Interpretation: Evidence indicates that iOAT can be successfully implemented using diverse service delivery models. Future work should facilitate scale-up of this evidence-based treatment where gaps persist in high-risk communities.
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http://dx.doi.org/10.9778/cmajo.20200021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034381PMC
July 2021

Canadian Society of Transplantation White Paper: Ethical and Legal Considerations for Alcohol and Cannabis Use in Solid Organ Listing and Allocation.

Transplantation 2021 Sep;105(9):1957-1964

Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada.

Alcohol and cannabis use as a contraindication to organ transplantation is a controversial issue. Until recently, patients in Canada with alcohol-associated liver disease were required to demonstrate abstinence for 6 mo to receive a liver transplant. There is no equivalent rule that is applied consistently for cannabis use. There is some evidence that alcohol and cannabis use disorder pretransplant could be associated with worse outcomes posttransplantation. However, early liver transplantation for patients with alcohol-associated liver disease in France and in the United States has led to challenges of the 6-mo abstinence rule in Canada in the media. It has also resulted in several legal challenges arguing that the rule violates human rights laws regarding discrimination in the provision of medical services and that the rule is also unconstitutional (this challenge is still before the court). Recent legalization of cannabis use for adults in Canada has led to questions about the appropriateness of limiting transplant access based on cannabis use. The ethics committee of the Canadian Society of Transplantation was asked to provide an ethical analysis of cannabis and alcohol abstinence policies. Our conclusions were as follows: neither cannabis use nor the 6-mo abstinence rule for alcohol use should be an absolute contraindication to transplantation, and transplant could be offered to selected patients, further research should be conducted to ensure evidence-based policies; and the transplant community has a duty not to perpetuate stigma associated with alcohol and cannabis use disorders.
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http://dx.doi.org/10.1097/TP.0000000000003618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376271PMC
September 2021

Combined effect of alcohol and cannabis on simulated driving.

Psychopharmacology (Berl) 2021 Feb 5. Epub 2021 Feb 5.

Department of Pharmacology and Toxicology, University of Toronto, 27 King's College Circle, Toronto, Ontario, M5S 3H7, Canada.

Rationale: With alcohol and cannabis remaining the most commonly detected drugs in seriously and fatally injured drivers, there is a need to understand their combined effects on driving.

Objectives: The present study examined the effects of combinations of smoked cannabis (12.5% THC) and alcohol (target BrAC 0.08%) on simulated driving performance, subjective drug effects, cardiovascular measures, and self-reported perception of driving ability.

Methods: In this within-subjects, double-blind, double-dummy, placebo-controlled, randomized clinical trial, cannabis users (1-7 days/week) aged 19-29 years attended four drug administration sessions in which simulated driving, subjective effects, cardiovascular measures, and whole blood THC and metabolite concentrations were assessed following placebo alcohol and placebo cannabis (<0.1% THC), alcohol and placebo cannabis, placebo alcohol and active cannabis, and alcohol and active cannabis.

Results: Standard deviation of lateral position in the combined condition was significantly different from the placebo condition (p < 0.001). Standard deviation of lateral position was also significantly different from alcohol and cannabis alone conditions in the single task overall drive (p = 0.029 and p = 0.032, respectively), from the alcohol alone condition in the dual task overall drive (p = 0.022) and the cannabis alone condition in the dual task straightaway drive (p = 0.002). Compared to the placebo condition, the combined and alcohol conditions significantly increased reaction time. Subjective effects in the combined condition were significantly greater than with either of the drugs alone at some time points, particularly later in the session. A driving ability questionnaire showed that participants seemed unaware of their level of impairment.

Conclusion: Combinations of alcohol and cannabis increased weaving and reaction time, and tended to produce greater subjective effects compared to placebo and the single drug conditions suggesting a potential additive effect. The fact that participants were unaware of this increased effect has important implications for driving safety.
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http://dx.doi.org/10.1007/s00213-021-05773-3DOI Listing
February 2021

Association of the Fatty Acid Amide Hydrolase C385A Polymorphism With Alcohol Use Severity and Coping Motives in Heavy-Drinking Youth.

Alcohol Clin Exp Res 2021 03 18;45(3):507-517. Epub 2021 Feb 18.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Reduced function of fatty acid amide hydrolase, the catabolic enzyme for the endocannabinoid anandamide, can be inherited through a functional genetic polymorphism (FAAH rs324420, C385A, P129T). The minor (A) allele has been associated with reduced FAAH enzyme activity and increased risk for substance use disorders in adults. Whether this inherited difference in endocannabinoid metabolism relates to alcohol use disorder etiology and patterns of alcohol use in youth is unknown.

Methods: To examine this question, heavy-drinking youth (n = 302; mean age = 19.74 ± 1.18) were genotyped for FAAH C385A. All subjects completed a comprehensive interview assessing alcohol use patterns including the Timeline Follow-back Method, Alcohol Use Disorders Identification Test (AUDIT), and Drinking Motives Questionnaire. Analyses of Covariance (ANCOVAs) were conducted to assess differences in drinking patterns and drinking motives between genotype groups, and mediation analyses investigated whether drinking motives accounted for indirect associations of genotype with alcohol use severity.

Results: Youth with the FAAH minor allele (AC or AA genotype) reported significantly more drinking days (p = 0.045), significantly more frequent heavy episodic drinking (p = 0.003), and significantly higher alcohol-related problems and consumption patterns (AUDIT score p = 0.045, AUDIT-C score p = 0.02). Mediation analyses showed that the association of FAAH C385A with drinking outcomes was mediated by coping motives.

Conclusions: These findings extend previous studies by suggesting that reduced endocannabinoid metabolism may be related to heavier use of alcohol in youth, prior to the onset of chronic drinking problems. Furthermore, differences in negative reinforcement-related drinking could account in part for this association.
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http://dx.doi.org/10.1111/acer.14552DOI Listing
March 2021

The CB1R rs2023239 receptor gene variant significantly affects the reinforcing effects of nicotine, but not cue reactivity, in human smokers.

Brain Behav 2021 02 25;11(2):e01982. Epub 2020 Dec 25.

Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.

Introduction: The cannabinoid CB1 receptor (CB1R) has been shown in preclinical studies to be involved in nicotine reinforcement and relapse-like behavior. The common single nucleotide polymorphism (SNP) rs2023239 may code for an alternative CB1R protein, alter CB1R expression, and be involved in nicotine dependence. To date, no study has explored the relationship between this SNP in CB1R and specific phenotypes of nicotine dependence.

Methods: The current study investigated the influence of CB1R rs2023239 in nicotine reinforcement and craving in regular cigarette smokers. Current smokers (n = 104, cigarettes per day ≥ 10) were genetically grouped (C allele group vs. No C allele group) and underwent laboratory measures of nicotine reinforcement and smoking cue-elicited craving. Nicotine reinforcement was assessed using a forced choice paradigm, while a cue-reactivity procedure measured cue-elicited craving.

Results: These results show that smokers with the C allele variant (CC + CT genotypes) experienced a lower nicotine reinforcement effect compared to those without the C allele (TT genotype). These results were similar in both our subjective and behavioral reinforcement measures, though the subjective effects did not withstand controlling for race. There was no difference between genotype groups with respect to cue-elicited craving, suggesting a lack of influence in cue reactivity.

Conclusion: Taken together, these results suggest that the variation in the CB1R (i.e., rs2023239 SNP) may play a larger role in nicotine reinforcement compared to cue reactivity. This work provides impetus to further understand the physiological mechanisms that explain how CB1Rs influence nicotine dependence phenotypes.
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http://dx.doi.org/10.1002/brb3.1982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882168PMC
February 2021

Consensus-based recommendations for titrating cannabinoids and tapering opioids for chronic pain control.

Int J Clin Pract 2021 Aug 18;75(8):e13871. Epub 2020 Dec 18.

Department of Physical Medicine and Rehabilitation, Stan Cassidy Centre for Rehabilitation, Fredericton, NB, Canada.

Aims: Opioid misuse and overuse have contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids.

Results: In patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid-related complications, despite psychological or physical interventions. There was consensus observed to initiate with a cannabidiol (CBD)-predominant oral extract in the daytime and consider adding tetrahydrocannabinol (THC). When adding THC, start with 0.5-3 mg, and increase by 1-2 mg once or twice weekly up to 30-40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as-needed medication to control pain and/or the cannabis dose has been optimised. The opioid tapering schedule may be 5%-10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥30% reduction in pain intensity, a ≥25% reduction in opioid dose, a reduction in opioid dose to <90 mg MED and/or reduction in opioid-related adverse events.

Conclusions: This five-stage modified Delphi process led to the development of consensus-based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids.
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http://dx.doi.org/10.1111/ijcp.13871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365704PMC
August 2021

Cannabis Legalization and Acute Harm From High Potency Cannabis Products: A Narrative Review and Recommendations for Public Health.

Front Psychiatry 2020 23;11:591979. Epub 2020 Sep 23.

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Legalization and commercial sale of non-medical cannabis has led to increasing diversity and potency of cannabis products. Some of the American states that were the first to legalize have seen rises in acute harms associated with cannabis use, e.g. Colorado has seen increases in emergency department visits for cannabis-related acute psychological distress and severe vomiting (hyperemesis), as well as a number of high-profile deaths related to ingestion of high doses of cannabis edibles. Over-ingestion of cannabis is related to multiple factors, including the sale of cannabis products with high levels of THC and consumers' confusion regarding labelling of cannabis products, which disproportionately impact new or inexperienced users. Based on our review of the literature, we propose three approaches to minimizing acute harms: early restriction of cannabis edibles and high-potency products; clear and consistent labelling that communicates dose/serving size and health risks; and implementation of robust data collection frameworks to monitor harms, broken down by cannabis product type (e.g. dose, potency, route of administration) and consumer characteristics (e.g. age, sex, gender, ethnicity). Ongoing data collection and monitoring of harms in jurisdictions that have existing legal cannabis laws will be vital to understanding the impact of cannabis legalization and maximizing public health benefits.
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http://dx.doi.org/10.3389/fpsyt.2020.591979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538627PMC
September 2020

Perioperative Pain and Addiction Interdisciplinary Network (PAIN): consensus recommendations for perioperative management of cannabis and cannabinoid-based medicine users by a modified Delphi process.

Br J Anaesth 2021 Jan 29;126(1):304-318. Epub 2020 Oct 29.

Department of Anesthesia and Pain Management, Toronto General Hospital and University of Toronto, Toronto, ON, Canada; Centre for Cannabinoid Therapeutics, Toronto, ON, Canada. Electronic address:

In many countries, liberalisation of the legislation regulating the use of cannabis has outpaced rigorous scientific studies, and a growing number of patients presenting for surgery consume cannabis regularly. Research to date suggests that cannabis can impact perioperative outcomes. We present recommendations obtained using a modified Delphi method for the perioperative care of cannabis-using patients. A steering committee was formed and a review of medical literature with respect to perioperative cannabis use was conducted. This was followed by the recruitment of a panel of 17 experts on the care of cannabis-consuming patients. Panellists were blinded to each other's participation and were provided with rater forms exploring the appropriateness of specific perioperative care elements. The completed rater forms were analysed for consensus. The expert panel was then unblinded and met to discuss the rater form analyses. Draft recommendations were then created and returned to the expert panel for further comment. The draft recommendations were also sent to four independent reviewers (a surgeon, a nurse practitioner, and two patients). The collected feedback was used to finalise the recommendations. The major recommendations obtained included emphasising the importance of eliciting a history of cannabis use, quantifying it, and ensuring contact with a cannabis authoriser (if one exists). Recommendations also included the consideration of perioperative cannabis weaning, additional postoperative nausea and vomiting prophylaxis, and additional attention to monitoring and maintaining anaesthetic depth. Postoperative recommendations included anticipating increased postoperative analgesic requirements and maintaining vigilance for cannabis withdrawal syndrome.
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http://dx.doi.org/10.1016/j.bja.2020.09.026DOI Listing
January 2021

Posttraumatic Stress Disorder After a Psychedelic Experience, a Case Report.

J Addict Med 2021 May-Jun 01;15(3):248-251

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada (ASR-K, ANH, BLF); Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada (ASR-K, ANH, BLF); Department of Psychiatry, King Abdul-Aziz University, Jeddah, Saudi Arabia (ANH); Departments of Family and Community Medicine, Pharmacology and Toxicology, University of Toronto, Toronto, Canada (ANH, BLF); Department of Psychiatry, Campbell Family Mental Health Research Institute, CAMH, Toronto, Canada (BLF); Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada (BLF).

In the last 2 decades, there is a renaissance in the scientific investigation of the therapeutic potential of psychedelic compounds. It is studied for the treatment of many psychiatric disorders, including posttraumatic stress disorder. The treatment is always done in the setting of psychedelic-assisted psychotherapy. A little is known about the potential effects, outside of the setting of psychedelic-assisted psychotherapy, on people diagnosed with a mental disorder or have a significant trauma history. In this case report, we present a young man who developed posttraumatic stress disorder after a psychedelic experience, induced by both Lysergic Acid Diethylamide (LSD) and N, N Dimethyltryptamine (DMT). In the psychedelic experience, a repressed memory of childhood sexual abuse was recovered. To our knowledge, this is the first report on posttraumatic stress disorder onset after a psychedelic experience. We believe that this case report is important since the history of trauma is prevalent among individuals with substance use disorder. Medical staff that treat people with either substance use disorder or trauma should be familiar with irregular presentations, such as the one described in this case.
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http://dx.doi.org/10.1097/ADM.0000000000000734DOI Listing
June 2021

Opioid-sparing effects of cannabinoids: Myth or reality?

Authors:
Bernard Le Foll

Prog Neuropsychopharmacol Biol Psychiatry 2021 03 21;106:110065. Epub 2020 Aug 21.

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada; Acute Care Program, Centre for Addiction and Mental Health, Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada.; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Electronic address:

A converging line of evidence is indicating that cannabinoids may have an opioid-sparing effect. This property, well validated in preclinical studies, allow when both drugs are co-administered to reduce the dose of opioids without loss of analgesic effects. A meta-analysis of pre-clinical studies indicated in 2017 that the median effective dose (ED) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower than the ED of morphine alone (Nielsen et al., 2017). However, very few studies have been conducted in humans to validate this effect. This narrative review provides an update on whether or not cannabinoid drugs can be used to produce an opioid sparing effect. For this, various lines of evidence ranging from preclinical, epidemiological and human studies will be summarized. Overall, this review indicates that the preclinical results are strongly and consistently supportive of the presence of an opioid sparing effect of cannabinoid drugs. However, to date the clinical studies have been mostly negative; and, the evidence collected in humans so far is so limited that it is premature to conclude. Therefore, prospective high quality controlled clinical trials are still required to validate this. Priorities for future research are also discussed.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110065DOI Listing
March 2021

Personalized dosing of nicotine replacement therapy versus standard dosing for the treatment of individuals with tobacco dependence: study protocol for a randomized placebo-controlled trial.

Trials 2020 Jun 29;21(1):592. Epub 2020 Jun 29.

Nicotine Dependence Services, Centre for Addiction and Mental Health, 175 College St, Toronto, Ontario, M5T 1P7, Canada.

Background: Medications for smoking cessation are currently only effective in helping a minority of smokers quit. Drug development is slow and expensive; as such, there is much interest in optimizing the effectiveness of existing treatments and medications. Current standard doses of nicotine replacement therapy are not effective for many smokers, and in many cases, the amount of nicotine provided is much less than when a smoker is smoking their usual number of cigarettes. The proposed study will test if titrating the dose of the nicotine patch (up to 84 mg) will improve quitting success compared to those receiving a 21-mg nicotine patch with increasing doses of placebo patch.

Methods: This is a multicenter, pragmatic, two-arm, placebo-controlled, block randomized controlled trial. We will recruit participants who smoke at least 10 cigarettes daily and are interested in making a quit attempt. After 2 weeks of usual treatment with a 21-mg patch, participants who fail to quit smoking (target n = 400) will be randomized to receive escalating doses of a nicotine patch vs matching placebo patches for an additional 10 weeks or up to a maximum dose of 84 mg per day. Those who stop smoking during the first 2 weeks of usual treatment will continue with 21 mg patch treatment for 10 weeks and will form an additional comparison arm. In addition to the medication, participants will receive brief behavioral counseling at each study visit. The primary outcome will be biochemically confirmed continuous abstinence from smoking during the last 4 weeks of treatment (weeks 9 to 12).

Discussion: Research evidence supporting the effectiveness of personalized doses of nicotine replacement therapy could change current practice in a variety of healthcare settings. Given the evidence that quitting smoking at any age diminishes the risk of tobacco-related morbidity and mortality, even small increases in absolute quit rates can have a substantial population-level impact on reducing smoking-related disease, mortality rates, and associated healthcare costs.

Trial Registration: ClinicalTrials.gov, NCT03000387 . Registered on 22 December 2016.
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http://dx.doi.org/10.1186/s13063-020-04532-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325031PMC
June 2020

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs.

Biomolecules 2020 06 4;10(6). Epub 2020 Jun 4.

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, 33 Russell Street, Toronto, ON M5S 2S1, Canada.

Obesity rates are increasing worldwide and there is a need for novel therapeutic treatment options. The endocannabinoid system has been linked to homeostatic processes, including metabolism, food intake, and the regulation of body weight. Rimonabant, an inverse agonist for the cannabinoid CB1 receptor, was effective at producing weight loss in obese subjects. However, due to adverse psychiatric side effects, rimonabant was removed from the market. More recently, we reported an inverse relationship between cannabis use and BMI, which has now been duplicated by several groups. As those results may appear contradictory, we review here preclinical and clinical studies that have studied the impact on body weight of various cannabinoid CB1 drugs. Notably, we will review the impact of CB1 inverse agonists, agonists, partial agonists, and neutral antagonists. Those findings clearly point out the cannabinoid CB1 as a potential effective target for the treatment of obesity. Recent preclinical studies suggest that ligands targeting the CB1 may retain the therapeutic potential of rimonabant without the negative side effect profile. Such approaches should be tested in clinical trials for validation.
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http://dx.doi.org/10.3390/biom10060855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356944PMC
June 2020

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs.

Biomolecules 2020 06 4;10(6). Epub 2020 Jun 4.

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, 33 Russell Street, Toronto, ON M5S 2S1, Canada.

Obesity rates are increasing worldwide and there is a need for novel therapeutic treatment options. The endocannabinoid system has been linked to homeostatic processes, including metabolism, food intake, and the regulation of body weight. Rimonabant, an inverse agonist for the cannabinoid CB1 receptor, was effective at producing weight loss in obese subjects. However, due to adverse psychiatric side effects, rimonabant was removed from the market. More recently, we reported an inverse relationship between cannabis use and BMI, which has now been duplicated by several groups. As those results may appear contradictory, we review here preclinical and clinical studies that have studied the impact on body weight of various cannabinoid CB1 drugs. Notably, we will review the impact of CB1 inverse agonists, agonists, partial agonists, and neutral antagonists. Those findings clearly point out the cannabinoid CB1 as a potential effective target for the treatment of obesity. Recent preclinical studies suggest that ligands targeting the CB1 may retain the therapeutic potential of rimonabant without the negative side effect profile. Such approaches should be tested in clinical trials for validation.
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http://dx.doi.org/10.3390/biom10060855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356944PMC
June 2020

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

Expert Opin Drug Discov 2020 09 19;15(9):1065-1080. Epub 2020 May 19.

Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto , Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1080/17460441.2020.1767581DOI Listing
September 2020

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Substance Use Disorders: A Synthesis of Preclinical and Human Evidence.

Cells 2020 05 12;9(5). Epub 2020 May 12.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, 27 King's College Circle, Toronto, ON M5S 3H7, Canada.

Targeting peroxisome proliferator-activated receptors (PPARs) has received increasing interest as a potential strategy to treat substance use disorders due to the localization of PPARs in addiction-related brain regions and the ability of PPAR ligands to modulate dopamine neurotransmission. Robust evidence from animal models suggests that agonists at both the PPAR-α and PPAR-γ isoforms can reduce both positive and negative reinforcing properties of ethanol, nicotine, opioids, and possibly psychostimulants. A reduction in the voluntary consumption of ethanol following treatment with PPAR agonists seems to be the most consistent finding. However, the human evidence is limited in scope and has so far been less promising. There have been no published human trials of PPAR agonists for treatment of alcohol use disorder, despite the compelling preclinical evidence. Two trials of PPAR-α agonists as potential smoking cessation drugs found no effect on nicotine-related outcomes. The PPAR-γ agonist pioglitazone showed some promise in reducing heroin, nicotine, and cocaine craving in two human laboratory studies and one pilot trial, yet other outcomes were unaffected. Potential explanations for the discordance between the animal and human evidence, such as the potency and selectivity of PPAR ligands and sex-related variability in PPAR physiology, are discussed.
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http://dx.doi.org/10.3390/cells9051196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291117PMC
May 2020

Acute and residual mood and cognitive performance of young adults following smoked cannabis.

Pharmacol Biochem Behav 2020 07 1;194:172937. Epub 2020 May 1.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, 27 King's College Circle, Toronto, Ontario M5S3H7, Canada; Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, 33 Russell Street, Toronto, Ontario M5S2S1, Canada; Controlled Substances and Cannabis Directorate, Health Canada, Ottawa, Ontario, Canada.

Objectives: To examine acute and residual mood and cognitive performance in young adult regular cannabis users following smoked cannabis.

Methods: Ninety-one healthy young adults completed this double-blind, placebo-controlled, parallel-groups study. Participants were randomized to receive active (12.5% THC) or placebo cannabis with a 2:1 allocation ratio, and mood [Profile of Mood States (POMS)] and cognitive performance [Hopkins Verbal Learning Test - Revised (HVLT-R), Digit Symbol Substitution Test (DSST), Continuous Performance Test (CPT), grooved pegboard (GPB)] were assessed before and 1, 24, and 48 (h) after smoking cannabis ad libitum. High and Low THC groups were based on blood THC concentrations.

Results: One hour after smoking cannabis, compared to Placebo, in both the High and Low THC groups, there were increases in POMS Arousal and Positive Mood, and in the High THC group only, increases in Confusion, Friendliness, and Elation, and a decrease in Fatigue. Increases in Friendliness and Elation in the High THC group remained significant for 24 h. The only significant acute effect of cannabis on cognition was a decrease in the percent of words retained in the HVLT-R in the High THC group compared to Placebo (mean difference = 15.8%, 95% CI = 3.6-28.0%, p = 0.006). Unexpectedly, compared to Placebo, both the High and Low THC groups improved in DSST performance at 48 h (p ≤ 0.016).

Conclusions: Under the present experimental conditions, in young regular cannabis users, smoking cannabis ad libitum had significant effects on mood, some of which persisted 24 h later, yet minimal effects on cognition, and no evidence of residual cognitive impairment.
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http://dx.doi.org/10.1016/j.pbb.2020.172937DOI Listing
July 2020
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