Bridging the Macro-micro Divide: A Qualitative Meta-synthesis on the Perspectives and Experiences of Health Care Providers on the Extramedical Use and Diversion of Buprenorphine.

OBJECTIVES: Opioid agonist therapy using buprenorphine is one of the most effective treatments for opioid use disorder. However, concerns regarding its extramedical use and diversion, such as adverse patient outcomes and damage to the legitimacy of addictions practice, are persistent. The aim of this review is to synthesize the perspectives and experiences of health care providers around the extramedical use of buprenorphine. METHODS: A qualitative meta-synthesis was conducted based on a systematic search of 8 databases. All primary qualitative and mixed-methods studies relating to the views of health care providers on the extramedical use of buprenorphine were included. A qualitative analysis informed by the constant comparative method was conducted, using NVivo for data management. RESULTS: Sixteen studies were included in this review. Findings were organizedunder 2 key themes: (1) Harm-producing versus harm-reducing effects of extramedical buprenorphine use and (2) driving forces of and responses to extramedical buprenorphine use. CONCLUSIONS: The studies included in our review identified a disconnect-health care providers noted that macro, health care system-level challenges drove extramedical use whereas the recommended solutions for prevention and management were primarily aimed at the micro, individual level. This study emphasizes the critical role that health care providers can play, in partnership with patients, in informing appropriate policies and health care system design to optimize the care for people with opioid use disorder.

Mal/adaptations: A qualitative evidence synthesis of opioid agonist therapy during major disruptions.

BACKGROUND: Opioid agonist therapy (OAT) has been severely disrupted by the COVID-19 pandemic. The risks of opioid withdrawal, overdose, and diversion have increased, so there is an urgent need to adapt OAT to best support people who use drugs (PWUD). This review examines the views and experiences of PWUD, health care providers, and health system administrators on OAT during major disruptions to medical care to inform appropriate health system responses during the current pandemic and beyond. METHODS: We conducted a systematic review and qualitative evidence synthesis. We searched three comprehensive datasets for qualitative and mixed-methods studies that examined OAT in the context of major disruptions such as natural disasters, and analyzed included studies using thematic analysis and the constant comparative method. We used conceptual frameworks of health systems resilience and adaptive systems to interpret our findings. RESULTS: We included 10 studies published between 2002 and 2020 that examined OAT in the context of hurricanes, earthquakes, and terrorist attacks. We organized our results into three themes: uncertainty, inconsistency, and vulnerability; regulatory inflexibility; and lack of coordination. The highly regulated but poorly coordinated systems of OAT provision lacked flexibility to adapt to major disruptions, thereby manufacturing vulnerability for both PWUD and health workers. CONCLUSIONS: OAT programs must be resilient and adaptable to face major disruptions while maintaining quality care. Our findings provide guidance to develop and implement innovative strategies that increase the adaptive potential of OAT programs while focusing on the needs of PWUD.

Beyond harm-producing versus harm-reducing: A qualitative meta-synthesis of people who use drugs' perspectives of and experiences with the extramedical use and diversion of buprenorphine.

INTRODUCTION: This review synthesizes the literature on the perspectives and experiences of people who use drugs to better understand motivations and behaviors related to the extramedical use and diversion of buprenorphine. Given the particular social construction of buprenorphine against methadone, and the centrality of concerns around extramedical use in delivering opioid agonist therapies, a focus on extramedical buprenorphine use can provide an important lens through which to analyze treatment for opioid use disorder. This review is framed within persistent tensions between potential harm-producing versus harm-reducing effects of extramedical use that have long been described for opioid agonist therapies. METHODS: The research team conducted a qualitative meta-synthesis based on a systematic search of eight databases as well as hand searching. The review includes all primary qualitative and mixed-methods studies related to the perspectives and experiences of people who use drugs on extramedical buprenorphine use. The study team carried out three rounds of qualitative coding using NVivo 12, and constructivist grounded theory and the constant comparative method informed the synthesis. RESULTS: The review includes twenty-one studies. Findings are organized into the following three themes: 1) the experiences of people who use drugs (PWUD) with extramedical use of buprenorphine and their motivations to engage in it (including the desire to self-medicate and achieve "stability", to manage ongoing use of other opioids, and to "get high"); 2) the relationship between extramedical use and formal medical opioid agonist therapy programs; and 3) the established drug economy of extramedical buprenorphine. CONCLUSIONS: The review identified varied and often divergent perspectives and experiences with extramedical buprenorphine use. An examination of the reported "normalizing" effects of extramedical buprenorphine suggests this practice as extending medicalized discipline beyond the clinical environment. Taken together, these findings identify a need to move beyond the tension of harm-reducing versus harm-producing effects toward forms of health care and promotion that focus on the needs, perspectives, and priorities of people who use drugs.

Exploring occupancy of the histamine H3 receptor by pitolisant in humans using PET.

BACKGROUND AND PURPOSE: BF2.649 (pitolisant, Wakix®) is a novel histamine H3 receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H3 receptors by BF2.649 using PET brain imaging with the H3 receptor antagonist radioligand [11 C]GSK189254. EXPERIMENTAL APPROACH: Six healthy adult participants were scanned with [11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 h after oral administration of placebo or after pitolisant hydrochloride (40 mg). [11 C]GSK189254 regional total distribution volumes were estimated in nine brain regions of interest with the two tissue-compartment model with arterial input function using a common VND across the regions. Brain receptor occupancies were calculated with the Lassen plot. KEY RESULTS: Pitolisant, at the dose administered, provided high (84 ± 7%; mean ± SD) occupancy of H3 receptors. The drug was well-tolerated, and participants experienced few adverse events. CONCLUSION AND IMPLICATIONS: The administration of pitolisant (40 mg) produces a high occupancy of H3 receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H3 receptors.

Pharmacotherapies for Cannabis Use Disorders: Clinical Challenges and Promising Therapeutic Agents.

This chapter reviews pharmacotherapies that have been trialled for cannabis dependence, identifying those that warrant further research and those of little or uncertain value. A diverse range of medicines have been tested, representing a broad range of pharmacological strategies. These include tetrahydrocannabinol preparations, various types of antidepressant, anxiolytics, a glutamatergic modulator and the neuropeptide oxytocin. Cannabinoid agonists warrant further research. For the FAAH inhibitor PF-04457845, oxytocin, varenicline and gabapentin, although there is a signal to indicate further research is warranted, these medications do not yet have sufficient evidence to support clinical use, and larger, longer-term trials are needed in representative treatment-seeking populations. Special populations that warrant consideration are those with cannabis dependence and concurrent mental health conditions and those that develop dependence through therapeutic use.

Assessing service and treatment needs and barriers of youth who use illicit and non-medical prescription drugs in Northern Ontario, Canada.

BACKGROUND: Illicit drug use rates are high among Canadian youth, and are particularly pronounced in Northern Ontario. The availability and accessibility of effective substance use-related treatments and services are required to address this problem, especially among rural and remote Northern communities. In order to assess specific service and treatment needs, as well as barriers and deterrents to accessing and utilizing services and treatments for youth who use illicit drugs in Northern Ontario, we conducted the present study. METHODS: This study utilized a mixed-methods design and incorporated a community-based participatory research approach. Questionnaires were administered in conjunction with audio-recorded semi-structured interviews and/or focus groups with youth (aged 14-25) who live in Northern Ontario and use illicit drugs. Interviews with 'key informants' who work with the youth in each community were also conducted. Between August and December 2017, the research team traveled to Northern Ontario communities and carried out data collection procedures. RESULTS: A total of 102 youth and 35 key informants from eleven different Northern Ontario communities were interviewed. The most commonly used drugs were prescription opioids, cocaine and crack-cocaine. Most participants experienced problems related to their drug use, and reported 'fair' mental and physical health status. Qualitative analyses highlighted an overall lack of services; barriers to accessing treatment and services included lack of motivation, stigmatization, long wait-lists and transportation/mobility issues. Articulated needs revolved around the necessity of harm reduction-based services, low-threshold programs, specialized programming, and peer-based counselling. CONCLUSIONS: Although each community varied in terms of drug use behaviors and available services, an overall need for youth-specific, low-threshold services was identified. Information gathered from this study can be used to help inform rural and remote communities towards improving treatment and service system performance and provision.

Pharmacotherapies for cannabis dependence.

BACKGROUND: Globally, cannabis use is prevalent and widespread. There are currently no pharmacotherapies approved for treatment of cannabis use disorders.This is an update of a Cochrane Review first published in the Cochrane Library in Issue 12, 2014. OBJECTIVES: To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or no pharmacotherapy (supportive care) for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use. SEARCH METHODS: We updated our searches of the following databases to March 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and Web of Science. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs involving the use of medications to treat cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in people diagnosed as cannabis dependent or who were likely to be dependent. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 21 RCTs involving 1755 participants: 18 studies recruited adults (mean age 22 to 41 years); three studies targeted young people (mean age 20 years). Most (75%) participants were male. The studies were at low risk of performance, detection and selective outcome reporting bias. One study was at risk of selection bias, and three studies were at risk of attrition bias.All studies involved comparison of active medication and placebo. The medications were diverse, as were the outcomes reported, which limited the extent of analysis.Abstinence at end of treatment was no more likely with Δ9-tetrahydrocannabinol (THC) preparations than with placebo (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.64 to 1.52; 305 participants; 3 studies; moderate-quality evidence). For selective serotonin reuptake inhibitor (SSRI) antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine, there was no difference in the likelihood of abstinence at end of treatment compared to placebo (low- to very low-quality evidence).There was qualitative evidence of reduced intensity of withdrawal symptoms with THC preparations compared to placebo. For other pharmacotherapies, this outcome was either not examined, or no significant differences was reported.Adverse effects were no more likely with THC preparations (RR 1.02, 95% CI 0.89 to 1.17; 318 participants; 3 studies) or N-acetylcysteine (RR 0.94, 95% CI 0.71 to 1.23; 418 participants; 2 studies) compared to placebo (moderate-quality evidence). For SSRI antidepressants, mixed action antidepressants, buspirone and N-acetylcysteine, there was no difference in adverse effects compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of withdrawal from treatment due to adverse effects with THC preparations, SSRIs antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of treatment completion with THC preparations, SSRI antidepressants, mixed action antidepressants and buspirone compared to placebo (low- to very low-quality evidence) or with N-acetylcysteine compared to placebo (RR 1.06, 95% CI 0.93 to 1.21; 418 participants; 2 studies; moderate-quality evidence). Anticonvulsants and mood stabilisers appeared to reduce the likelihood of treatment completion (RR 0.66, 95% CI 0.47 to 0.92; 141 participants; 3 studies; low-quality evidence).Available evidence on gabapentin (anticonvulsant), oxytocin (neuropeptide) and atomoxetine was insufficient for estimates of effectiveness. AUTHORS' CONCLUSIONS: There is incomplete evidence for all of the pharmacotherapies investigated, and for many outcomes the quality of the evidence was low or very low. Findings indicate that SSRI antidepressants, mixed action antidepressants, bupropion, buspirone and atomoxetine are probably of little value in the treatment of cannabis dependence. Given the limited evidence of efficacy, THC preparations should be considered still experimental, with some positive effects on withdrawal symptoms and craving. The evidence base for the anticonvulsant gabapentin, oxytocin, and N-acetylcysteine is weak, but these medications are also worth further investigation.

Psychosocial and Pharmacological Interventions for the Treatment of Cannabis Use Disorder.

(Reprinted with permission from Sabioni P and Le Foll B. Psychosocial and pharmacological interventions for the treatment of cannabis use disorder [version 1; referees: 3 approved]. F1000Research 2018, 7(F1000 Faculty Rev):173 (https://doi.org/10.12688/f1000research.11191.1)).

Psychosocial and pharmacological interventions for the treatment of cannabis use disorder.

Cannabis use has been continuously increasing, and cannabis use disorder (CUD) has become a public health issue. Some psychosocial interventions have demonstrated the ability to reduce cannabis use; however, there are no pharmacotherapies approved for the treatment of CUD. Some drugs have shown limited positive effects on use and withdrawal symptoms, but no controlled studies have been able to show strong and persistent effects on clinically meaningful outcomes. The aim of this review is to synthesize the evidence from the available literature regarding the effectiveness of psychosocial and pharmacological treatments for CUD among adults (that is, 18 years old or older). An analysis of the evidence shows that the current best psychosocial intervention to reduce cannabis use is the combination of motivational enhancement therapy and cognitive-behavioral therapy, preferably accompanied by a contingency management approach. In regard to pharmacological interventions, there are mostly unclear findings. Some drugs, such as CB1 agonists, gabapentin, and N-acetylcysteine, have been shown to produce improvements in some symptoms of CUD in single studies, but these have not been replicated. Other classes of medications, including antidepressants and antipsychotics, have been unsuccessful in producing such effects. There is an imminent need for more clinical trials to develop more effective treatments for CUD.

Assessing service and treatment needs of young people who use illicit and non-medical prescription drugs living in Northern Ontario, Canada.

Background: The use of illicit and prescription drugs for non-medical purposes among youth and young adults living in Northern Ontario communities is a major public health concern. This problem is amplified in that there is insufficient knowledge on the types of services and treatment centers available for and utilized by young people with substance use issues in Northern Ontario. This needs assessment study aims to examine the service and treatment needs of youth and young adults who use drugs in Northern Ontario communities. Methods/Design: A mixed-methods study design will be used to assess the service and treatment needs of youth and young adults (aged 14-25) who have used one or more illicit drug (excluding cannabis) and/or psychoactive prescription drug for non-medical purposes for at least 3 months and on at least 10 days in the last month. Participants will be recruited from approximately ten Northern, remote and rural communities across Northern Ontario using a mobile research lab. Eligible study candidates from each community will be asked to partake in a focus group and questionnaire exploring service and treatment utilization and needs. We will additionally collect basic socio-demographic information as well as examine patterns of problematic drug use. Interviews with service providers and community organizers will also be conducted in each community.  Discussion: Findings from our study will highlight the availability, accessibility and utilization of existing services; identify the gaps and barriers in current service provision; and provide insight into the service and treatment needs of youth and young adults who use drugs in Northern Ontario communities. Assessing the needs of young people who use drugs will allow service providers, community organizers and health policymakers to improve addiction-related services and treatment centers in Northern Ontario.

Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations.

BACKGROUND: Cannabis use is common in North America, especially among young people, and is associated with a risk of various acute and chronic adverse health outcomes. Cannabis control regimes are evolving, for example toward a national legalization policy in Canada, with the aim to improve public health, and thus require evidence-based interventions. As cannabis-related health outcomes may be influenced by behaviors that are modifiable by the user, evidence-based Lower-Risk Cannabis Use Guidelines (LRCUG)-akin to similar guidelines in other health fields-offer a valuable, targeted prevention tool to improve public health outcomes. OBJECTIVES: To systematically review, update, and quality-grade evidence on behavioral factors determining adverse health outcomes from cannabis that may be modifiable by the user, and translate this evidence into revised LRCUG as a public health intervention tool based on an expert consensus process. SEARCH METHODS: We used pertinent medical search terms and structured search strategies, to search MEDLINE, EMBASE, PsycINFO, Cochrane Library databases, and reference lists primarily for systematic reviews and meta-analyses, and additional evidence on modifiable risk factors for adverse health outcomes from cannabis use. SELECTION CRITERIA: We included studies if they focused on potentially modifiable behavior-based factors for risks or harms for health from cannabis use, and excluded studies if cannabis use was assessed for therapeutic purposes. DATA COLLECTION AND ANALYSIS: We screened the titles and abstracts of all studies identified by the search strategy and assessed the full texts of all potentially eligible studies for inclusion; 2 of the authors independently extracted the data of all studies included in this review. We created Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow-charts for each of the topical searches. Subsequently, we summarized the evidence by behavioral factor topic, quality-graded it by following standard (Grading of Recommendations Assessment, Development, and Evaluation; GRADE) criteria, and translated it into the LRCUG recommendations by the author expert collective on the basis of an iterative consensus process. MAIN RESULTS: For most recommendations, there was at least "substantial" (i.e., good-quality) evidence. We developed 10 major recommendations for lower-risk use: (1) the most effective way to avoid cannabis use-related health risks is abstinence, (2) avoid early age initiation of cannabis use (i.e., definitively before the age of 16 years), (3) choose low-potency tetrahydrocannabinol (THC) or balanced THC-to-cannabidiol (CBD)-ratio cannabis products, (4) abstain from using synthetic cannabinoids, (5) avoid combusted cannabis inhalation and give preference to nonsmoking use methods, (6) avoid deep or other risky inhalation practices, (7) avoid high-frequency (e.g., daily or near-daily) cannabis use, (8) abstain from cannabis-impaired driving, (9) populations at higher risk for cannabis use-related health problems should avoid use altogether, and (10) avoid combining previously mentioned risk behaviors (e.g., early initiation and high-frequency use). AUTHORS' CONCLUSIONS: Evidence indicates that a substantial extent of the risk of adverse health outcomes from cannabis use may be reduced by informed behavioral choices among users. The evidence-based LRCUG serve as a population-level education and intervention tool to inform such user choices toward improved public health outcomes. However, the LRCUG ought to be systematically communicated and supported by key regulation measures (e.g., cannabis product labeling, content regulation) to be effective. All of these measures are concretely possible under emerging legalization regimes, and should be actively implemented by regulatory authorities. The population-level impact of the LRCUG toward reducing cannabis use-related health risks should be evaluated. Public health implications. Cannabis control regimes are evolving, including legalization in North America, with uncertain impacts on public health. Evidence-based LRCUG offer a potentially valuable population-level tool to reduce the risk of adverse health outcomes from cannabis use among (especially young) users in legalization contexts, and hence to contribute to improved public health outcomes.

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED50 of morphine alone. In addition, the ED50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Psychosocial interventions for cannabis use disorder.

BACKGROUND: Cannabis use disorder is the most commonly reported illegal substance use disorder in the general population; although demand for assistance from health services is increasing internationally, only a minority of those with the disorder seek professional assistance. Treatment studies have been published, but pressure to establish public policy requires an updated systematic review of cannabis-specific treatments for adults. OBJECTIVES: To evaluate the efficacy of psychosocial interventions for cannabis use disorder (compared with inactive control and/or alternative treatment) delivered to adults in an out-patient or community setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE, EMBASE, PsycINFO, the Cumulaive Index to Nursing and Allied Health Literature (CINAHL) and reference lists of articles. Searched literature included all articles published before July 2015. SELECTION CRITERIA: All randomised controlled studies examining a psychosocial intervention for cannabis use disorder (without pharmacological intervention) in comparison with a minimal or inactive treatment control or alternative combinations of psychosocial interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS: We included 23 randomised controlled trials involving 4045 participants. A total of 15 studies took place in the United States, two in Australia, two in Germany and one each in Switzerland, Canada, Brazil and Ireland. Investigators delivered treatments over approximately seven sessions (range, one to 14) for approximately 12 weeks (range, one to 56).Overall, risk of bias across studies was moderate, that is, no trial was at high risk of selection bias, attrition bias or reporting bias. Further, trials included a large total number of participants, and each trial ensured the fidelity of treatments provided. In contrast, because of the nature of the interventions provided, participant blinding was not possible, and reports of researcher blinding often were unclear or were not provided. Half of the reviewed studies included collateral verification or urinalysis to confirm self report data, leading to concern about performance and detection bias. Finally, concerns of other bias were based on relatively consistent lack of assessment of non-cannabis substance use or use of additional treatments before or during the trial period.A subset of studies provided sufficient detail for comparison of effects of any intervention versus inactive control on primary outcomes of interest at early follow-up (median, four months). Results showed moderate-quality evidence that approximately seven out of 10 intervention participants completed treatment as intended (effect size (ES) 0.71, 95% confidence interval (CI) 0.63 to 0.78, 11 studies, 1424 participants), and that those receiving psychosocial intervention used cannabis on fewer days compared with those given inactive control (mean difference (MD) 5.67, 95% CI 3.08 to 8.26, six studies, 1144 participants). In addition, low-quality evidence revealed that those receiving intervention were more likely to report point-prevalence abstinence (risk ratio (RR) 2.55, 95% CI 1.34 to 4.83, six studies, 1166 participants) and reported fewer symptoms of dependence (standardised mean difference (SMD) 4.15, 95% CI 1.67 to 6.63, four studies, 889 participants) and cannabis-related problems compared with those given inactive control (SMD 3.34, 95% CI 1.26 to 5.42, six studies, 2202 participants). Finally, very low-quality evidence indicated that those receiving intervention reported using fewer joints per day compared with those given inactive control (SMD 3.55, 95% CI 2.51 to 4.59, eight studies, 1600 participants). Notably, subgroup analyses found that interventions of more than four sessions delivered over longer than one month (high intensity) produced consistently improved outcomes (particularly in terms of cannabis use frequency and severity of dependence) in the short term as compared with low-intensity interventions.The most consistent evidence supports the use of cognitive-behavioural therapy (CBT), motivational enhancement therapy (MET) and particularly their combination for assisting with reduction of cannabis use frequency at early follow-up (MET: MD 4.45, 95% CI 1.90 to 7.00, four studies, 612 participants; CBT: MD 10.94, 95% CI 7.44 to 14.44, one study, 134 participants; MET + CBT: MD 7.38, 95% CI 3.18 to 11.57, three studies, 398 participants) and severity of dependence (MET: SMD 4.07, 95% CI 1.97 to 6.17, two studies, 316 participants; MET + CBT: SMD 7.89, 95% CI 0.93 to 14.85, three studies, 573 participants), although no particular intervention was consistently effective at nine-month follow-up or later. In addition, data from five out of six studies supported the utility of adding voucher-based incentives for cannabis-negative urines to enhance treatment effect on cannabis use frequency. A single study found contrasting results throughout a 12-month follow-up period, as post-treatment outcomes related to overall reduction in cannabis use frequency favoured CBT alone without the addition of abstinence-based or treatment adherence-based contingency management. In contrast, evidence of drug counselling, social support, relapse prevention and mindfulness meditation was weak because identified studies were few, information on treatment outcomes insufficient and rates of treatment adherence low. In line with treatments for other substance use, abstinence rates were relatively low overall, with approximately one-quarter of participants abstinent at final follow-up. Finally, three studies found that intervention was comparable with treatment as usual among participants in psychiatric clinics and reported no between-group differences in any of the included outcomes. AUTHORS' CONCLUSIONS: Included studies were heterogeneous in many aspects, and important questions regarding the most effective duration, intensity and type of intervention were raised and partially resolved. Generalisability of findings was unclear, most notably because of the limited number of localities and homogeneous samples of treatment seekers. The rate of abstinence was low and unstable although comparable with treatments for other substance use. Psychosocial intervention was shown, in comparison with minimal treatment controls, to reduce frequency of use and severity of dependence in a fairly durable manner, at least in the short term. Among the included intervention types, an intensive intervention provided over more than four sessions based on the combination of MET and CBT with abstinence-based incentives was most consistently supported for treatment of cannabis use disorder.

Effect of a D3 receptor antagonist on context-induced reinstatement of nicotine seeking.

Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7 days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation.

Off-Label Use of Medications for Treatment of Benzodiazepine Use Disorder.

There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multiple indications (anxiety, seizures, alcohol withdrawal, muscular relaxation and anesthesia). Benzodiazepines are also addictive substances and a non-negligible fraction of regular users will develop dependence. There is currently no approved pharmacotherapy for benzodiazepine use disorder treatment and optimal strategies for treatment are unclear. In this review, we aimed to summarize the findings on off-label pharmacologic therapy that have been used for BZD dependence. One classical approach is to provide a slow taper associated with counseling. Anti-epileptic drugs appear also to alleviate symptoms of withdrawal. The long-term strategies of maintenance therapy (with benzodiazepine) or of blocking therapy (with a GABA antagonist such as flumazenil) could provide some clinical benefit but have not yet been tested appropriately. Pregabalin appears promising and deserves further investigation. There is a clear need for more clinical trials in this area to improve care.

Effects of biperiden on the treatment of cocaine/crack addiction: a randomised, double-blind, placebo-controlled trial.

Cocaine use affects approximately 13.4 million people, or 0.3% of the world's population between 15 and 64 years of age. Several authors have described drug addiction as a disease of the brain reward system. Given that the cholinergic system impacts reward mechanisms and drug self-administration, acetylcholine (ACh) might play an important role in the cocaine addiction process. We evaluated the efficacy of biperiden (a cholinergic antagonist) in reducing craving and the amount used, and in increasing compliance with treatment for cocaine/crack addiction. It was a study double-blind, randomised, placebo-controlled, 8-week trial of 111 cocaine or crack addicted male patients between 18 and 50 years old. Two groups were compared: placebo (n=55) or biperiden (n=56) combined with weekly sessions of brief group cognitive-behavioural therapy. The efficacy of treatment was evaluated according to the patients' compliance and several instruments: the Minnesota Cocaine Craving Scale, the Beck Depression and Anxiety Scales and a questionnaire assessing the amount of drug used. All of the patients attended weekly sessions for two months. We analysed the data considering the patients' intention to treat based on our last observation. Of the 56 patients in the biperiden group, 24 completed the treatment (42.8%) compared with only 11 patients in the placebo group (20%), which was a significant difference (p=0.009). Compliance with treatment was 118% higher in the biperiden group, which was also the group that presented a statistically significant reduction in the amount of cocaine/crack use (p<0.001). There was statistically significant difference between the craving score in the biperiden group. Pharmacological blockade of the cholinergic system with biperiden is a promising alternative to treat cocaine/crack addiction, helping patients to reduce the amount used and improving compliance with psychotherapy treatment.

The effectiveness of treatments for cocaine dependence in schizophrenic patients: a systematic review.

OBJECTIVES: To evaluate and compare the effectiveness of available treatments for cocaine dependence in schizophrenic patients. METHOD: We searched articles published between May 2002 and June 2012 in the following databases: Scopus, Pubmed and Web of Knowledge. The key words utilised were "schizophrenia", "dementia praecox", "schizophrenic disorder", "cocaine related disorder", "cocaine abuse", "cocaine addiction", "cocaine dependence", "treatment", "therapeutic", and "drug therapy". SELECTION OF STUDIES AND DATA EXTRACTION: Original articles in English, Portuguese and Spanish were selected. Controlled, double-blind and open-label studies involving only human subjects were included in this review. DATA SYNTHESIS: We found studies on typical and atypical antipsychotics and one monoamine transporter antagonist. There were few indications of the effectiveness of atypical antipsychotic medications for the treatment of cocaine dependence in patients with schizophrenia. CONCLUSIONS: We suggest that further studies be conducted with atypical antipsychotic medicationsand greater methodological strictness, including using a placebo group in the studies, so that health professionals can determine the real effectiveness of this class of medication for the treatment of cocaine dependence in schizophrenic patients.

SKF 38393 reverses cocaine-conditioned place preference in mice.

Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.

Behavioral, neurochemical and histological alterations promoted by bilateral intranigral rotenone administration: a new approach for an old neurotoxin.

Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In order to counteract these limitations, this study characterized a precise neurotoxin-delivery strategy employing the bilateral intranigral administration protocol of rotenone as a reliable model of PD. We performed bilateral intranigral injections of rotenone (12 µg) and subsequent general activity (1, 10, 20, and 30 days after rotenone) and cognitive (7, 8, 15, and 30 days after rotenone) evaluations followed by neurochemical and immunohistochemical tests. We have observed that rotenone was able to produce a remarkable reduction on the percentage of tyrosine hydroxylase immunoreactive neurons (about 60%) within the substantia nigra pars compacta. Dopamine (DA) was severely depleted at 30 days after rotenone administration, similarly to its metabolites. In addition, an increase in DA turnover was detected at the same time-point. In parallel, striatal serotonin and its metabolite were found to be increased 30 days after the neurotoxic insult, without apparent modification in the serotonin turnover. Besides, motor behavior was impaired, mainly 1 day after rotenone. Furthermore, learning and memory processes were severely disrupted in different time-points, particularly at the training and test session (30 days). We now provide further evidence of a time-dependent neurodegeneration associated to cognitive impairment after the single bilateral intranigral administration of rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.

The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC-inhibiting and antiestrogenic drugs.

Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150 mg/kg, i.p.), tamoxifen (1.0 mg/kg, i.p.) and chelerythrine (1 microg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0 mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0 mg/g) and higher (6.0 mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.