A systematic review and meta-analysis of neuromodulation therapies for substance use disorders.

While pharmacological, behavioral and psychosocial treatments are available for substance use disorders (SUDs), they are not always effective or well-tolerated. Neuromodulation (NM) methods, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) may address SUDs by targeting addiction neurocircuitry. We evaluated the efficacy of NM to improve behavioral outcomes in SUDs. A systematic literature search was performed on MEDLINE, PsychINFO, and PubMed databases and a list of search terms for four key concepts (SUD, rTMS, tDCS, DBS) was applied. Ninety-four studies were identified that examined the effects of rTMS, tDCS, and DBS on substance use outcomes (e.g., craving, consumption, and relapse) amongst individuals with SUDs including alcohol, tobacco, cannabis, stimulants, and opioids. Meta-analyses were performed for alcohol and tobacco studies using rTMS and tDCS. We found that rTMS reduced substance use and craving, as indicated by medium to large effect sizes (Hedge's g > 0.5). Results were most encouraging when multiple stimulation sessions were applied, and the left dorsolateral prefrontal cortex (DLPFC) was targeted. tDCS also produced medium effect sizes for drug use and craving, though they were highly variable and less robust than rTMS; right anodal DLPFC stimulation appeared to be most efficacious. DBS studies were typically small, uncontrolled studies, but showed promise in reducing misuse of multiple substances. NM may be promising for the treatment of SUDs. Future studies should determine underlying neural mechanisms of NM, and further evaluate extended treatment durations, accelerated administration protocols and long-term outcomes with biochemical verification of substance use.

Contingency Management for Treatment of Cannabis Use Disorder in Co-Occurring Mental Health Disorders: A Systematic Review.

Amongst individuals with a mental health disorder, a comorbid diagnosis of cannabis use disorder (CUD) is associated with numerous adverse consequences, including more severe symptom profiles, poorer treatment response, and reduced psychosocial functioning. Contingency management (CM), a method to specifically reinforce target behavior attainment (e.g., substance use abstinence), may provide an effective intervention in treating cannabis use in patients with a dual diagnosis of CUD and a mental health disorder. A systematic search examining the effects of CM on cannabis use, clinical, cognitive, and psychosocial outcomes in patients with a mental health disorder on PubMed, PsycINFO, and EMBASE databases up to November 2022 was performed. Six studies met inclusion criteria for our review. We found CM to be efficacious in producing cannabis use reductions and abstinence amongst individuals with a psychotic-spectrum or major depressive disorder. Additional longitudinal studies with larger sample sizes, other psychiatric populations, and longer follow-up periods are needed to evaluate the sustained effects of CM.

Long-Acting Injectable Antipsychotic Treatment in Schizophrenia and Co-occurring Substance Use Disorders: A Systematic Review.

Objectives: Co-occurring substance use disorders (SUDs) among individuals with schizophrenia are a prevalent and complex psychiatric comorbidity, which is associated with increased symptom severity, worsened illness trajectory and high rates of treatment non-adherence. Recent evidence suggests that the use of long-acting injectable (LAI) antipsychotics may provide an effective treatment option for individuals with this dual-diagnosis. Methods: A systematic review of the literature was conducted using the databases PubMed, PsychInfo and Google Scholar for English-language studies, investigating the use of LAIs in co-occurring schizophrenia and substance use disorders (SCZ-SUDs). Results: Eight reports [one case study (n = 1), one case series (n = 8), three open-label retrospective studies (n = 75), and three randomized controlled trials (n = 273)] investigated the use of LAI antipsychotics in 357 participants with SCZ-SUDs [alcohol use disorder: 5 studies, n = 282; cocaine use disorder: 5 studies, n = 85; amphetamine use disorder: 1 study, n = 1; cannabis use disorder: 3 studies, n = 160; opioid use disorder: 3 studies, n = 19; methylenedioxymethamphetamine (MDMA) use disorder: 2 studies, n = 9; ketamine use disorder: 1 study, n = 4] and were included in this systematic review. Findings indicate significant improvements in substance use related outcomes across 7 of 8 studies, while in 6 of 8 studies, significant improvements in psychopathology-related outcomes were reported. Conclusions: LAI antipsychotics may be an efficacious intervention option for the treatment of SCZ-SUDs. However, varying methodological rigor, generally small sample sizes and heterogeneity of samples, settings, substances of abuse, tested LAIs and comparators, as well as psychosocial cotreatments and level of reported detail across studies requires that these findings be considered preliminary and interpreted with caution. Further research is required to better understand the effects of LAIs among individuals with SCZ-SUDs.

Cannabis and Cannabinoids in Mood and Anxiety Disorders: Impact on Illness Onset and Course, and Assessment of Therapeutic Potential.

BACKGROUND AND OBJECTIVES: Cannabis use is common in people with and mood and anxiety disorders (ADs), and rates of problematic use are higher than in the general population. Given recent policy changes in favor of cannabis legalization, it is important to understand how cannabis and cannabinoids may impact people with these disorders. We aimed to assess the effects of cannabis on the onset and course of depression, bipolar disorder, ADs, and post-traumatic stress disorder (PTSD), and also to explore the therapeutic potential of cannabis and cannabinoids for these disorders. METHODS: A systematic review of the literature was completed. The PubMed® database from January 1990 to May 2018 was searched. We included longitudinal cohort studies, and also all studies using cannabis or a cannabinoid as an active intervention, regardless of the study design. RESULTS: Forty-seven studies were included: 32 reported on illness onset, nine on illness course, and six on cannabinoid therapeutics. Cohort studies varied significantly in design and quality. The literature suggests that cannabis use is linked to the onset and poorer clinical course in bipolar disorder and PTSD, but this finding is not as clear in depression and anxiety disorders (ADs). There have been few high-quality studies of cannabinoid pharmaceuticals in clinical settings. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These conclusions are limited by a lack of well-controlled longitudinal studies. We suggest that future research be directed toward high-quality, prospective studies of cannabis in clinical populations with mood and ADs, in addition to controlled studies of cannabinoid constituents and pharmaceuticals in these populations. (Am J Addict 2019;00:00-00).

Pharmacotherapies for co-occurring substance use and bipolar disorders: A systematic review.

OBJECTIVES: Substance use disorders (SUDs), including those for alcohol, stimulants, tobacco, opioids and cannabis, in patients with bipolar disorder are a major clinical and public health problem, and are present in the majority of these patients. Nonetheless, the development of effective pharmacological treatments for co-occurring SUDs in bipolar illness have not been well-developed and may be an important practical reason for the reduced effectiveness of these medications in community practice. METHODS: We conducted a systematic review of the literature (PubMed, Medline, Google Scholar), and identified N = 29 clinical studies, which evaluated both mental health and SUD outcomes in patients with co-occurring bipolar disorders and SUDs. RESULTS: Our findings suggest the potential of valproate sodium and lamotrigine as preferred pharmacological agents for the treatment of co-occurring psychiatric and substance use outcomes in these patients. However, many of the reviewed studies are of open-label designs and of modest sample sizes. CONCLUSIONS: Thus, given the gaps in our knowledge, recommendations for treatment of this common and important co-morbidity are preliminary. Accordingly, the conduct of larger, randomized controlled trials for this co-morbidity is clearly needed.

The neurobiology of impulsivity and substance use disorders: implications for treatment.

Impulsivity is strongly associated with substance use disorders (SUDs). Our review discusses impulsivity as an underlying vulnerability marker for SUDs, and treatment of co-occurring impulsivity in SUDs. Three factors should be considered for the complex relationship between impulsivity and a SUD: (1) the trait effect of impulsivity, centering on decreased cognitive and response inhibition, (2) the state effect resulting from either acute or chronic substance use on brain structure and function, and (3) the genetic and environmental factors (e.g., age and sex) may influence impulsive behavior associated with SUDs. Both subjective and objective measures are used to assess impulsivity. Together, treatment developments (pharmacological, behavioral, and neurophysiological) should consider these clinically relevant dimensions assessed by a variety of measures, which have implications for treatment matching in individuals with SUD. Despite its heterogeneity, impulsivity is a marker associated with SUDs and may be understood as an imbalance of bottom-up and top-down neural systems. Further investigation of these relationships may lead to more effective SUD treatments.

Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial.

BACKGROUND: The current lack of pharmacological treatments for cannabis use disorder (CUD) warrants novel approaches and further investigation of promising pharmacotherapy. We previously showed that nabiximols (27 mg/ml Δ9-tetrahydrocannabinol (THC)/ 25 mg/ml cannabidiol (CBD), Sativex®) can decrease cannabis withdrawal symptoms. Here, we assessed in a pilot study the tolerability and safety of self-titrated nabiximols vs. placebo among 40 treatment-seeking cannabis-dependent participants. METHODS: Subjects participated in a double blind randomized clinical trial, with as-needed nabiximols up to 113.4 mg THC/105 mg CBD or placebo daily for 12 weeks, concurrently with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT). Primary outcome measures were tolerability and abstinence, secondary outcome measures were days and amount of cannabis use, withdrawal, and craving scores. Participants received up to CDN$ 855 in compensation for their time. RESULTS: Medication was well tolerated and no serious adverse events (SAEs) were observed. Rates of adverse events did not differ between treatment arms (F1,39 = 0.205, NS). There was no significant change in abstinence rates at trial end. Participants were not able to differentiate between subjective effects associated with nabiximols or placebo treatments (F1,40 = 0.585, NS). Cannabis use was reduced in the nabiximols (70.5%) and placebo groups (42.6%). Nabiximols reduced cannabis craving but no significant differences between the nabiximols and placebo groups were observed on withdrawal scores. CONCLUSIONS: Nabiximols in combination with MET/CBT was well tolerated and allowed for reduction of cannabis use. Future clinical trials should explore the potential of high doses of nabiximols for cannabis dependence.

Integrated care pathway for co-occurring major depressive and alcohol use disorders: Outcomes of the first two years.

BACKGROUND: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are highly prevalent, comorbid, and have significant impact on morbidity, mortality, and socioeconomic burden in Canada. Combined psycho- and pharmacotherapies for both conditions promise better outcomes than treatment as usual (TAU). At the Centre for Addiction and Mental Health, Toronto, Canada, we developed and implemented an Integrated Care Pathway (ICP) specifically for treatment of concurrent MDD and AUD. The goal of the study is to assess the clinical effectiveness of the ICP approach in comparison to TAU. MATERIALS AND METHODS: Non-randomized design, clinical chart review, Chi-square and t-tests, Cohen's d, Linear Mixed Effects Models, Kaplan-Meier, and log-rank analyses. RESULTS: Eighty-one ICP patients were included, matched to 81 controls by age, sex, severity of depressive symptoms, and patterns of drinking. ICP cohort had a significantly lower dropout rate (18.5% vs 69.1%, p < .001; at 16 weeks of treatment, respectively), both cohorts demonstrated significant reduction in the number of heavy drinking days (ß = .01, p < .001) and standard drinks per week (ß = .15, p < .001) with a significantly higher reduction of both indicators over time in the ICP cohort. Significant reduction in depressive symptoms severity (QIDS: 14.6 vs 10.0, p < .001; BDI: 26.3 vs 16.2, p < .001) was observed in ICP cohort (no data for TAU cohort). CONCLUSIONS: The ICP patients demonstrated improvements on several levels including depressive symptoms, and changes in alcohol drinking patterns. The study demonstrated the overall effectiveness of the ICP and apparent advantage over TAU, which must be corroborated through a randomized clinical trial. (Am J Addict 2017;26:602-609) SCIENTIFIC SIGNIFICANCE: This study is one of the first works showing the outcomes of an ICP developed in the mental health area and for co-occurring disorders. Despite the limitations, the relative advantage of the ICP methodology warrants future research in this area.

Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series.

OBJECTIVES: Cannabis is the most commonly used illicit drug; a substantial minority of users develop dependence. The current lack of pharmacological treatments for cannabis dependence warrants the use of novel approaches and further investigation of promising pharmacotherapy. In this case series, we assessed the use of self-titrated dosages of Sativex (1:1, Δ-tetrahydrocannabinol [THC]/cannabidiol [CBD] combination) and motivational enhancement therapy and cognitive behavioral therapy (MET/CBT) for the treatment of cannabis dependence among 5 treatment-seeking community-recruited cannabis-dependent subjects. METHODS: Participants underwent a 3-month open-label self-titration phase with Sativex (up to 113.4 of THC/105 mg of CBD) and weekly MET/CBT, with a 3-month follow-up. RESULTS: Sativex was well-tolerated by all participants (average dosage 77.5 THC/71.7 mg CBD). The combination of Sativex and MET/CBT reduced the amount of cannabis use and progressively reduced craving and withdrawal scores. THC/CBD metabolite concentration indicated reduced cannabis use and compliance with medication. CONCLUSIONS: In summary, this pilot study found that with Sativex in combination with MET/CBT reduced cannabis use while preventing increases in craving and withdrawal in the 4 participants completing the study. Further systematic exploration of Sativex as a pharmacological treatment option for cannabis dependence should be performed.

Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial.

BACKGROUND AND OBJECTIVE: Tobacco and cannabis are frequently used in combination and cannabis co-use may lead to poor tobacco cessation outcomes. Therefore, it is important to explore if cannabis co-use is associated with a reduced likelihood of achieving successful tobacco abstinence among treatment-seeking tobacco smokers. The present study examined whether current cannabis use moderated tobacco cessation outcomes after 12 weeks of pharmacological treatment (varenicline vs. nicotine patch vs. placebo) with adjunctive behavioral counseling. METHODS: Treatment-seeking tobacco smokers (N = 1,246) were enrolled in an intent-to-treat study, of which 220 were current cannabis users. Individuals were randomly assigned to 12 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioral counseling. The primary endpoint was biochemically verified 7-day point prevalence abstinence at the end of treatment. RESULTS: Controlling for rate of nicotine metabolism, treatment arm, age, sex, alcohol, and level of nicotine dependence, cannabis users were as successful at achieving biochemically verified 7-day point prevalence abstinence compared to tobacco-only smokers. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Findings suggest that cannabis use does not hinder the ability to quit tobacco smoking. Future tobacco cessation studies should employ prospective, longitudinal designs investigating cannabis co-use over time and at different severity levels. (Am J Addict 2016;25:291-296).

Brain stimulation methods to treat tobacco addiction.

BACKGROUND: Tobacco smoking is the leading cause of preventable deaths worldwide, but many smokers are simply unable to quit. Psychosocial and pharmaceutical treatments have shown modest results on smoking cessation rates, but there is an urgent need to develop treatments with greater efficacy. Brain stimulation methods are gaining increasing interest as possible addiction therapeutics. OBJECTIVES: The purpose of this paper is to review the studies that have evaluated brain stimulation techniques on tobacco addiction, and discuss future directions for research in this novel area of addiction interventions. METHODS: Electronic and manual literature searches identified fifteen studies that administered repetitive transcranial magnetic stimulation (rTMS), cranial electrostimulation (CES), transcranial direct current stimulation (tDCS) or deep brain stimulation (DBS). RESULTS: rTMS was found to be the most well studied method with respect to tobacco addiction. Results indicate that rTMS and tDCS targeted to the dorsolateral prefrontal cortex (DLPFC) were the most efficacious in reducing tobacco cravings, an effect that may be mediated through the brain reward system involved in tobacco addiction. While rTMS was shown to reduce consumption of cigarettes, as yet no brain stimulation technique has been shown to significantly increase abstinence rates. It is possible that the therapeutic effects of rTMS and tDCS may be improved by optimization of stimulation parameters and increasing the duration of treatment. CONCLUSION: Although further studies are needed to confirm the ability of brain stimulation methods to treat tobacco addiction, this review indicates that rTMS and tDCS both represent potentially novel treatment modalities.

Treatment of tobacco dependence in people with mental health and addictive disorders.

People with mental health and addictive disorders (MHADs) have higher rates of cigarette smoking, and less success in quitting smoking compared with the general population. Moreover, tobacco-related medical illness may be the leading cause of death in the MHAD population. We discuss the scope of this comorbidity, and approaches to the treatment of tobacco dependence in people with MHAD, including schizophrenia, mood disorders, anxiety disorders, and alcohol and substance use disorders. Finally, at the level of health systems, we emphasize the importance of integrated treatment of tobacco dependence in MHADs.

Correlation of prepulse inhibition and Wisconsin Card Sorting Test in schizophrenia and controls: effects of smoking status.

BACKGROUND: In schizophrenia, neurocognitive deficits associated with the illness are modulated by tobacco smoking. However, little is known about how smoking status modulates the relationships between neurocognitive measures in schizophrenia and healthy control subjects. OBJECTIVE: The goal of this study was to evaluate the relationship between sensorimotor gating assessed by prepulse inhibition (PPI) and executive cognitive function using the Wisconsin Card Sorting Test (WCST) in schizophrenia and controls as a function of smoking status. METHOD: We studied PPI and neuropsychological function in four groups (N=50); smokers with schizophrenia (SS; n=15), control smokers (CS; n=13), non-smokers with schizophrenia (SNS; n=11) and control non-smokers (CNS; n=11). RESULTS: SNS demonstrated the poorest PPI, while SS showed comparably high levels of PPI to CNS. Non-psychiatric controls outperformed patients on WCST outcomes irrespective of smoking status. Several prefrontal outcome measures on the WCST (categories completed, percentage perseverative and non-perseverative errors) correlated significantly with PPI at the 60 and 120 ms prepulse intervals. In contrast, there were no significant correlations between PPI and any WCST outcomes in SNS, CS or CNS, and few significant correlations between PPI and other neuropsychological measures. DISCUSSION: Our preliminary data suggests that the correlation between sensorimotor gating (PPI) and prefrontal executive cognitive functioning (WCST) is enhanced by acute cigarette smoking in schizophrenia.

Treatment of tobacco dependence in mental health and addictive disorders.

People with mental health and addictive (MHA) disorders smoke at high rates and require tobacco treatment as a part of their comprehensive psychiatric care. Psychiatric care providers often do not address tobacco use among people with mental illness, possibly owing to the belief that their patients will not be able to quit successfully or that even short-term abstinence will adversely influence psychiatric status. Progress in the development of treatments has been slow in part because smokers with current MHA disorders have been excluded from most smoking cessation trials. There are several smoking cessation treatment options, including psychological and pharmacological interventions, that should be offered to people with an MHA disorder who smoke. Building motivation and readiness to quit smoking is a major challenge, and therefore motivational interventions are essential. We review the treatment options for people with tobacco dependence and MHA disorders, offer recommendations on tobacco assessment and tailored treatment strategies, and provide suggestions for future research. Treatment efficacy could be enhanced through promoting smoking reduction as an initial treatment goal, extending duration of treatment, and delivering it within an integrated care model that also aims to reduce the availability of tobacco in MHA treatment settings and in the community.

Prepulse inhibition deficits in schizophrenia are modified by smoking status.

BACKGROUND: Schizophrenia is associated with high rates of cigarette smoking and deficits in sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. However, the relationship between PPI deficits and smoking status is unclear. We examined whether smoking status modifies PPI deficits in schizophrenia. METHODS: We studied PPI as a function of smoking status and schizophrenia diagnosis in four groups using a cross-sectional design: Smokers with schizophrenia (SS; n=14), non-smokers with schizophrenia (SNS; n=15), control smokers (CS; n=11), and control non-smokers (CNS; n=10). PPI in smokers was recorded under conditions of smoking satiation, and smoking status was verified biochemically. RESULTS: The Diagnosis x Smoking Status x Prepulse Interval interaction was significant (F(11,140)=5.01, p<0.001). At all prepulse to pulse intervals (PPTPIs; 30, 60 and 120 ms), we found that SNS had reductions (~50%; p<0.01) in PPI compared to CNS. However, when SS were compared to CS under conditions of smoking satiation, SS had comparable levels of PPI to CS, and significantly higher levels of PPI than SNS. CONCLUSIONS: Our findings suggest that PPI deficits are present in nonsmokers with schizophrenia, and may be modified by smoking status. Acute smoking in schizophrenia is associated with an elevation of PPI to the levels in non-psychiatric control smokers. These findings have significant implications for understanding vulnerability to tobacco dependence in schizophrenia, which may lead to the development of more effective treatments for PPI deficits and tobacco dependence in this population.