Highlights • Methamphetamine continues to pose a significant public health problem in the U.S. • This review provides an update to the literature on methamphetamine use and addiction. • Current ...treatments for methamphetamine dependence are only modestly effective. • Future directions include development of medications with novel molecular targets.
This meta-analysis examined 53 controlled trials of cognitive-behavioral treatment (CBT) for adults diagnosed with alcohol- or illicit-drug-use disorders. The aims were to provide an overall picture ...of CBT treatment efficacy and to identify client or treatment factors predictive of CBT effect magnitude.
The inverse variance weighted effect size (Hedges' g) was calculated for each study and pooled using fixed and random effects methods. Potential study-level moderators were assessed in subgroup analyses by primary drug, type of CBT, and type of comparison condition. In addition, seven client and treatment variables were examined in meta-regression analyses.
Across studies, CBT produced a small but statistically significant treatment effect (g = 0.154, p < .005). The pooled effect was somewhat lower at 6-9 months (g = 0.1 15, p < .005) and continued to diminish at 12-month follow-up (g = 0.096, p < .05). The effect of CBT was largest in marijuana studies (g = 0.513, p < .005) and in studies with a no-treatment control as the comparison condition (g = 0.796, p < .005). Meta-regression analyses indicated that the percentage of female participants was positively associated and the number of treatment sessions was negatively associated with effect size.
The findings demonstrate the utility of CBT across a large and diverse sample of studies and under rigorous conditions for establishing efficacy. CBT effects were strongest with marijuana users, when CBT was compared with no treatment, and may be larger with women than with men and when delivered in a brief format.
Co-use of alcohol and cannabis is highly prevalent and often problematic. However, mechanisms underlying their co-use remain unclear. This randomized and crossover study tests cross-substance ...subjective craving for alcohol and cannabis. A community sample of nontreatment-seeking alcohol and cannabis co-users (N = 30 completers, 40% female) reporting high-risk levels of alcohol and cannabis use completed two experimental sessions in their homes and were monitored remotely using internet meeting technology (i.e., Zoom). The two counterbalanced and randomized sessions were as follows: (a) consumption of a standard alcoholic beverage followed by cannabis cue exposure and (b) consumption (i.e., smoking) of a miniature cannabis cigarette (containing 18%-22% tetrahydrocannabinol), followed by alcohol cue exposure. Participants rated their subjective craving for both alcohol and cannabis at baseline, following alcohol/cannabis administration, and following the presentation of cross-substance-related cues. Repeated measures analysis of variances revealed a statistically significant difference in cannabis craving across time, such that craving for cannabis was significantly higher following cannabis cue reactivity, compared to baseline and following alcohol administration (p's < .001). Similarly, there was a statistically significant difference in alcohol craving across time, such that craving for alcohol was significantly higher following alcohol cue reactivity, compared to baseline and following cannabis administration (p's < .001). Overall, results suggest that individuals who co-use alcohol and cannabis are most sensitive to the cue-induced, rather than the pharmacologically induced effects, of substance administration on cross-substance craving. This pattern of findings does not support a complementarity model. Conversely, these results may be interpreted as indicative of a substitution model for alcohol and cannabis co-use.
Public Health Significance
Despite their frequent co-use, mechanisms underlying alcohol and cannabis co-use remain poorly understood. In a sample of nontreatment-seeking individuals reporting high-risk levels of alcohol and cannabis use, participants were most sensitive to the cue-reactive over pharmacological effects on subjective craving. Notably, there were no significant cross-substance effects on subjective craving.
Rationale
Delayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across ...the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups.
Objectives
The meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias.
Methods
Literature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total
N
= 56,013).
Results
From the total comparisons identified, a small magnitude effect was evident (
d
= .15;
p
< .00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons (
n
= 3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect (
d
= .58;
p
< .00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples (
d
= .61) compared with studies using nonclinical samples (
d
= .45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate.
Conclusions
These results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed.
Background: Neurobiological theories of addiction have highlighted disruption in stress pathways as a central feature of addictive disorders, and pharmacological treatments targeting stress ...mechanisms hold great promise. This study examines genetic determinants of stress‐induced and cue‐induced craving in heavy drinkers by testing single‐nucleotide polymorphisms (SNPs) of the corticotrophin‐releasing hormone binding protein (CRH‐BP) gene and the mu‐opioid receptor (OPRM1) gene.
Methods: This study combines guided imagery stress exposure and in vivo alcohol cue exposure in a sample of 64 (23 women) non‐treatment‐seeking heavy drinkers.
Results: Analyses, uncorrected for multiple comparisons, revealed that a tag SNP of the CRH‐BP gene (rs10055255) moderated stress‐induced craving in this sample. The same SNP predicted greater affective responses to the stress manipulation, including greater levels of subjective tension and negative mood. The Asp40 allele of the OPRM1 was associated with greater cue‐induced alcohol craving following the neutral imagery condition.
Conclusions: These initial results extend recent preclinical and clinical findings implicating the CRH‐BP in stress‐related alcoholism and confirm the role of the Asp40 allele of the OPRM1 gene in reward‐driven alcohol phenotypes. Human laboratory models of stress and cue‐induced craving may be useful in pharmacotherapy development targeting dysregulation of stress systems. Larger studies are needed to validate these preliminary findings, which should also be extended to clinical samples.
Novel medications for problematic alcohol use Heilig, Markus; Witkiewitz, Katie; Ray, Lara A ...
The Journal of clinical investigation,
06/2024, Letnik:
134, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Alcohol-related harm, a major cause of disease burden globally, affects people along a spectrum of use. When a harmful pattern of drinking is present in the absence of significant behavioral ...pathology, low-intensity brief interventions that provide information about health consequences of continued use provide large health benefits. At the other end of the spectrum, profound behavioral pathology, including continued use despite knowledge of potentially fatal consequences, warrants a medical diagnosis, and treatment is strongly indicated. Available behavioral and pharmacological treatments are supported by scientific evidence but are vastly underutilized. Discovery of additional medications, with a favorable balance of efficacy versus safety and tolerability can improve clinical uptake of treatment, allow personalized treatment, and improve outcomes. Here, we delineate the clinical conditions when pharmacotherapy should be considered in relation to the main diagnostic systems in use and discuss clinical endpoints that represent meaningful clinical benefits. We then review specific developments in three categories of targets that show promise for expanding the treatment toolkit. GPCRs remain the largest category of successful drug targets across contemporary medicine, and several GPCR targets are currently pursued for alcohol-related indications. Endocrine systems are another established category, and several promising targets have emerged for alcohol indications. Finally, immune modulators have revolutionized treatment of multiple medical conditions, and they may also hold potential to produce benefits in patients with alcohol problems.
Abstract
Aims
The goal of this study was to develop a standard measure of AUD severity that includes multiple dimensions and can be used in clinical settings to inform treatment selection.
Methods
A ...large sample (n = 1939) of moderate to heavy drinkers was amassed from six psychopharmacology studies. The severity factor was comprised of four dimensions: withdrawal, craving, AUD symptoms and alcohol-related consequences. First, a confirmatory factor analysis (CFA) was conducted to examine model fit. Next, a comprehensive item list from the four measures (i.e. CIWA, DrinC, PACs and SCID-5 AUD criteria) was reduced through exploratory factor analysis (EFA). Once the final items were merged into a preliminary assessment, an EFA was run to observe the factor structure. Initial validation of the measure was obtained via associations with clinical endpoints.
Results
The chi-square test statistic (${\chi}^2(2)=2.432\ P=0.297$) for a single-factor model of severity demonstrated good fit. Additional goodness-of-fit indices from the CFA revealed similar support for the single-factor model of severity (i.e. SRMSR = 0.011; RMSEA = 0.011; CFI = 0.999). Next, nine items from the individual EFAs were selected based on factor loading. The final EFA conducted on the 9-item scale demonstrated that a single factor model of severity best fit the data. Analysis of the psychometric properties revealed good internal consistency ($\alpha$= 0.79).
Conclusions
The current study extends upon the measurement of severity and supports a brief severity measure. This brief 9-item scale can be leveraged in future studies as a screening instrument and as a tool for personalized medicine.
Abstract Background Koob's allostatic model of addiction emphasizes the transition from positive reinforcement to negative reinforcement as dependence develops. This study seeks to extend this ...well-established neurobiological model to humans by examining subjective response to alcohol (SR) as a biobehavioral marker of alcohol reinforcement. Specifically, this study examines (a) differential SR in heavy drinkers (HDs) vs. alcohol dependent individuals (ADs) and (b) whether HDs and ADs differ in terms of the association between SR and craving. Methods Data was culled from two alcohol challenge studies, totalling 91 participants (oversampled on OPRM1 Asp40 carriers). Alcohol was administered intravenously and participants completed standard measures of SR and craving at BrAC's of 0.02, 0.04, and 0.06 g/dl. SR was modeled as a multi-dimensional construct consisting of stimulation, sedation, and tension relief. Results ADs reported significantly higher sedation and craving initially and exhibited a blunted response to alcohol along escalating BrACs. ADs exhibited greater initial tension but did not differ from HDs in tension reduction across rising BrACs. Further, alcohol-induced stimulation was associated with alcohol craving to a significantly greater degree in HDs, as compared to ADs. Conclusions This study provides initial evidence that HDs and ADs differ in their subjective experience of alcohol and in the association between dimensions of SR and craving for alcohol. Hypotheses derived from the allostatic model were partially supported, such that, while ADs and HDs did not differ on stimulation response, there was a relative dissociation between positive reinforcement and craving in ADs as compared to HDs.
Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. ...Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by ∼50%. To advance medication development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in nontreatment-seeking individuals with current (ie, past month) mild-to-severe AUD. This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50 mg b.i.d.) on primary measures of subjective response to alcohol as well as secondary measures of cue- and stress-induced changes in craving and mood. Participants (N=24) completed two separate 7-day intensive outpatient protocols that included daily visits for medication administration and testing. Upon reaching a stable target dose of IBUD (or matched placebo), participants completed a stress-exposure session (day 5; PM), an alcohol cue-exposure session (day 6; AM), and an i.v. alcohol administration session (day 6; PM). Participants stayed overnight after the alcohol administration, and discharge occurred on day 7 of the protocol. Medication conditions were separated by a washout period that was ⩾7 days. IBUD was well tolerated; however, there were no medication effects on primary measures of subjective response to alcohol. IBUD was associated with mood improvements on the secondary measures of stress exposure and alcohol cue exposure, as well as reductions in tonic levels of craving. Exploratory analyses revealed that among individuals with higher depressive symptomatology, IBUD attenuated the stimulant and mood-altering effects of alcohol as compared with placebo. Together, these findings extend preclinical demonstrations of the potential utility of IBUD for the treatment of AUD and suggest that depressive symptomatology should be considered as a potential moderator of efficacy for pharmacotherapies with neuroimmune effects, such as IBUD.
Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is ...unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin,
N
-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.
PDF
