Cingulate Cortex Structural Alterations in Substance Use Disorder Psychiatric Inpatients.

BACKGROUND AND OBJECTIVES: Substance use disorder (SUD) includes maladaptive patterns of substance use despite negative consequences. Previous structural neuroimaging studies showed some structural alterations in SUD, but it remains unknown whether these alterations are specifically associated with SUD or common comorbidities. This study attempts to validate the findings of structural differences between SUD, healthy controls (HC), and psychiatric controls (PC). METHODS: We used HC (N = 86) matched for demographics, and PC (N = 86) matched for demographics and psychiatric diagnoses to a group of SUD patients (N = 86). We assessed the group differences of subcortical volumes, cortical volumes, thickness, and surface areas between SUD and HC. We then analyzed the group differences between SUD and PC within regions showing differences between SUD and HC. RESULTS: SUD had smaller left nucleus accumbens, right thalamus, right hippocampus, left caudal anterior cingulate cortex (ACC) volume, and larger right caudal ACC volume, and right caudal ACC, right caudal middle frontal gyrus (MFG), and right posterior cingulate cortex (PCC) surface than HC. Increased right caudal ACC volume and right PCC surface in SUD were the only findings when compared with PC. Several areas showed thickness alterations between SUD and HC, but none survived multiple comparisons vs PC. DISCUSSION AND CONCLUSIONS: Our findings suggest that cingulate structures may be altered in SUD compared with both HC and PC. SCIENTIFIC SIGNIFICANCE: These results are among the first to indicate that some structural alterations may be SUD-specific, and highlight a cautionary note about using HC in psychiatric biomarker research. (Am J Addict 2021;30:72-79).

Use of Guanfacine for Cannabis Use Disorder and Related Symptomology.

BACKGROUND AND OBJECTIVES: No medication has Food and Drug Administration approval for cannabis use disorder (CUD), and most medication development focuses on the withdrawal syndrome. We evaluated the effects of short-term treatment using the α-2A-adrenergic receptor agonist, guanfacine, on withdrawal symptoms in volunteers with CUD and a history of early onset of cannabis use. METHODS: Non-treatment-seeking healthy volunteers (n = 7) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for CUD participated in a two-phase, within-subjects study. Volunteers received placebo or guanfacine (3 mg/day) for the first 8-day inpatient study and the alternative medication for the second 8-day inpatient study. On day 1 of both treatment periods, participants received 30 mg of synthetic Δ9 -tetrahydrocannabinol for standardization of abstinence onset. On days 2 to 7, participants received study medication. Cannabis withdrawal symptoms, sleep, craving, and physiology were assessed on all inpatient days. RESULTS: Compared with placebo, guanfacine did not show significant effects on withdrawal, craving, or sleep, although there were trends for guanfacine to increase positive mood symptoms and decrease craving-associated compulsivity. DISCUSSION AND CONCLUSIONS: Compared with former studies, we could not prove significant improvement in sleep or decrease of negative symptoms, but we found trends for increased positive mood symptoms. Our data did not show significant effects of guanfacine on withdrawal symptoms or craving. Due to early and longer cannabis use, our subjects indicate a great severity of illness increasing the likelihood of treatment resistance. SCIENTIFIC SIGNIFICANCE: On the basis of trends demonstrated here and other lines of evidence, further investigation is warranted regarding the utility of guanfacine as a potential treatment for CUD. (Am J Addict 2019;00:1-10).

Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study.

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits.

Current status and future prospects for the development of substance abuse vaccines.

INTRODUCTION: Substance use disorders (SUD) are a significant threat to both individual and public health. To date, SUD pharmacotherapy has focused primarily on agonist medications (i.e. nicotine replacement therapy for tobacco use disorder; methadone and buprenorphine for opioid use disorder), antagonist medications (i.e. naltrexone for opioid use disorder), and aversive therapy (i.e. disulfiram for alcohol use disorder). Pharmacotherapeutic approaches utilizing an immunological framework for medication development represent an important focus of study for treatment of these illnesses. Areas covered: This review discusses vaccines for treatment of substance use disorders. Using PubMed ( https://www.ncbi.nlm.nih.gov/pubmed/ ), we searched both preclinical and human clinical trials of vaccines for treatment of nicotine, cocaine, methamphetamine, and opioid use disorders. In addition, we searched for recently developed strategies for enhancement of the immunologic response through alteration of conjugate molecules and adjuvants. Expert commentary: Despite challenges in human clinical trials of SUD vaccines, a number of strategies have been introduced which may ultimately improve efficacy. These challenges, as well as their implications for vaccine development, are discussed. Additionally, the optimal conditions for research study and treatment are considered.

The future potential for cocaine vaccines.

INTRODUCTION: Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine's pharmacodynamic effects. AREAS COVERED: This paper discusses the implications of cocaine pharmacokinetics for robust vaccine antibody responses, the results of human vaccine clinical trials, new developments in animal models for vaccine evaluation, alternative vaccine formulations and complementary therapy to enhance anticocaine effectiveness. EXPERT OPINION: Robust anti-cocaine antibody responses are required for benefit to cocaine abusers, but since any reasonably achievable antibody level can be overcome with higher drug doses, sufficient motivation to discontinue use is also essential so that the relative barrier to cocaine effects will be appropriate for each individual. Combining a vaccine with achievable levels of an enzyme to hydrolyze cocaine to inactive metabolites, however, may substantially increase the blockade and improve treatment outcomes.

Epidemiological trends and the advances of treatments of amphetamine-type stimulants (ATS) in China.

BACKGROUND AND OBJECTIVES: Amphetamine-type stimulants (ATS) have quickly spread and been widely abused in many parts of the world, particularly in China. This review focuses on and describes the epidemiological trends and the advances of treatments of ATS in China. METHODS: A descriptive study based on literature identified from searches of the China National Knowledge Infrastructure (1979-2013), PubMed databases, hand-picked references, and online references with emphasis on epidemiology, treatment and traditional Chinese medicine. This review covers some traditional Chinese treatments and their complementary Western approaches. RESULTS AND CONCLUSIONS: The epidemiological trends of ATS in China have led to its being 2.2 times the rate of morphine abuse and second only to marijuana abuse. The treatment programs in China have used traditional herbal approaches as well as acupuncture, often in combination with Western medications such as fluoxetine for depression associated with ATS abuse. Other herbal treatments have reversed the cardiac arrhythmias associated with ATS intoxication, and acupuncture has been used successfully for the protracted depressive and somatic symptoms of ATS withdrawal over a period of 3 months. SCIENTIFIC SIGNIFICANCE: These traditional Chinese treatments may be increasingly available to the world, but will remain a consistent complementary therapy for ATS in China and the Far East, where ATS has become such a prevalent problem.

Pharmacotherapeutics for substance-use disorders: a focus on dopaminergic medications.

INTRODUCTION: Illicit substance-use is a substantial public health concern, contributing over $150 billion in costs annually to Americans. A complex disease, a substance-use disorder affects neural circuits involved in reinforcement, motivation, learning and memory, and inhibitory control. AREAS COVERED: The modulatory influence of dopamine in mesocorticolimbic circuits contributes to encoding the primary reinforcing effects of substances and numerous studies suggest that aberrant signaling within these circuits contributes to the development of a substance-use disorder in some individuals. Decades of research focused on the clinical development of medications that directly target dopamine receptors has led to recent studies of agonist-like dopaminergic treatments for stimulant-use disorders and, more recently, cannabis-use disorder. Human studies evaluating the efficacy of dopaminergic agonist-like medications to reduce reinforcing effects and substance-use provide some insight into the design of future pharmacotherapy trials. A search of PubMed using specific brain regions, medications, and/or the terms 'dopamine', 'cognition', 'reinforcement', 'cocaine', 'methamphetamine', 'amphetamine', 'cannabis', 'treatment/pharmacotherapy', 'addiction/abuse/dependence' identified articles relevant to this review. EXPERT OPINION: Conceptualization of substance-use disorders and their treatment continues to evolve. Current efforts increasingly focus on a strategy fostering combination pharmacotherapies that target multiple neurotransmitter systems.

Extract of Ginkgo biloba is equivalent to vitamin E in attenuating and preventing vacuous chewing movements in a rat model of tardive dyskinesia.

Free radical-mediated abnormalities may contribute toward the pathogenesis of tardive dyskinesia (TD). Many studies have reported the protective antioxidant and free radical-scavenging activities of extract of Ginkgo biloba (EGb761) against free radical-induced cell damage and dysfunction. This study aimed to compare the efficacy of EGb761 with that of vitamin E for the prevention and treatment of TD in a rat model. We carried out two studies. First, rats were injected with haloperidol (2 mg/kg intraperitoneally) daily for 5 weeks. EGb761 (50 mg/kg/day) or vitamin E (20 mg/kg/day) were then administered for another 5 weeks, and their effects on vacuous chewing movements (VCMs) were compared. Second, we compared 10 weeks of haloperidol alone with 10 weeks of haloperidol plus EGb761 or vitamin E. The administration of haloperidol led to a progressive increase in VCMs, which peaked at week 5. In study one, EGb761 and vitamin E, administered by an oral gavage for 5 weeks during withdrawal from chronic haloperidol treatment, decreased VCMs significantly, showing 83.8 and 91.0% reduction, respectively, compared with the haloperidol-alone group. In study two, the concomitant administration of EGb761 and vitamin E led to significantly fewer VCMs, by 64.4 and 73.9%, respectively, compared with the haloperidol-alone group. There was no significant difference in either study between EGb761 and vitamin E treatment. EGb761 shows promise for the prevention and treatment of TD in a rat model with a magnitude that was similar to that of vitamin E.

Spirituality and confidence to resist substance use among celebrate recovery participants.

Since self-efficacy is a positive predictor of substance use treatment outcome, we investigated whether it is associated with spirituality within a religious 12-step program. This was a cross-sectional survey (N = 91) of 10 different Celebrate Recovery sites held at community churches. The mean spirituality score for those with high confidence was significantly greater than those with low confidence. Spirituality associated with greater confidence to resist substance use (OR = 1.09, 95% CI 1.02-1.17, P < 0.05). So every unit increase of measured spirituality increased the odds of being above the median in self-efficacy by 9%. We conclude that spirituality may be an important explanatory variable in outcomes of a faith-based 12-step recovery program.

Brain-derived neurotrophic factor levels and its Val66Met gene polymorphism predict tardive dyskinesia treatment response to Ginkgo biloba.

BACKGROUND: Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain-derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. Ginkgo biloba (EGb-761) is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. We hypothesized that treatment with EGb-761 would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). METHODS: Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n = 368) and without (n = 563) TD as well as healthy control subjects (n = 546). About half of the TD patients (n = 157) then participated in a double-blind, randomized, placebo-control 12-week treatment with 240 mg per day of EGb-761. Serum BDNF levels were measured again at posttreatment. Clinical efficacy was determined using the Abnormal Involuntary Movement Scale (AIMS). RESULTS: TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761 treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. CONCLUSIONS: The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Furthermore, patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761 treatment.

Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial.

CONTEXT: Cocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy. OBJECTIVES: To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence. DESIGN: A 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24. SETTING: Cocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut. PARTICIPANTS: One hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%). INTERVENTION: Over 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein. Main Outcome Measure Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL. RESULTS: The 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 microg/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 microg/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths. CONCLUSIONS: Attaining high (>or=43 microg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. Trial Registration clinicaltrials.gov Identifier: NCT00142857.

Effect of rapamycin on cue-induced drug craving in abstinent heroin addicts.

The mammalian target of rapamycin is an evolutionarily conserved serine-threonine kinase (mTOR), which controls protein synthesis and catabolism in response to environmental cues. This randomized double-blind clinical trial enrolled 60 abstinent heroin addicts and randomly assigned them to three groups: placebo, 2.5 mg and 5 mg rapamycin. The participants were given the cue-reactivity paradigm with 5 min exposures to neutral and drug-related imagery while craving, anxiety, blood pressure and heart rate pre- and post-exposure were assessed. We found that drug-related cues increased both craving and anxiety of abstinent heroin addicts, and had no effect on blood pressure and heart rate. A single high-dose of rapamycin significantly reduced the craving, but not anxiety induced by drug-related cues. Our findings suggested that rapamycin merits outpatient clinical trials as a potential pharmacotherapy for relapse prevention from drug-related cue induced craving.

Circadian alteration in neurobiology during 30 days of abstinence in heroin users.

BACKGROUND: Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility. METHODS: Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects. RESULTS: Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels. CONCLUSIONS: These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.

Traditional medicine in the treatment of drug addiction.

AIMS: To evaluate clinical trials and neurochemical mechanisms of the action of traditional herbal remedies and acupuncture for treating drug addiction. METHODS: We used computerized literature searches in English and Chinese and examined texts written before these computerized databases existed. We used search terms of treatment and neurobiology of herbal medicines, and acupuncture for drug abuse and dependence. RESULTS: Acupuncture showed evidence for clinical efficacy and relevant neurobiological mechanisms in opiate withdrawal, but it showed poor efficacy for alcohol and nicotine withdrawal or relapse prevention, and no large studies supported its efficacy for cocaine in well-designed clinical trials. Clinical trials were rare for herbal remedies. Radix Puerariae showed the most promising efficacy for alcoholism by acting through daidzin, which inhibits mitocochondrial aldehyde dehydrogenase 2 and leads to disulfiram-like alcohol reactions. Peyote also has some evidence for alcoholism treatment among Native Americans. Ginseng and Kava lack efficacy data in addictions, and Kava can be hepatotoxic. Thunbergia laurifolia can protect against alcoholic liver toxicity. Withania somnifera and Salvia miltiorrhiza have no efficacy data, but can reduce morphine tolerance and alcohol intake, respectively, in animal models. CONCLUSIONS: Traditional herbal treatments can compliment pharmacotherapies for drug withdrawal and possibly relapse prevention with less expense and perhaps fewer side effects with notable exceptions. Both acupuncture and herbal treatments need testing as adjuncts to reduce doses and durations of standard pharmacotherapies.

Substance abuse vaccines.

Conventional substance-abuse treatments have only had limited success for drugs such as cocaine, nicotine, methamphetamine, and phencyclidine. New approaches, including vaccination to block the effects of these drugs on the brain, are in advanced stages of development. Although several potential mechanisms for the effects of antidrug vaccines have been suggested, the most straightforward and intuitive mechanism involves binding of the drug by antibodies in the bloodstream, thereby blocking entry and/or reducing the rate of entry of the drug into the central nervous system. The benefits of such antibodies on drug pharmacodynamics will be influenced by both the quantitative and the qualitative properties of the antibodies. The sum of these effects will determine the success of the clinical applications of antidrug vaccines in addiction medicine. This review will discuss these issues and present the current status of vaccine development for nicotine, cocaine, methamphetamine, phencyclidine, and morphine.

Association of spirituality and sobriety during a behavioral spirituality intervention for Twelve Step (TS) recovery.

Twelve-Step (TS) recovery utilizes spirituality to promote sobriety, yet there are no proven programs designed to facilitate spiritual involvement. We developed a seven-week behavioral spirituality intervention titled "Knowing Your Higher Power" for implementation along with usual TS care. Twenty-six participants from a recovery center enrolled. We assessed behavior at baseline, 7-week, and 12-week follow-up. The sample showed significant increase in spiritual involvement and beliefs over the 12-week measurement period and a significantly greater spirituality score in those maintaining total sobriety compared to those that relapsed. These findings encourage a controlled trial to determine if this work has efficacy for practitioners in substance abuse treatment.

Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings.

OBJECTIVE: A preliminary study examined whether lofexidine decreases stress-induced and cue-induced opioid craving and improves opioid abstinence in naltrexone-treated opioid-dependent individuals. MATERIALS AND METHODS: Eighteen opioid-dependent patients were stabilized for 4 weeks with naltrexone (50 mg daily) and lofexidine (2.4 mg bid) before entering a 4-week randomized, double-blind placebo-controlled discontinuation study where one group continued on lofexidine for an additional 4 weeks, while the second was tapered to placebo (Lofexidine-naltrexone vs Placebo-naltrexone). Ten patients also participated in guided imagery exposure to stress, drug cue, and neutral scenarios in a single laboratory session. RESULTS: Lofexidine-naltrexone patients had higher opioid abstinence rates and improved relapse outcomes as compared to the Placebo-naltrexone group. Furthermore, Lofexidine-naltrexone patients had significantly lower heart rates and an attenuated stress and drug cue-induced opioid craving response in the laboratory as compared to the Placebo-naltrexone group. CONCLUSIONS: Although preliminary, these findings are the first to document lofexidine's potential in addressing stress-related opioid craving and relapse outcomes in humans. The results also suggest that combination therapies that target both drug-related reinforcement (naltrexone) and stress- and cue-related aspects of drug seeking could be beneficial in addiction relapse prevention. Further development of lofexidine to address stress-related opioid craving and relapse is warranted.

Emerging pharmacological strategies in the fight against cocaine addiction.

Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a beta-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials.

Antisocial personality and stress-induced brain activation in cocaine-dependent patients.

We explore the neural correlates underlying distress processing in antisocial personality in cocaine-dependent individuals. Twenty-seven abstinent cocaine-dependent individuals took part in script-guided stress imagery in a functional magnetic resonance imaging study. Regional brain activation during stress imagery was compared with a baseline period, for male and female participants separately. Their California Psychological Inventory socialization scores were then correlated in region of interest analysis with corticolimbic brain regions that showed significant activation during stress. The effect size of activity change in the medial prefrontal cortex is associated with lower socialization score (i.e. greater sociopathy) and with the change in heart rate, but only among female participants. These results highlight important sex differences in the association between antisocial personality and distress processing in cocaine-dependent individuals.