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Rationale: Since substance use disorders have few or no effective pharmacotherapies, researchers have developed vaccines as immune-therapies against nicotine, cocaine, methamphetamine, and opioids including fentanyl. Objectives: We focus on enhancing antibody (AB) production through stimulation of toll-like receptor-5 (TLR5) during active vaccination. The stimulating adjuvant is Entolimod, a novel protein derivative of flagellin. We review the molecular and cellular mechanisms underlying Entolimod's actions on TLR5. Results: Entolimod shows excellent efficacy for increasing AB levels to levels well beyond those produced by anti-addiction vaccines alone in animal models and humans. These ABs also significantly block the behavioral effects of the targeted drug of abuse. The TLR5 stimulation involves a wide range of immune cell types such as dendritic, antigen presenting, T and B cells. Entolimod binding to TLR5 initiates an intracellular signaling cascade that stimulates cytokine production of tumor necrosis factor and two interleukins (IL-6 and IL-12). While cytokine release can be catastrophic in cytokine storm, Entolimod produces a modulated release with few side effects even at doses 30 times greater than doses needed in these vaccine studies. Entolimod has markedly increased AB responses to all of our anti-addiction vaccines in rodent models, and in normal humans. Conclusions: Entolimod and TLR5 stimulation has broad application to vaccines and potentially to other psychiatric disorders like depression, which has critical inflammatory contributions that Entolimod could reduce. [ABSTRACT FROM AUTHOR]

Background/objectives: Certain medical consequences seem unique to synthetic cannabinoid (SC) and not cannabis use. We report the case of an adolescent, whose drug expectancies appear to minimize the severity of SC-related adverse events.Methods/results: An 18-year-old male presented with altered mental status and seizure, complicated by respiratory failure. He was stabilized and on discharge, despite counseling on the harms of SC usage, the patient planned to resume use, insisting that the hospitalization was "just one bad high".Discussion/conclusions/scientific Significance: Diminished negative expectancies related to SC use among adolescents may reflect generalizations from cannabis. Effective interventions should counter cannabis-related expectancies of minimal harm. (Am J Addict 2016;XX:1-3). [ABSTRACT FROM AUTHOR]

Substance use is a major public health concern worldwide. In the United States, drug-related deaths have increased many-fold in the past two decades due to the infiltration of more potent and lethal drugs such as fentanyl. Despite significant advancement in medicine, the management of substance use disorders (SUD) continues to be fraught with high attrition, relapse, morbidity, and mortality. The conceptual transition of a SUD from a moral failing to a chronic disease caused by substances facilitated the expansion of biological treatments, including pharmacotherapy, neurostimulation, and immunotherapy. While the quest for vaccines against drugs of abuse had an optimistic start in animal models, clinical trials in humans have yielded disappointing results. This paper provides a brief review on the current progress of vaccines against nicotine, stimulants (cocaine and methamphetamine), opioids including fentanyl, novel psychoactive substances (synthetic cathinones and synthetic cannabis), and discusses prospects for vaccine technology in the treatment of SUD. • Vaccines for substance use disorders have faced significant challenges in transition for use in humans. • vaccines against drugs of abuse maybe more helpful for some lethal substances as part of overdose prevention • The cocaine and nicotine vaccines have not been successful at promoting abstinence or reducing use in humans. • Vaccines against methamphetamine, fentanyl, synthetic cathinones, synthetic cannabis show promise in animal studies • The search for a vaccine against drugs of abuse continues with advancements in vaccine technology [ 1–68 ] [ABSTRACT FROM AUTHOR]

Background: Despite progress in cocaine immunotherapy, the kinetic and thermodynamic properties of antibodies which bind to cocaine and its metabolites are not well understood. It is also not clear how the interactions between them differ in a complex matrix such as the serum present in the human body. In the present study, we have used microscale thermophoresis (MST), isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR) we have evaluated the affinity properties of a representative mouse monoclonal (mAb08) as well as those of polyclonal antibodies purified from vaccinated mouse and human patient serum. Results: MST analysis of fluorescently tagged mAb08 binding to cocaine reveals an approximately 15 fold decrease in its equilibrium dissociation constant in 20-50% human serum compared with that in saline buffer. A similar trend was also found using enriched polyclonal antibodies purified from vaccinated mice and patient serum, for which we have used fluorescently tagged bovine serum albumin conjugated to succinyl norcocaine (BSA-SNC). This conjugate closely mimics both cocaine and the hapten used to raise these antibodies. The ITC data also revealed that cocaine has a moderate affinity of about 2 mM to 20% human serum and very little interaction with human serum albumin or nonspecific human IgG at that concentration range. In a SPR inhibition experiment, the binding of mAb08 to immobilized BSA-SNC was inhibited by cocaine and benzoylecgonine in a highly competitive manner, whereas the purified polyclonal antibodies from vaccinated humans and mice, revealed preferential selectivity to pharmacologically active cocaine but not to the inactive metabolite benzoylecgonine. We have also developed a simple binding model to simulate the challenges associated with cocaine immunotherapy using the variable quantitative and kinetic properties of the antibodies. Conclusions: High sensitivity calorimetric determination of antibody binding to cocaine and its metabolites provide valuable information for characterization of their interactions and thermodynamic properties. In addition MST measurements of antibody affinity in the presence of biological fluids will provide a better opportunity to make reliable decisions and facilitate the design of cocaine vaccines and immunization conditions. The methods should be more widely adopted in characterization of antibody complexes. [ABSTRACT FROM AUTHOR]

Background: Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α1 receptor antagonist doxazosin on the positive subjective effects of cocaine. Methods: Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebocontrolled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind. Results: Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of "high", "stimulated", "like cocaine", "desire cocaine", "any drug effect", and "likely to use cocaine if had access" (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of "stimulated", "like cocaine", and "likely to use cocaine if had access" (p<.05). There were trends for doxazosin to reduce ratings of "stimulated", "desire cocaine", and "likely to use cocaine if had access" (p<.10). Conclusions: Medications that block noradrenergic α1 receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further. [ABSTRACT FROM AUTHOR]

The article presents a case study of a patient detected with opioid abuse through physical observations and drug screening tests. It mentions that the patient shows signs of substance abuse intoxication including constricted pupils, slurred speech, and euphoria. It focuses on patient's history of substance abuse on hydrocodone, acetaminophen, and naloxone. It discusses the dependence of Americans on prescription pain medication and the move of Food and Drug Administration (FDA) to mitigate it.

Stress is associated with relapse to drugs after abstinence, but the mechanisms for this association are unclear. One mechanism may be that stress enhances abstinent addicts’ recall of memories of drugs as stress relievers. This study assessed the effects of stress on free recall and cued recall of 10 heroin-related and 10 neutral words learned 24 h earlier by 102 abstinent heroin addicts. These participants were randomly assigned to three experiments that also assessed attention and working memory. Experiment 1 used a psychosocial stressor (Trier social stress test (TSST)) before testing for recall of heroin-related words. Experiment 2 added administration of the β-adrenoceptor antagonist propranolol 1 h before the psychosocial stressor. Experiment 3 added administration of either cortisol with propranolol, cortisol alone, or propranolol alone 1 h before word recall to determine whether stress enhancement of heroin-related word recall required noradrenergic-glucocorticoid interactions. We found that free recall of heroin-related words in abstinent addicts was enhanced after stress or cortisol administration when compared with a non-stress condition or placebo, respectively, whereas these interventions had no effect on neutral word recall. β-adrenergic blockade blocked the enhancing effect of stress or cortisol on free recall of heroin-related words. Neither stress nor cortisol affected cued recall, attention, or working memory. The potential of β-adrenergic blockade to reduce or block stress-induced enhancement of drug-related memory retrieval may be relevant to preventing stress-induced relapse in abstinent heroin addicts. [ABSTRACT FROM AUTHOR]

Rationale: Heroin use and withdrawal cause abnormality in the endocrine system. However, the time course of neuroendocrine alterations in heroin addicts during pharmacologically unassisted withdrawal is still unclear. Objectives: To investigate alterations in cortisol, adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-EP), leptin, and neuropeptide Y (NPY) during the first month of abstinence in heroin addicts. Methods: Twelve heroin addicts and eight matched healthy control subjects were recruited for this study. The neuroendocrine alterations and self-reported heroin craving, anxiety, and depression in heroin addicts were assessed at different time points (days 3, 10, and 30) of first month of abstinence from heroin use. Results: Self-reported heroin craving, anxiety, and depression in heroin addicts decreased gradually during the first month of abstinence. The cortisol levels increased from abstinence day 3 to 30, while ACTH and beta-EP levels decreased over this period in heroin addicts. The leptin and NPY levels were significantly decreased on days 3 and 10 but had normalized on day 30 of abstinence. A positive correlation between cortisol level and heroin craving, anxiety, and depression was observed, while a negative correlation was observed between beta-EP level and craving and anxiety and between leptin and depression and NPY and anxiety. Conclusions: Abnormal alterations in the neuroendocrine system, including levels of cortisol, ACTH and beta-EP persist throughout the first month of abstinence. These results suggest that neuroendocrine system dysfunctions in heroin abusers is independent of the acute and protracted withdrawal syndromes, and may thus contribute to relapse to heroin use. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Psychiatric pharmacogenetics involves the use of genetic tests that can predict the effectiveness of treatments for individual patients with mental illness such as drug dependence. This review aims to cover these developments in the pharmacotherapy of alcohol and opiates, two addictive drugs for which we have the majority of our FDA approved pharmacotherapies. Methods: We conducted a literature review using Medline searching terms related to these two drugs and their pharmacotherapies crossed with related genetic studies. Results: Alcohol's physiological and subjective effects are associated with enhanced β-endorphin release. Naltrexone increases baseline β-endorphin release blocking further release by alcohol. Naltrexone's action as an alcohol pharmacotherapy is facilitated by a putative functional single nucleotide polymorphism (SNP) in the opioid mu receptor gene (Al18G) which alters receptor function. Patients with this SNP have significantly lower relapse rates to alcoholism when treated with naltrexone. Caucasians with various forms of the CYP2D6 enzyme results in a 'poor metabolizer' phenotype and appear to be protected from developing opioid dependence. Others with a “ultra-rapid metabolizer” phenotype do poorly on methadone maintenance and have frequent withdrawal symptoms. These patients can do well using buprenorphine because it is not significantly metabolized by CYP2D6. Conclusions: Pharmacogenetics has great potential for improving treatment outcome as we identify gene variants that affect pharmacodynamic and pharmacokinetic factors. These mutations guide pharmacotherapeutic agent choice for optimum treatment of alcohol and opiate abuse and subsequent relapse. [ABSTRACT FROM AUTHOR]

Several studies indicate abnormalities in the hypothalamic-pituitary-adrenal axis (HPA) during acute opiate withdrawal, but protracted withdrawal has gotten less study. The current study further characterized the 24-hour time course of plasma cortisol levels in heroin-dependent individuals who were abstinent for 10-15 days, which is beyond the 5 days of acute withdrawal, compared to demographically matched healthy controls using samples collected every 3 hours over 24 hours and assessed with radioimmunoassay (RIA). The abstinent heroin-dependent participants had significantly higher plasma cortisol levels nocturnally suggesting a loss of diurnal variation in these heroin subjects. [ABSTRACT FROM AUTHOR]

Over the past decade, a large number of potential medications have been examined in clinical trials for cocaine dependence. Unfortunately, no effective pharmacotherapies for cocaine dependence have been found to date. Although effective treatments for cocaine dependence are still being investigated, a few variables have been found to significantly predict cocaine treatment response. These variables include cocaine use variables, such as days of cocaine use in the month before treatment, baseline urine cocaine results, and cocaine withdrawal symptoms. Comorbid depression and alcohol use have also been shown to be risk factors for relapse. Among personality variables, impulsivity and similar personality traits may predict treatment response. Initial promising findings with genetic polymorphism, brain activation, and stress response have also been found and need to be replicated in future studies. [ABSTRACT FROM AUTHOR]

Background: The prevalence, efficacy, and risk for addiction for persons receiving opioids for chronic back pain are unclear. Purpose: To determine the prevalence of opioid treatment, whether opioid medications are effective, and the prevalence of substance use disorders among patients receiving opioid medications for chronic back pain. Data Sources: English-language studies from MEDLINE (1966- March 2005), EMBASE (1966-March 2005), Cochrane Central Register of Controlled Clinical Trials (to 4th quarter 2004), PsychInfo (1966-March 2005), and retrieved references. Study Selection: Articles that studied an adult, nonobstetric sample; used oral, topical, or transdermal opioids; and focused on treatment for chronic back pain. Data Extraction: Two investigators independently extracted data and determined study quality. Data Synthesis: Opioid prescribing varied by treatment setting (range, 3% to 66%). Meta-analysis of the 4 studies assessing the efficacy of opioids compared with placebo or a nonopioid control did not show reduced pain with opioids (g, -0.199 composite standardized mean difference [95% CI, -0.49 to 0.11]; P = 0.136). Meta-analysis of the 5 studies directly comparing the efficacy of different opioids demonstrated a nonsignificant reduction in pain from baseline (g, -0.93 composite standardized mean difference [CI, -1.89 to -0.03]; P = 0.055). The prevalence of lifetime substance use disorders ranged from 36% to 56%, and the estimates of the prevalence of current substance use disorders were as high as 43%. Aberrant medication-taking behaviors ranged from 5% to 24%. Limitations: Retrieval and publication biases and poor study quality. No trial evaluating the efficacy of opioids was longer than 16 weeks. Conclusions: Opioids are commonly prescribed for chronic back pain and may be efficacious for short-term pain relief. Long-term efficacy (≥16 weeks) is unclear. Substance use disorders are common in patients taking opioids for back pain, and aberrant medication- taking behaviors occur in up to 24% of cases. [ABSTRACT FROM AUTHOR]

This study used functional magnetic resonance imaging (fMRI) to examine the association between brain activation during exposure to cocaine-related cues and relapse to drug use in cocaine-dependent (CD) patients. We imaged 17 CD subjects during a 2-week in-patient stay. The subjects then entered a 10-week outpatient placebo-controlled, double-blind randomized clinical trial where urine toxicologies were assessed three times weekly to calculate the treatment effectiveness score (TES). Worse TES correlated with BOLD activation in the left precentral, superior temporal, and posterior cingulate cortices (PCC), and right middle temporal and lingual cortices (R>0.65; P<0.005). The left PCC activation also distinguished eight nonrelapsers (TES above mean and completed treatment) from nine relapsers. Cocaine-free urines were significantly greater in the nonrelapsers (92%) than in the relapsers (66%), who also remained in treatment for an average of only 3.2 weeks. Self-reports of craving during fMRI did not differ between nonrelapsers and relapsers and did not correlate with TES. Relapse to cocaine abuse was associated with increased activation in the sensory association cortex, the motor cortex, and PCC while viewing images of cocaine-related cues. These results suggest that relapse to cocaine abuse is associated with increased brain activation to cocaine cues in sensory, motor, and cognitive-emotional processing areas. This physiological activation was a better predictor of relapse than subjective reports of craving, and may be a useful target for treatment development.Neuropsychopharmacology (2006) 31, 644–650. doi:10.1038/sj.npp.1300851; published online 10 August 2005 [ABSTRACT FROM AUTHOR]

Objective: Stress is known to increase cocaine craving and relapse risk in cocaine dependence. Identifying neural activity associated with stress and stress-induced cocaine craving is important in understanding the neurobiology of cocaine craving and relapse. Method: Blood oxygenation level dependent (BOLD) signal changes were assessed in a functional magnetic resonance imaging (fMRI) session with healthy controls and treatment-engaged, abstinent, cocaine-dependent individuals (patients) as they participated in brief guided imagery and recall of three personal stress and three personal neutral situations. Results: During stress, patients showed significantly less BOLD activation than controls in specific frontal and paralimbic regions, such as the anterior cingulate (AC) region, left hippocampal/parahippocampal region, right fusiform gyrus, and the right postcentral gyrus. On the other hand, patients had increased activity in the caudate and dorsal striatum region during stress, activation that was significantly associated with stress-induced cocaine craving ratings. Conclusions: Patients failed to activate AC and related circuits during stress, regions associated with control, and regulation of emotion and distress states. Instead, they exhibited greater craving-related activation in the dorsal striatum, a region related to reward pathways and part of the obsessive-compulsive circuitry. Such functional alterations in stress processing may underlie the stress-related vulnerability to cocaine relapse often observed in cocainedependent individuals in early recovery. [ABSTRACT FROM AUTHOR]

Immunotherapies, including vaccines, monoclonal and catalytic antibodies, are an exciting and novel approach to treating problems of drug dependence. Drugs of abuse currently being tested using immunotherapy include nicotine, cocaine, phencyclidine (PCP) and methamphetamine. Data from animal models demonstrate that immunotherapies reduce drug seeking and drug toxicity. Preliminary clinical data show immunotherapies induce antibody titers, produce few side effects, can reduce drug use and thus have tremendous potential as an innovative option to drug treatment. [Copyright &y& Elsevier]

The aims of this study are to assess psychiatrists' comfort using office-based opiate agonist treatment (OBOT) and to identify psychiatrist characteristics associated with OBOT comfort. A random sample of 2,323 AMA Masterfile of Physicians psychiatrists were surveyed through the 2002 APIRE National Survey of Psychiatric Practice (NSSP). Of the 52% responding (N = 1,203), 80.6% (SE = 1.8%) were not comfortable providing OBOT. Males, addiction-certified psychiatrists, and those treating substance abuse patients were more comfortable providing OBOT. These findings highlight significant barriers in providing buprenorphine treatment. Increasing the understanding of specific financing and services delivery barriers that clinicians face is needed to inform the development of effective integrated services models and policies to facilitate OBOT implementation. Am J Addict 2004;13[Suppl 1]:S8-S16) [ABSTRACT FROM AUTHOR]

We sought to evaluate the safety and efficacy of the GABAergic agent tiagabine in reducing cocaine use among methadone-treated patients. Ten-week randomized double-blind placebo-controlled trial. Opiate Treatment Research Program, Veteran's Affairs Connecticut Healthcare System in West Haven, Connecticut, USA. The participants were 45 cocaine-dependent methadone-treated patients who were predominately Caucasian (75.6%), male (77.8%) and never married (53%) with an average age of 38 years (SD = 6.5). Comparison groups received tiagabine 12 mg/day ( n = 15), tiagabine 24 mg/day ( n = 15) or placebo ( n = 15). Baseline assessments included the Structured Clinical Interview for DSM-IV, the Addiction Severity Index, a urine drug test, self-reported use and opiate withdrawal scales. Urine drug tests were performed thrice weekly. Treatment retention was over 80% for all treatment groups. The sample mean (± SE) of cocaine-free urines for the first week after study entry and before tiagabine was started was 1.16 (0.19) urines/week. During weeks 9 and 10 cocaine-free urines increased significantly from baseline by 33% with high-dose tiagabine (24 mg/day), by 14% with low-dose tiagabine (12 mg/day) and decreased by 10% with placebo (hierarchical linear model, Z= 2.03; P < 0.05). Self-reported cocaine use also decreased significantly more with active medications than with placebo. Tiagabine at 24 mg/day was well tolerated among these methadone-treated patients with only one reporting headache. Tiagabine appears to be a promising GABAergic medication that moderately improves cocaine-free urines. [ABSTRACT FROM AUTHOR]

Depression is common among patients who abuse both opiates and cocaine, and its treatment has had mixed success. This study compares buprenorphine-maintained patients with lifetime major depressive disorder (MDD, N = 53) with those never depressed (ND, N = 96) on cocaine and opiate-free urines during a 12-week outpatient double-blind, placebo-controlled, randomized clinical trial. The 149 subjects were assigned to four groups: 1) desipramine (DMI) + contingency management (CM); 2) DMI + noncontingency management (NCM); 3) placebo + CM; and 4) placebo + NCM. Depression assessments included Hamilton Depression Rating Scale, Center for Epidemiological Studies Depression Inventory, and Structured Clinical Interview for DSM-IV interview for diagnosis of lifetime MDD. Urine toxicologies were performed thrice weekly and the CES-D was performed monthly. The MDD group had a larger proportion of females (45% vs 21%, P = 0.02) and were more likely to be married (13.2% vs 7.3%, P = 0.02) than the ND group. Treatment retention did not vary by depression status. Hierarchical Linear Modeling found that depressive symptoms decreased comparably across the four treatment groups. Although participation in CM improved drug-free urines more for patients with MDD than for the ND group (Z = 2.44, P = 0.01), treatment with DMI was significantly more efficacious for the ND group than for the MDD group (Z = -2.89, P = 0.003). These results suggest that patients with MDD may respond better to behavioral treatments such as CM than to desipramine plus buprenorphine. The ND cocaine-abusing, opiate-dependent patients may be more responsive to the anticraving effects of DMI. [ABSTRACT FROM AUTHOR]

Nine cocaine abusers with cerebral blood flow (CBF) deficits (hypo-perfused areas) on HMPAO SPECT scans were compared to six without these deficits after six doses of isradipine (5 mg TID). When comparing the scan before isradipine to that after using SPM analysis, the ratio of hypo- to hyper-fusion showed a 16% increase in the maximum Z scores and 30% fewer areas of hypo-perfusion among those cocaine abusers with deficits. These deficits may represent segmental cerebral vasospasm that was reversed by this vasodilating agent in cocaine abusers with areas of hypo-perfusion (deficits) as baseline. [ABSTRACT FROM AUTHOR]

The utility of the crossover design in substance abuse research was examined in a 26-week, double-blind clinical trial that evaluated the efficacy of desipramine (0 or 150 mg/day) in 109 male and female cocaine- and opiate-dependent patients maintained on buprenorphine (12 mg/day) or methadone (65 mg/day). After being stabilized on buprenorphine or methadone (weeks 1-2), half of the patients were randomly assigned to receive desipramine for the first half of the trial and placebo for the second, with the order reversed for the second half. Analyses using hierarchical linear models (HLM) indicated that desipramine reduced the use of opiates only when administered at the start (rather than the middle) of the trial, whereas cocaine use was reduced when desipramine was introduced at either time. [ABSTRACT FROM AUTHOR]

Self-report and physiological data from 27 male and 8 female cocaine-abusing volunteers exposed to cocaine (80 mg/70 kg p.o.) and placebo were examined for sex differences in their responses. Females reported significantly greater baseline ratings on the Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) (sedation) and Lysergic Acid Diethylamide (LSD) (dysphoria) subscales of the Addiction Research Center Inventory-Short Form (ARCI) relative to males. In addition, females reported significantly greater ratings on the Visual Analogs Scales (VAS) Bad Drug Effects and Anxious/Nervous scales relative to males, regardless of drug. Cocaine produced greater increase in systolic blood pressure in males following cocaine, whereas females showed greater increases following placebo. These results suggest that a placebo control is necessary to determine sex differences in response to an active drug. [ABSTRACT FROM AUTHOR]

We evaluated the effects of acute pretreatment with lamotrigine, a putative glutamate release inhibitor, on the physiological and behavioral responses to intranasal cocaine in cocaine-dependent volunteers (N = 8). The study employed a double-blind, placebo-controlled, within-subject design. Subjects participated in six experimental sessions. On each study day, placebo, lamotrigine 125 mg, or lamotrigine 250 mg was administered orally in the morning, followed 2 hours later by intranasal cocaine 120 mg/70 kg or placebo. Measurements of heart rate and blood pressure were acquired, and subjects responded to mood state questionnaires at predetermined time intervals. Cocaine alone produced increases in heart rate, blood pressure, and several measures of pleasurable mood and drug effects. Lamotrigine alone produced a mild relaxing effect. Lamotrigine pretreatment altered neither the physiological responses nor the subjective ratings of cocaine's pleasurable or aversive mood effects. [ABSTRACT FROM AUTHOR]

This double blind, placebo controlled study of acute calcium channel antagonist use during cocaine administration in five patients found that 60 mg of nimodipine treatment attenuated the systolic, but not diastolic, blood pressure effects of cocaine. In three subjects, a 90 mg dose of nimodipine showed a greater attenuation than that of 60 mg. Subjective effects of cocaine were not altered by either dose of nimodipine. [ABSTRACT FROM AUTHOR]

Theoretical considerations as well as pre-clinical data suggest a potential role for glutamate-inhibiting agents in the treatment of cocaine addiction. At present, however, there is little clinical data to inform the use of these agents for this application. In this preliminary study eighteen HIV-seropositive cocaine dependent, opiate-agonist maintained patients received lamotrigine (300 mg/day), an indirect glutamate release inhibitor, on either a standard (n = 8) or accelerated (n = 10) induction schedule for 12 weeks. Results showed a significant decrease in percentage of cocaine-positive urine screens in the standard induction lamotrigine group but not in the accelerated induction group. There were fewer reports of side-effects and fewer dropouts in the standard-induction lamotrigine group compared to the accelerated induction group. Neuropsychological assessments suggested a decrement in the Trail Making Tests, but no other decreases in cognitive functioning. We conclude that standard-induction lamotrigine warrants further investigation for the treatment of cocaine abuse in this patient population. [ABSTRACT FROM AUTHOR]

Five inpatients dependent on both intravenous cocaine and heroin were detoxified from opiates. They were then given 5 days of double-blind treatment with active or placebo buprenorphine 2 mg/d sublingually, followed by a crossover to the converse for 5 days (buprenorphine or placebo). Intranasal cocaine challenges (2 mg/kg) were performed on Days 3 and 5 of each treatment. Buprenorphine significantly enhanced patients' ratings of cocaine-induced pleasurable effects, and augmented cocaine-induced pulse increases. The buprenorphine enhancement of subjective cocaine effects appeared to be more prominent on Day 3 than on Day 5. This reduction from Day 3 to Day 5 suggests that cocaine may interact differently with buprenorphine as treatment is more prolonged. [ABSTRACT FROM AUTHOR]

The article relates the author's appreciation as the editor-in-chief of the journal "American Journal of Drug and Alcohol Abuse." He has shared about his gratitude for following the path of former editor Edward Kaufman, who had served for 30 years in the journal. The author has stressed about Kaufman's guiding light for the journal by striving to have a translational research forum that communicates innovative ideas and treatments to the addiction research and treatment communities. According to the author, the journal and its editorial board had the vision not only to see how the research base for addictions was rapidly expanding, but also to provide a forum where quantitative and qualitative clinical research in addictions would be welcome.

An introduction is presented in which the editor discusses various articles within the issue on topics including articles from American Academy of Addiction Psychiatry (AAAP) Newsletter; a report National Institute on Drug Abuse on progress in precision medicine in the treatment of opiate.

Highlights • Use of synthetic cannabinoids (SC) has become prevalent in the US. • Role of SC in psychosis is more complex than that of any single chemical component. • These effects may not be a simple extension of the typical effects of cannabis. Abstract Synthetic cannabinoid (SC) products have gained popularity as abused drugs over the past decade in many countries. The SCs broadly impact psychological state (e.g., mood, suicidal thoughts and psychosis) and physiological functions (e.g., cardiovascular, gastrointestinal and urinary). This review is about the effects of SCs on psychotic symptoms in clinical settings and the potentially relevant chemistry and mechanisms of action for SCs. Induction of psychotic symptoms after consuming SC products were reported, including new-onset psychosis and psychotic relapses. The role of SCs in psychosis is more complex than any single chemical component might explain, and these effects may not be a simple extension of the typical effects of cannabis or natural cannabinoids. [ABSTRACT FROM AUTHOR]

The article discusses various reports published within the issue, including one about the interactions of modafinil and cocaine and another about behavior therapy to augment oral naltrexone for opioid dependence.

A letter to the editor is presented about the use of bromocriptine for cocaine abuse among patients maintained on methadone.

We recently reported that progesterone treatment attenuated some of the subjective effects of smoked cocaine in female cocaine users. In this study, we further examined the interaction between progesterone and cocaine in both male and female cocaine users using subjective, physiological and behavioral outcomes. A total of 10 subjects, 6 male and 4 female cocaine users, had two experimental sessions. Before each session, participants received either two oral doses of 200 mg of progesterone or placebo. Two hours after the second dose of medication treatment, the participants received a 0.3 mg/kg dose of cocaine intravenously and started the self-administration period, in which five optional doses of cocaine were available. Progesterone treatment attenuated the cocaine-induced diastolic blood pressure increases without affecting the systolic blood pressure and heart rate increases. Progesterone treatment also attenuated the subjective ratings of high and feel the effect of last dose in response to cocaine but did not affect cocaine self-administration behavior. These results suggest that progesterone attenuates some of the physiological and subjective effects of cocaine in both male and female participants. The effects of progesterone treatment on cocaine dependence need to be further studied in controlled trials. [Copyright &y& Elsevier]

Preclinical studies suggested that combination of naltrexone and isradipine may be useful for the treatment of cocaine addiction. This study examined whether naltrexone and isradipine, alone or in combination, would attenuate the subjective and physiological effects of cocaine in humans. Seven cocaine users participated in a randomized, double-blind, placebo-controlled inpatient study. Before each of the seven experimental sessions, subjects were treated orally with naltrexone (50 mg or placebo), isradipine (10 mg or placebo), or naltrexone plus isradipine. Subjects then received a single dose of intranasal cocaine (4 mg or 100 mg/70 kg). Isradipine alone attenuated the systolic blood pressure response to cocaine. In contrast, isradipine plus naltrexone treatment attenuated both the systolic and diastolic blood pressure responses. Naltrexone alone did not affect the blood pressure response to cocaine. For subjective response to cocaine, isradipine, alone or in combination with naltrexone, did not have significant effects. Naltrexone treatment alone attenuated the rating of “good effects” from cocaine without affecting other subjective responses. These results suggest that isradipine alone or in combination with naltrexone attenuates some of the physiological effects of cocaine. [Copyright &y& Elsevier]

Abstract: Background: Disulfiram may be efficacious for treating cocaine dependence or abuse, possibly through inhibiting dopamine β-hydroxylase (DβH). Consequently, this randomized, placebo-controlled clinical trial of disulfiram during buprenorphine maintenance treatment evaluated the study hypothesis that disulfiram is superior to placebo and explored whether disulfiram response is greatest for participants with a single nucleotide polymorphism coding for genetically low DβH (T-allele carriers). Methods: We randomized 177 buprenorphine-treated opioid dependent participants with cocaine dependence or abuse to 12 weeks of double-blind treatment with disulfiram 250mg daily (n =91) or placebo (n =86). Of 155 participants genotyped, 84 were CC-homozygous, and 71 CT or TT genotypes. Primary outcomes included days per week cocaine use, number of cocaine-negative urine tests, and maximum consecutive weeks of cocaine abstinence. We analyzed an intention-to-treat comparison between disulfiram and placebo. We also explored potential pharmacogenetic interactions and examined treatment responses of four participant groups based on medication (disulfiram or placebo) by genotype (CC-homozygous or T-allele carrier) classification. Results: Disulfiram participants reported significantly less frequent cocaine use; the differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant. Frequency of cocaine use was lowest in disulfiram-treated T-allele carriers; differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant among the four medication-genotype groups. Conclusions: The findings provide limited support for the efficacy of disulfiram for reducing cocaine use and suggest that its mechanism of action may involve inhibition of DβH. Further studies of its efficacy, mechanism of action, and pharmacogenetics of response are warranted. [Copyright &y& Elsevier]

Abstract: Background: GABAergic medications appear to reduce the reinforcing effects of cocaine by attenuating cocaine-induced dopamine release. This study evaluated gabapentin and tiagabine compared to placebo in reducing cocaine taking behavior. Methods: A total of 76 treatment seeking, cocaine dependent, methadone-treated, predominately Caucasian male subjects were randomly assigned to tiagabine 24mg/day (N =25), gabapentin 2400mg/day (N =26) or placebo (N =25) in a 10-week double-blind placebo-controlled trial. Study medications were slowly increased to their full dosages by the end of week 5 and maintained through week 10. The primary outcome measure was thrice-weekly drug free urine samples. Results: Treatment retention was significantly less for the gabapentin group relative to the other groups (log rank=5.29, d.f.=1, p =0.02). The proportion of cocaine-free urine samples during weeks 6–10 was significantly larger in the tiagabine treated group (p <0.05). The longitudinal data showed significant change in thrice-weekly cocaine free urines that reached a greater abstinent rate for the tiagabine treated group (22%) compared to gabapentin (5%) or placebo (13%) treated groups. Mixed-effects ordinal regression models showed a significant tiagabine by time interaction compared to gabapentin (Z =2.48, d.f.=1, p =0.01) and placebo (Z =3.90, d.f.=1, p =0.0001). The gabapentin group did not differ from placebo. Conclusion: Gabapentin showed poor treatment retention and ineffectiveness in reducing cocaine use. Tiagabine significantly reduced cocaine taking behavior compared to placebo or gabapentin among methadone-stabilized cocaine abusers. [Copyright &y& Elsevier]

Abstract: In preclinical studies, medications which increase the synaptic GABA levels have been shown to block cocaine reinforcement. In this study, we examined the interaction between a GABA enhancing medication, tiagabine, and cocaine in cocaine users. A total of 7 subjects, 5 male and 2 female cocaine users had 2 experimental sessions. Before each session, subjects received either two oral doses of 4 mg of tiagabine or placebo. Starting 2 h after the second dose of medication treatment, subjects received an injection of saline followed by 2 escalating cocaine doses (0.15 and 0.3 mg/kg) intravenously. Tiagabine treatment did not affect the cocaine-induced blood pressure and heart rate changes. Tiagabine treatment attenuated the subjective ratings of “stimulated” and “crave cocaine” in response to cocaine administration. These results suggest that tiagabine treatment attenuates some of the subjective effects of cocaine without affecting its cardiovascular effects. GABA medications, including tiagabine, are currently being evaluated in controlled clinical trials for the treatment of cocaine dependence. [Copyright &y& Elsevier]

Abstract: Opioid- and cocaine-dependent participants (N =140) were randomly assigned to one of the following in a 12-week clinical trial: LAAM (30, 30, 39mg/MWF) with contingency management (CM) procedures (LC); LAAM (30, 30, 39mg/MWF) without CM (LY); LAAM (100, 100, 130mg/MWF) with CM (HC); LAAM (100, 100, 130mg/MWF) without CM (HY). Urine samples were collected thrice-weekly. In CM, each urine negative for both opioids and cocaine resulted in a voucher worth a certain monetary value that increased for consecutively drug-free urines. Subjects not assigned to CM received vouchers according to a yoked schedule. Vouchers were exchanged for mutually agreed upon goods and services. Groups generally did not differ on retention and baseline characteristics. Overall opioid use was least in the HC and HY groups; opioid use decreased most rapidly over time in the HC group relative to the HY, LC and LY groups. Overall cocaine use was least in the HC group relative to the HY, LC, and LY groups; cocaine use decreased over time most rapidly in the HC and LY groups. Abstinence from both was greatest in the HC group. Opioid withdrawal symptoms decreased most rapidly in the high-dose groups relative to the low-dose groups. These results suggest that an efficacious maintenance dose is necessary for contingencies to be effective in facilitating both opioid and cocaine abstinence. [Copyright &y& Elsevier]

Background: Cocaine abuse has no established pharmacotherapy, but active immunotherapy with a cocaine vaccine shows promise as a therapeutic intervention. Methods: An open label, fourteen week, dose-escalation study evaluated the safety, immunogenicity, and clinical efficacy of a novel human cocaine vaccine (TA-CD) in eighteen cocaine dependent subjects. Ten subjects (400 μg total dose group) received four-100 μg injections over the course of eight weeks. Subsequently, eight subjects (2000 μg total dose group) received five-400 μg vaccinations over twelve weeks. Intent to treat analysis of thrice weekly urine toxicologies and cocaine antibody titers were compared. Results: Sixteen of 18 subjects completed the study. There were no serious adverse reactions and the vaccine was well tolerated. The 2000 μg total dose group had a significantly higher mean antibody titer response (2000 units) as compared to the 400 μg total dose group (1000 units) (p = .05). The 2000 μg group was more likely to maintain cocaine free urines than those in the 400 μg group (Z = −3.12, p = .002). Despite relapse in both groups, most reported an attenuation of cocaine''s usual euphoric effects at the six month follow-up time points (63% in the 400 μg and 100% in the 2000 μg groups). Conclusions: The conjugated cocaine vaccine was well tolerated and cocaine specific antibodies persisted at least six months. The likelihood of using cocaine decreased in subjects who received the more intense vaccination schedule. [Copyright &y& Elsevier]

: BackgroundDisulfiram (DS; Antabuse) inhibits dopamine-β-hydroxylase leading to increased brain dopamine levels and shows treatment efficacy for cocaine addiction. Yet few preclinical studies have been performed. This study establishes the effects of DS on locomotor sensitization to cocaine in rats.: MethodsRats were administered vehicle, cocaine (10 mg/kg; intraperitoneally [IP]), or DS (50 or 100 mg/kg; IP) alone or in combination for 5 days (development phase). Locomotor activity was measured for 60-min each day. After a 10-day drug washout, rats were administered cocaine, and locomotor activity was measured (expression phase). Plasma cocaine levels were assessed in separate groups of rats administered one of two cocaine doses (0 or 10 mg/kg) and one of two DS doses (0 or 100 mg/kg) for 5 days. Ten days later, blood was collected 60-min postcocaine injection.: ResultsThe development of cocaine locomotor sensitization was facilitated by DS even though DS alone had minimal effect on activity levels. Furthermore, expression of sensitization was greatest in rats previously administered DS, an effect that cannot be attributed to altered plasma cocaine levels.: ConclusionsBecause DS shows treatment efficacy for cocaine addiction, results from this study suggest potential treatment agents should enhance, not attenuate, locomotor sensitization in rats. [Copyright &y& Elsevier]