Search

Objectives: This paper outlines the experience developing Addiction Medicine Practice-Based Research Network (AMNet), which promotes the adoption of patient-reported outcome measures (PROMs) and measurement-based care in outpatient addiction treatment practices and creates a platform for quality improvement and research., Methods: From August 2019 to July 2023, the AMNet team selected patient-reported outcome measures for implementation in the American Psychiatric Association's clinical data registry (PsychPRO), recruited addiction medicine providers, and collected PROMs data., Results: AMNet selected 12 PROMs for implementation in PsychPRO. Through July 2023, 1565 providers expressed interest, of whom 216 of the 929 eligible providers (23%) attended an onboarding call/webinar. Two hundred six providers (95%) from 54 practices returned Participation Agreements. Subsequently, 65 providers (32%) from 39 practices withdrew, resulting in 141 (68%) providers from 15 practices. From November 2020 to July 2023, 38 providers submitted PROMs data using 1 of 3 PsychPRO patient portals. Sixteen of the 53 providers (30%) who signed up for the initial portal collected data from 468 patients. As of July 2023, 83 of the 141 providers (59%) opted to submit PROMs data from their own portal or electronic health record., Conclusions: Next steps will include continued recruitment of providers, addressing barriers to data transfer and integrating data from providers' portals into the registry to create a platform for future research., Competing Interests: Conflicts of interest: Dr Schwartz has served as a consultant for Verily Life Sciences and as one of multiple principal investigators for a National Institute on Drug Abuse cooperative study that received free medications from Alkermes and Indivior. Dr Vocci has served as a consultant to Lyndra Therapeutics, Takeda Pharmaceuticals, and a group of generic buprenorphine manufacturers; he has received free medications from Alkermes and Braeburn for clinical studies, meals from Braeburn, and meals and travel reimbursements from IntraTab Labs, Lyndra Therapeutics, Takeda Pharmaceuticals, and a group of generic buprenorphine manufacturers. Dr Clarke has served on the Mental Health Landscape Project Advisory Panel for RAND, a project funded by Otsuka. The other authors report no financial relationships with commercial interests., (Copyright © 2024 American Society of Addiction Medicine.)

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants., Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD ( DSM-5 ) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35)., Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant ( P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% ( P = .076), and response rates were 39.8% and 27.2% ( P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 ( P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups., Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies., Trial Registration: ClinicalTrials.gov identifier: NCT04688164., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Objective: The authors investigated adaptations to outpatient care delivery and changes in treatment demand and engagement among patients receiving medications for opioid use disorder (MOUD) in the months after the declaration of the COVID-19 public health emergency in 2020., Methods: Data were collected through an online survey (June-November 2020) of outpatient MOUD prescribers. The survey obtained information on outpatient practices' adaptations to MOUD treatment and urine drug screening (UDS) and elicited provider views on the effects of the COVID-19 pandemic on patient demand for, and engagement in, treatment. Multivariable regression analyses were used to examine associations among practice characteristics, patient engagement, and service adaptations., Results: Of 516 respondents, 74% reported adaptations to MOUD delivery during the pandemic. Most respondents implemented virtual visits for initial (67%) and follow-up (77%) contacts. Prescribers of buprenorphine were more likely than those who did not prescribe the medication to report MOUD adaptations. Among respondents reporting any MOUD adaptation, 77% made adaptations to their UDS practices. Among 513 respondents who answered COVID-19-related questions, 89% reported that the pandemic had affected the treatment and engagement of their patients. Of these respondents, 30% reported increased difficulty with patient engagement, and 45% reported that their patients preferred virtual visits during this period, whereas 18% endorsed patient preference for in-person visits., Conclusions: Telehealth and federal regulatory easements in response to the COVID-19 pandemic enabled providers to continue treating patients for opioid use disorder in 2020. The results suggest that care adaptations and changes in patient demand and engagement were common in the practices surveyed., Competing Interests: Dr. Schwartz has served as a consultant for Verily Life Sciences and as one of multiple principal investigators for a National Institute on Drug Abuse cooperative study that received free medications from Alkermes and Indivior. Dr. Vocci has served as a consultant to Lyndra Therapeutics, Takeda Pharmaceuticals, and a group of generic buprenorphine manufacturers; he has received free medications from Alkermes and Braeburn for clinical studies, meals from Braeburn, and meals and travel reimbursements from IntraTab Labs, Lyndra Therapeutics, Takeda Pharmaceuticals, and a group of generic buprenorphine manufacturers. Dr. Clarke has served on the Mental Health Landscape Project Advisory Panel for RAND, a project funded by Otsuka. The other authors report no financial relationships with commercial interests.

New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled globally. The implications of the CSA for research and medicines development, the path to approval of medicines, and their subsequent removal from Schedule I in the US are discussed. This entire process occurs within the framework of the CSA in the US and its counterparts internationally in accordance with international drug control treaties. Abuse potential related research in the US informs the eight factors of the CSA which provide the basis for rescheduling actions that must occur upon approval of a drug that contains a Schedule I substance. Abuse-related research also informs drug product labeling and the risk evaluation and mitigation strategies (REMS) will likely be required for approved medicines. Human abuse potential studies typically employed in CNS drug development may be problematic for substances with strong hallucinogenic effects such as psilocybin, and alternative strategies are discussed. Implications for research, medicinal development, and controlled substance scheduling are presented in the context of the US CSA and FDA requirements with implications for global regulation. We also discuss how abuse-related research can contribute to understanding mechanisms of action and therapeutic effects as well as the totality of the effects of the drugs on the brain, behavior, mood, and the constructs of spirituality and consciousness., (Copyright © 2022. Published by Elsevier Ltd.)

This study is a randomized, open label, controlled trial of extended-release buprenorphine (XR-B; BRIXADI™ formulation) versus extended-release naltrexone (XR-NTX) in Maryland jails. A 7-site, open-label, equivalence design will randomly assign 240 adults with a history of opioid use disorder (OUD), stratified by gender and jail, who are nearing release to one of two treatment arms: 1) XR-B in jail or 2) XR-NTX in jail, both followed by 6 monthly injections postrelease at a community treatment program. The primary aim is to determine the rate of pharmacotherapy adherence (number of monthly injections received) of XR-B compared to XR-NTX. The proposed study is innovative because it will be the first randomized clinical trial in the U.S. assessing the effectiveness of receiving XR-B vs. XR-NTX in county jails. The public health impact of the study will be highly significant and far-reaching because most individuals with OUD do not receive treatment while incarcerated, thereby substantially raising their likelihood of relapse to drug use, overdose death, and re-incarceration. Understanding how to expand acceptance of medications for OUD in jails, particularly extended-release medications, and supporting treatment engagement and medication adherence in transition to the community, has far-reaching implications for improving treatment access and success in this population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This column describes the collaboration among the American Psychiatric Association (APA), American Society of Addiction Medicine, Friends Research Institute, and the National Institute on Drug Abuse to create the Addiction Medicine Practice-Based Research Network (AMNet). The collaboration, which aims to address the opioid overdose epidemic in the United States, leverages the APA's clinical data registry (PsychPRO) and is recruiting office-based addiction medicine and addiction psychiatry practices for AMNet. AMNet aims to address knowledge gaps regarding patient care in such practices, facilitate performance improvement efforts, and serve as a research platform.

Background: Persons with an opioid use disorder (OUD) who were incarcerated face many challenges to remaining abstinent; concomitantly, opioid-overdose is the leading cause of death among this population, with the initial weeks following release proving especially fatal. Extended-release naltrexone (XR-NTX) is the most widely-accepted, evidence-based OUD pharmacotherapy in criminal justice settings, and ensures approximately 30 days of protection from opioid overdose. The high cost of XR-NTX serves as a barrier to uptake by many prison/jail systems; however, the cost of the medication should not be viewed in isolation. Prison/jail healthcare budgets are ultimately determined by policymakers, and the benefits/cost-offsets associated with effective OUD treatment will directly and indirectly affect their overall budgets, and society as a whole., Methods: This protocol describes a study funded by the National Institute of Drug Abuse (NIDA) to: evaluate changes in healthcare utilization, health-related quality-of-life, and other resources associated with different strategies of XR-NTX delivery to persons with OUD being released from incarceration; and estimate the relative "value" of each strategy. Data from two ongoing, publicly-funded, randomized-controlled trials will be used to evaluate these questions. In Study A, (XR-NTX Before vs. After Reentry), participants are randomized to receive their first XR-NTX dose before release, or at a nearby program post-release. In Study B, (enhanced XR-NTX vs. XR-NTX), both arms receive XR-NTX prior to release; the enhanced arm receives mobile medical (place of residence) XR-NTX treatment post-release, and the XR-NTX arm receives referral to a community treatment program post-release. The economic data collection instruments required to evaluate outcomes of interest were incorporated into both studies from baseline. Moreover, because the same instruments are being used in both trials on comparable populations, we have the opportunity to not only assess differences in outcomes between study arms within each trial, but also to merge the data sets and test for differences across trials., Discussion: Initiating XR-NTX for OUD prior to release from incarceration may improve patient health and well-being, while also producing downstream cost-offsets. This study offers the unique opportunity to assess the effectiveness and cost-effectiveness of multiple strategies, according to different stakeholder perspectives.

Background: It has been estimated that approximately 15% of people who are incarcerated in the US have histories of opioid use disorder. Relapse to opioid use after release from prison poses a serious risk of HIV infection. Prison-initiated buprenorphine may help to reduce HIV infection given the association between opioid use and HIV-risk behaviors., Methods: The present study is a secondary analysis of longitudinal data gathered from a randomized controlled trial of buprenorphine-naloxone for people who were incarcerated (N = 211) between 2008 and 2012. It compares the impact of assignment to initiate buprenorphine in prison (N = 106 randomized, N = 104 analyzed) versus in the community (N = 107 randomized, N = 107 analyzed) and whether or not participants entered community treatment on the frequency of HIV-risk behaviors in the 12 months following release from prison. Data were analyzed hierarchically and for each outcome variable, a multilevel, over-dispersed Poisson model was fit to the data. Outcome variables were the number of times the following behaviors occurred in the last 30 days: (1) having sex without a condom (2) injecting drugs (3) using unsterilized needles, and (4) sharing injection paraphernalia., Results: Participants assigned to begin buprenorphine in the community experienced a greater decrease in injection drug use over time compared to participants assigned to begin buprenorphine in prison. There were no significant associations between treatment assignment or community treatment entry and instances of having sex without a condom, sharing injection paraphernalia, or using unsterilized needles., Conclusions: Overall, the present study did not find support for the initiation of buprenorphine in prison (as opposed to the community) as a means to reduce incidences of HIV-risk behaviors. Avenues for future research in the nexus of HIV-risk reduction, criminal justice, and pharmacotherapy are discussed. Trial registration This study was supported by the National Institute on Drug Abuse (NIDA), Buprenorphine for Prisoners (PI: Kinlock; R01DA021579). ClinicalTrials.gov identifier: NCT00574067.

Background: Buprenorphine can be effective in a variety of community substance use treatment settings outside of methadone programs, including outpatient programs and medical practices. In these settings, it has been found to be effective in reducing opioid use and retaining patients in treatment. Despite its effectiveness and safety, it is rarely provided to individuals with opioid use disorders in probation and parole settings., Methods: Male and female individuals under probation or parole supervision (N = 320) with histories of opioid use disorder will be enrolled in this randomized controlled trial. Participants will be randomized to one of two study arms: Buprenorphine Bridge Treatment (BBT): Participants will begin buprenorphine using the MedicaSafe dispensing device immediately after an on-site intake at a community supervision office and continue such treatment until they are transitioned to a community program; or Treatment as Usual (TAU): Participants will receive a referral to buprenorphine pharmacotherapy treatment in the community. Treatment outcomes will be: (a) illicit opioid oral saliva drug test results; and (b) treatment adherence (i. entered community based treatment; ii. number of days receiving opioid treatment)., Results: We describe the background and rationale for the study, its aims, hypotheses, and study design., Conclusions: If shown to increase compliance rates with conditions of probation and parole, buprenorphine treatment co-located at community supervision field offices could have a major impact on delivery of buprenorphine treatment to the criminal justice population. The public health impact of the proposed study would be widespread because this intervention could be implemented throughout areas of the US., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Aims: Extended-release naltrexone (XR-NTX), a μ-opioid receptor antagonist for prevention of relapse to opioid dependence, has demonstrated efficacy compared with placebo and comparative effectiveness with buprenorphine-naloxone. We report outcomes for XR-NTX in Vivitrol's Cost and Treatment Outcomes Registry., Design: Observational, open-label, single-arm, multi-center registry assessing baseline characteristics and clinical and health-related quality-of-life outcomes associated with XR-NTX treatment in clinical practice., Setting: 32 US treatment centers from 2011 to 2013., Participants: Patients with opioid dependence who were prescribed XR-NTX treatment and then enrolled into the registry., Measurements: Monthly visits were evaluated for the full population and for patient ubgroups retrospectively, defined by injection number, focusing on the period between baseline and month 6 (1-, 2/3- or 6-XR-NTX)., Findings: Of 403 enrolled patients, 395 were analyzed. Most patients (n = 349) received out-patient care. On average, patients received five injections (median = 3; range = 1-25). The median number of injections administered within 6 months was higher in patients who at baseline were employed (three versus two unemployed, P = 0.02) or had private insurance (five versus two self-payment, P = 0.005; versus two state-funded, P < 0.001). The 1-, 2/3- and 6-XR-NTX groups had 132, 152 and 111 patients, respectively. At baseline, the 6-XR-NTX patients were more likely to meet normal/minimal mental illness criteria and attend school and less likely to report recent drug use. Within 6 months, the 6-XR-NTX group demonstrated improvements in employment, mental health and psychosocial functioning, and decreases in opioid craving, drug use and drug-related behavior., Conclusions: Among opioid-dependent people receiving XR-NTX treatment, better mental health, higher education and lower recent drug use at baseline are associated with greater treatment duration; in turn, longer treatment duration is associated with lower relapse rates and improved outcomes generally., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Background: This secondary analysis of a randomized trial examines the association between initiation of buprenorphine treatment prior to, versus post-release, and rearrests during the 12-months following release., Methods: Official rearrest data (N = 199) for the 12-months post-release were examined. Four outcomes were measured: (1) rearrested (yes/no), (2) time to rearrest, (3) number of rearrests, and (4) severity of charges (less severe vs. severe)., Results: A minority (43.1%) of the sample were rearrested (N = 91). There were no significant differences between study conditions in the proportion of rearrested participants [P = 0.28] nor in the mean number of arrests [P  = 0.15]. Likewise, the condition was not a significant predictor of the hazard of rearrest [p = 0.10]. The mean number of days until rearrest for the in prison vs. post-release buprenorphine conditions were not significantly different (205.8 days (SD  = 104.6) vs. 170.8 days (SD  = 113.1), respectively; P  = 0.13]. Treatment condition was not a significant predictor of the likelihood of rearrest for a severe crime compared to a less severe crime [P  = 0.09]., Conclusion: Despite the parent study finding of higher rates of post-release drug treatment entry in the group assigned to start buprenorphine treatment prior to, compared to post-release, there were no significant differences in the proportion of individuals arrested, the mean number of arrests, the time to first arrest, or the severity of their charges., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Avatar-assisted therapy (AAT) is a novel and emerging technology that uses the Internet to enable clinicians and clients in substance abuse treatment to participate in group counseling sessions from separate and remote locations in real time through the use of avatars and virtual environments., Objectives: The current study is a pilot proof-of-concept feasibility study involving individuals in outpatient substance abuse treatment. This report addresses two questions: (1) are individuals who present for substance abuse treatment interested in receiving AAT and (2) what factors are associated with better treatment success., Methods: Individuals who presented at the treatment clinic who met study eligibility criteria, and provided their written informed consent to participate, were included in the current study (N = 59; 78% male)., Results: Twenty-eight (47.5%) participants completed 16 weeks of treatment and attended more sessions compared to non-completers (M = 14.3 vs. 7.5 p < .05). Those individuals who completed treatment were less likely to have a positive urine drug screen at baseline (21.5 vs. 78.6%; p < .05). Furthermore, those individuals who successfully completed treatment were less likely to have positive urine drug screens during treatment compared to those who did not complete (29.7% vs. 70.3%, p < .05). There were no arrests during treatment for completers and non-completers., Conclusion: Poor retention in substance use disorder treatment has long been a major problem for public health. AAT is a feasible approach that has the potential to expand treatment to individuals who might have difficulty accessing treatment. Moreover, AAT may be appealing to clients who are concerned about anonymity and confidentiality.

Background: This study examined whether starting buprenorphine treatment prior to prison and after release from prison would be associated with better drug treatment outcomes and whether males and females responded differently to the combination of in-prison treatment and post-release service setting., Methods: Study design was a 2 (In-Prison Treatment: Condition: Buprenorphine Treatment: vs. Counseling Only)×2 [Post-Release Service Setting Condition: Opioid Treatment: Program (OTP) vs. Community Health Center (CHC)]×2 (Gender) factorial design. The trial was conducted between September 2008 and July 2012. Follow-up assessments were completed in 2014. Participants were recruited from two Baltimore pre-release prisons (one for men and one for women). Adult pre-release prisoners who were heroin-dependent during the year prior to incarceration were eligible. Post-release assessments were conducted at 1, 3, 6, and 12-month following prison release., Results: Participants (N=211) in the in-prison treatment condition effect had a higher mean number of days of community buprenorphine treatment compared to the condition in which participants initiated medication after release (P=0.005). However, there were no statistically significant hypothesized effects for the in-prison treatment condition in terms of: days of heroin use and crime, and opioid and cocaine positive urine screening test results (all Ps>0.14) and no statistically significant hypothesized gender effects (all Ps>0.18)., Conclusions: Although initiating buprenorphine treatment in prison compared to after-release was associated with more days receiving buprenorphine treatment in the designated community treatment program during the 12-months post-release assessment, it was not associated with superior outcomes in terms of heroin and cocaine use and criminal behavior., Competing Interests: This study was supported by an unrestricted, unsolicited investigator initiated request from Reckitt Benckiser Pharmaceuticals, Inc. (provided study drug only) who had no role in study design; collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. The authors alone are responsible for the content and writing of this manuscript. Drs. Gordon, Kinlock, and Fitzgerald received funding from Alkermes on a prior study. Dr. Schwartz did a one-time consultation for Reckitt-Benckiser on behalf of his employer (the Friends Research Institute). Dr. O’Grady has in the past received funding for his time from Reckitt-Benckiser. Dr. Vocci has consulted with and received other funding (meals, travel expenses) from the following companies: Braeburn Pharmaceuticals, Demerx, Indivior, Pinney Associates. He has received travel and meal expenses from Intratab Labs Inc., and received consulting fees from Alkermes and Usona Institute. All of Dr. Vocci’s consulting fees go to his employer, Friends Research Institute, Inc., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases has been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment., Methods: Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors., Results: We describe the background and rationale for the study, its aims, hypotheses, and study design., Conclusions: The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. ClinicalTrials.gov: NCT02867124., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Importance: The effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion., Objective: To determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence., Design, Setting, and Participants: Outpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study conducted at 21 US sites from June 26, 2014, through May 18, 2015. Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician., Interventions: Participants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks)., Main Outcome Measure: The primary end point was between-group difference in proportion of responders (≥4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). The noninferiority established for the lower bound of the 95% confidence interval was greater than -0.20 (P < .025). Secondary end points included cumulative percentage of negative opioid urine results, abstinence, and time to first illicit opioid use. Safety was assessed by adverse event reporting., Results: Of 177 participants (mean age, 39 years; 40.9% female), 90 were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ∞; P < .001 for noninferiority). Over 6 months, 72 of 84 (85.7%) receiving buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95% CI, 0.018-0.258; P = .03). Non-implant-related and implant-related adverse events occurred in 48.3% and 23% of the buprenorphine implant group and in 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively., Conclusions and Relevance: Among adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine, the use of buprenorphine implants compared with continued sublingual buprenorphine did not result in an inferior likelihood of remaining a responder. However, the study population had an exceptionally high response rate in the control group, and further studies are needed in broader populations to assess the efficacy in other settings., Trial Registration: clinicaltrials.gov Identifier: NCT02180659.

This was a Phase 4, pilot, open-label feasibility study of extended-release injectable naltrexone (XR-NTX) administered to pre-release prisoners having a history of pre-incarceration opioid disorder. We evaluated the relationship between XR-NTX adherence and criminal recidivism (re-arrest and re-incarceration) and opioid and cocaine use. Twenty-seven pre-release male and female prisoners who had opioid disorders during the year prior to index incarceration were recruited and received one XR-NTX injection once each month for 7 months (1 injection pre-release from prison and 6 injections in the community) and of those 27, 10 (37%) were retained in treatment at 7-months post release. Results indicate those completing 6 compared to those completing <6 injections were less likely to test positive for opioids in the community (0% vs. 62.5%, respectively; p=0.003). Although not statistically significant, individuals who did not complete all 6 injections were more likely to be re-arrested compared to those completing all 6 community injections (31.3% vs. 0%, respectively; p=0.123). Contingent upon further study of a randomized controlled trial, XR-NTX may be a feasible option in the prison setting in view of the lack of potential for diversion. Furthermore, these data suggest that completing the entire course of treatment (6 injections) may reduce opioid use and, to a lesser degree, re-arrest and re-incarceration., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In a previously reported randomized controlled trial, formerly opioid-dependent prisoners were more likely to enter community drug abuse treatment when they were inducted in prison onto buprenorphine/naloxone (hereafter called buprenorphine) than when they received counseling without buprenorphine in prison (47.5% vs. 33.7%, p=0.012) (Gordon et al., 2014). In this communication we report on the results of the induction schedule and the adverse event profile seen in pre-release prisoners inducted onto buprenorphine., Method: This paper examines the dose induction procedure, a comparison of the proposed versus actual doses given per week, and side effects reported for 104 adult participants who were randomized to buprenorphine treatment in prison. Self-reported side effects were analyzed using generalized estimated equations to determine changes over time in side effects., Results: Study participants were inducted onto buprenorphine at a rate faster than the induction schedule. Of the 104 (72 males, 32 females) buprenorphine recipients, 64 (37 males, 27 females) remained on medication at release from prison. Nine participants (8.6%) discontinued buprenorphine because of unpleasant opioid side effects. There were no serious adverse events reported during the in-prison phase of the study. Constipation was the most frequent symptom reported (69 percent)., Conclusion: Our findings suggest that buprenorphine administered to non-opioid-tolerant adults should be started at a lower, individualized dose than customarily used for adults actively using opioids, and that non-opioid-tolerant pre-release prisoners can be successfully inducted onto therapeutic doses prior to release., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Objectives: Most studies on e-cigarettes have come from population-based surveys. The current research aimed to provide initial data on e-cigarette awareness, perceptions, use, and reasons for use among adults seeking substance use treatment., Methods: A survey was conducted among 198 participants ≥18 years old in a community-based outpatient substance use treatment program., Results: Of the 198 participants, 69% currently smoked cigarettes, 92% were aware of e-cigarettes, and 58% had ever used e-cigarettes. The proportion of the number of participants who had ever used e-cigarettes to the number who currently smoked (89.7%) appeared higher than the corresponding proportion in the 2012-13 National Adult Tobacco Survey (78.3%). Almost half of the sample who reported ever using e-cigarettes endorsed quitting or reducing smoking as a reason for use, and 32% endorsed reasons for use relating to curiosity/experimentation. A greater likelihood of e-cigarette ever-use was significantly associated with younger age (adjusted odds ratio [AOR] = 0.94, 95%confidence interval [CI] = 0.90, 0.98) and perceptions related to using e-cigarettes in public places where smoking cigarettes is not allowed (AOR = 2.96, 95%CI = 1.18, 7.42) but was not associated with primary drug of choice., Discussion and Conclusions: E-cigarette use in adults seeking substance use treatment appears higher than it is in the US general population of smokers. The high frequency of use may be due to curiosity/experimentation or attempts to quit or reduce smoking., Scientific Significance: Future research may consider how e-cigarettes interact with other substance use and affect high rates of nicotine and tobacco use in this population., (© American Academy of Addiction Psychiatry.)

Introduction: Medication-assisted treatment (MAT) is effective for alcohol and opioid use disorders but it is stigmatized and underutilized in criminal justice settings., Methods: This study cluster-randomized 20 community corrections sites to determine whether an experimental implementation strategy of training and an organizational linkage intervention improved staff perceptions of MAT and referral intentions more than training alone. The 3-hour training was designed to address deficits in knowledge, perceptions and referral information, and the organizational linkage intervention brought together community corrections and addiction treatment agencies in an interagency strategic planning and implementation process over 12 months., Results: Although training alone was associated with increases in familiarity with pharmacotherapy and knowledge of where to refer clients, the experimental intervention produced significantly greater improvements in functional attitudes (e.g. that MAT is helpful to clients) and referral intentions. Corrections staff demonstrated greater improvements in functional perceptions and intent to refer opioid dependent clients for MAT than did treatment staff., Conclusion: Knowledge, perceptions and information training plus interorganizational strategic planning intervention is an effective means to change attitudes and intent to refer clients for medication assisted treatment in community corrections settings, especially among corrections staff., (Published by Elsevier Inc.)

Background: Pharmacotherapy studies involving buprenorphine have rarely been conducted with U.S. community corrections populations. This is one of the first reports of buprenorphine treatment outcomes of adult opioid-dependent probationers and parolees., Methods: This longitudinal study examined the 3-month treatment outcomes for a sample of probation and parole clients (N = 64) who received community-based buprenorphine treatment., Results: Approximately two thirds of the sample (67%) were still in treatment at 3 months post baseline. Furthermore, there was a significant decline in the number of self-reported heroin use days and crime days from baseline to 3 months post baseline. Although there was not a significant reduction in reincarcerations, there was no evidence that they had increased., Conclusions: Given that buprenorphine is approved by the Food and Drug Administration (FDA) as a safe, effective treatment for opioid use disorders, individuals on parole or probation should have the opportunity to benefit from it through community-based programs.

Background: Buprenorphine is a promising treatment for heroin addiction. However, little is known regarding its provision to pre-release prisoners with heroin dependence histories who were not opioid-tolerant, the relative effectiveness of the post-release setting in which it is provided, and gender differences in treatment outcome in this population., Methods: This is the first randomized clinical trial of prison-initiated buprenorphine provided to male and female inmates in the US who were previously heroin-dependent prior to incarceration. A total of 211 participants with 3-9 months remaining in prison were randomized to one of four conditions formed by crossing In-Prison Treatment Condition (received buprenorphine vs. counseling only) and Post-release Service Setting (at an opioid treatment center vs. a community health center). Outcome measures were: entered prison treatment; completed prison treatment; and entered community treatment 10 days post-release., Results: There was a significant main effect (p=.006) for entering prison treatment favoring the In-Prison buprenorphine Treatment Condition (99.0% vs. 80.4%). Regarding completing prison treatment, the only significant effect was Gender, with women significantly (p<.001) more likely to complete than men (85.7% vs. 52.7%). There was a significant main effect (p=.012) for community treatment entry, favoring the In-Prison buprenorphine Treatment Condition (47.5% vs. 33.7%)., Conclusions: Buprenorphine appears feasible and acceptable to prisoners who were not opioid-tolerant and can facilitate community treatment entry. However, concerns remain with in-prison treatment termination due to attempted diversion of medication., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: African American youth who use marijuana are less likely to attend and complete treatment than white youth. Limited information is available on racial and age variation in treatment attendance and completion among adults who use marijuana., Methods: The current research examined differences in community-based substance abuse treatment attendance and completion between adult African American and white marijuana users in 2 independent samples from the US southeastern (N = 160; 70.6% African American) and mid-Atlantic (N = 450; 34.7% African American) regions., Outcomes: Attended at least 3 treatment sessions, successful treatment completion, number of days in treatment, and percentage of positive urine drug screens. Adjusted regression models examined the association of race, age, and the interaction of race and age with treatment attendance and completion., Results: In the southeastern sample, successful treatment completion was significantly associated with the interaction of race and age (adjusted odds ratio = 1.35, 95% confidence interval = 1.08-1.69); whereas younger African Americans were less likely to complete treatment than older African Americans, age was unrelated to treatment completion among whites. In the mid-Atlantic sample, African Americans were significantly less likely to attend at least 3 treatment sessions (adjusted odds ratio = 0.37, 95% confidence interval = 0.23-0.58), and younger adult marijuana users were retained for fewer days in treatment (adjusted β = 0.13, 95% confidence interval = 0.27-2.48). Among African Americans, 37.9% (SD = 38.0) of urine drug screens tested positive for at least 1 illicit drug, and among whites, 34.2% (SD = 37.8%) tested positive; the percentage of positive urine drug screens was not associated with race or age., Conclusions: Among marijuana-using adults, treatment attendance and completion differ by race and age, and improvements in treatment completion may occur as some African Americans mature out of young adulthood.

Early-onset methamphetamine use increases the lifetime prevalence of methamphetamine dependence. An earlier onset of methamphetamine use leads to greater damage to the terminal ends of serotonin neurons, more reduction in serotonin transporter (5-HTT) density, and an increased propensity toward further methamphetamine use. Because the 5-HTT-linked polymorphic region (5'-HTTLPR) within the promoter region of the 5-HTT gene leads to differential expression of the 5-HTT, we examined, for the first time, whether there is a differential association between the long (L) and short (S) alleles of the 5'-HTTLPR and the age of first methamphetamine use (AMU). The study included 120 methamphetamine-dependent adults of European descent. Diagnosis of methamphetamine dependence and AMU were collected using structured questionnaires, and the 5'-HTTLPR genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism method. Statistical analysis with the general linear model detected a significant interactive effect of 5'-HTTLPR genotypes (SS vs. L-carriers) and gender, associated with AMU (F = 3.99; p = 0.048). Further analysis of 5'-HTTLPR effects on AMU in males and females separately showed that the SS genotype compared with L-carriers had about two times greater risk of an earlier onset of methamphetamine use in men (hazard ratio = 1.839; 95% confidence interval = 1.042-3.246; p = 0.036) but not in women. Together, our findings in this preliminary study suggest a greater risk for earlier onset methamphetamine use associated with the SS genotype of the 5'-HTTLPR among methamphetamine-dependent Caucasian males.

Treatment of substance abuse disorders is often characterized by high dropout rates. Patients who fail to complete a treatment course often are worse at follow-up than those patients who received the full treatment course. Cognitive deficits, including impulsivity, have been noted as a major determinant of treatment retention and successful outcomes. This review summarizes the recent literature on cognitive deficits in stimulant users and their remediation. Cognitive deficits can be remediated through computer-assisted cognitive rehabilitation in residential settings. A few studies have shown this can be transferred to the outpatient setting although much research remains to be done in this setting. Pharmacological remediation of cognitive deficits is a new target for medications development in the treatment of substance abuse disorders. Psychiatric disorders; for example, attention deficit hyperactivity disorder, are amenable to pharmacological remediation of cognitive deficits. Several cognitive deficits (set-shifting, attentional bias, reversal learning, impulsivity, and risky decision making) and their possible remediation with pharmacological agents are presented in the review. Recommendations for the research agenda include comments on testing hierarchies, clinical trial design issues, and types of pharmacological agents., ((c) 2008 APA, all rights reserved.)

Background: Methamphetamine abuse has become an increasing problem in both the United States and globally with concomitant increases in adverse medical, social and environmental sequelae. Behavioral therapies have been used with some success to treat methamphetamine abusers and dependent individuals, but are not universally efficacious. Methamphetamine has a rich pharmacology that theoretically provides many opportunities for potential pharmacotherapeutic intervention. Nevertheless, there are no approved medications with an indication for treating methamphetamine abusers or addicts at this time., Aim: To describe briefly how methamphetamine functions and affects function in brain and report how basic researchers and clinicians are attempting to exploit and exploiting this knowledge to discover and develop effective pharmacotherapies., Results: Scientifically based approaches to medications development by evaluating medications that limit brain exposure to methamphetamine; modulate methamphetamine effects at vesicular monoamine transporter-2 (VMAT-2); or affect dopaminergic, serotonergic, GABAergic, and/or glutamatergic brain pathways that participate in methamphetamine's reinforcing effects are presented., Conclusion: The evidence supports the rationale that pharmacotherapies to decrease methamphetamine use, or reduce craving during abstinence may be developed from altering the pharmacokinetics and pharmacodynamics of methamphetamine or its effects on appetitive systems in the brain.

In 1989, the National Institute on Drug Abuse (NIDA) established its Medications Development Program. This program has concentrated on developing pharmacotherapies for opiate and cocaine dependence and, more recently, for methamphetamine and cannabis dependence. The major goals of this program are to optimize existing treatments and to expand treatment options for physicians and patients. This review will concentrate on the development of pharmacotherapies for the following substance abuse disorders: opiate, cocaine, methamphetamine, and cannabis dependence. Left untreated, opiate and stimulant dependence are responsible for significant morbidity and mortality. For example, use of illicit opiates is associated with an increased risk of hepatitis C infection, HIV infection, and other medical consequences, e.g., an overdose. The NIDA Medications Development Program has had success in developing, with pharmaceutical partners, levomethadyl acetate, buprenorphine, and buprenorphine/naloxone for opiate dependence. Moreover, several marketed medications have shown promise in reducing cocaine use. Of interest, these medications likely operate through diverse neurochemical mechanisms, suggesting that combination therapy may be a rational next step that could increase treatment gains further in cocaine-dependent patients. The Medications Development Program has also identified multiple neuronal mechanisms that are altered by chronic administration of drugs of abuse. Advances in neuroscience have identified changes in conditioned cueing, drug priming, stress-induced increases in drug intake, and reduced frontal inhibitory mechanisms as all being possible for the development of, maintenance of, and possible relapse to, addiction. Potential medications that modulate these mechanisms are highlighted.

Purpose of Review: This review examines progress being made in the treatment of cocaine abuse and dependence, with a particular focus on pharmacotherapies. Medications with apparently very different mechanisms of action have been reported to reduce cocaine use in controlled clinical trials in outpatient settings. This review will summarize the latest findings in this area., Recent Findings: Of all the medications tested to date, disulfiram has demonstrated the most consistent effect to reduce cocaine use. Several medications have been reported to reduce cocaine use in double-blind, placebo-controlled clinical trials, namely baclofen, modafinil, tiagabine, and topiramate. All pharmacotherapy trials in cocaine-dependent patients include a behavioral therapy that is common to all participants. Consequently, these pharmacotherapy trials can be considered to evaluate whether the medication is adding to the effect of the behavioral therapy., Summary: Confirmatory clinical studies are necessary to replicate the initial efficacy findings for baclofen, modafinil, tiagabine, and topiramate. More research is needed in both cocaine and cocaine-alcohol dependent populations. Once confirmatory studies have been carried out, testing of rational medication combinations with different behavioral therapies is an obvious next step to increase the ability to manage cocaine dependence.

Opiate addiction is a chronic, relapsing disorder. Left untreated, high morbidity and mortality rates are seen. Pharmacotherapies for this disorder using mu opiate agonists (methadone and levomethadyl acetate) and partial agonists have been developed in the last 40 years. Agonist pharmacotherapy with oral methadone for the treatment of opiate dependence was developed in clinical pharmacology studies at Rockefeller University by Dole, Nyswander, and Kreek. Further studies by this laboratory and others established that moderate to high dose treatment with methadone (80-120 mg) reduced or eliminated opiate use in outpatient settings with consequent reductions in morbidity and up to 4-fold reductions in mortality. Levomethadyl acetate (LAAM), a congener of methadone, is biotransformed to active metabolites responsible for its longer duration of action. The Federal Regulations regarding the dispensation of methadone and LAAM have recently been revised to facilitate the treatment of patients under a "medical maintenance" model. Future regulatory reform will likely involve the establishment of rules for "office based opioid treatment.", (Copyright 2002 Elsevier Science Inc.)

Cigarette smoking is the most preventable cause of death in industrialised countries. 30% of all deaths in smokers in the 35 to 69 years age range are attributed to chronic cigarette smoking; smokers dying in this age cohort lose an average of 23 years of life. Public health campaigns have attempted to reduce initiation of smoking in adolescents and to foster quitting in dependent smokers. The prevalence of smoking has declined in the US to 25% of the population, but this figure has held constant for the last decade. Vaccines against nicotine are a novel concept in the field of smoking cessation research and have not yet reached the stage of clinical testing. Vaccines could reduce smoking behaviour in 3 groups of smokers: (i) current smokers attempting to quit; (ii) former smokers wanting to avoid the possibility of relapse; and (iii) adolescent smokers before they become confirmed smokers. The rationale behind the approach is that nicotine is the pharmacological agent controlling the rate of cigarette smoking, and reducing its rate and extent of uptake into the brain may have therapeutic benefits.

New technologies utilized for monitoring brain function can be more sensitive in the assessment of desired or undesired pharmacological effects than can clinical examination. Nonetheless, careful case-by-case analysis is required to determine to what extent a change detected with a sensitive imaging modality will have clinical significance. Whereas in some instances the technology may suggest a subclinical condition years before clinical signs develop, in other instances changes seen may be compensated for through system reserves, redundancy, or plasticity. Furthermore, simultaneous application of several assay instruments, including behavioral, electrophysiological, and nuclear medicine approaches, may be appropriate and useful for establishing correlations between changes in specific aspects of brain function and amelioration of a disease (drug abuse disorder) or its sequelae. In the example of ibogaine, a testing strategy was developed to assess human subjects for possible changes in cerebellar function (that were suggested by preclinical findings indicating subtle damage). Thus, subjects may be tested for subclinical alterations during and immediately following a clinical trial. This "harbinger of toxicity" approach would provide clinicians the critical data necessary for appropriate follow-up of subjects as well as the propriety of continuance of the clinical trials within the ibogaine project.

Fifty cocaine-dependent patients completed a 2-week double-blind, double-dummy, parallel-group comparison of four dosage levels of diethylpropion and placebo. This clinical trial was designed to evaluate both diethylpropion's ability to attenuate cocaine cue-induced craving and its potential for development as a medication with cocaine-agonist properties. The results indicated that diethylpropion was not superior to placebo and confirmed earlier reports that craving for cocaine diminishes over the course of an inpatient hospitalization. Moreover, the results showed that the cocaine cue-induced craving paradigm employed is effective in stimulating craving for cocaine. Medications that are effective in attenuating this type of "conditioned" craving may have relevance to the breaking of the cycle of relapse and long-term treatment of cocaine dependence. Diethylpropion may not be an appropriate candidate for future medication development because of its lack of obvious therapeutic efficacy and the emergence of a significant number of side effects. However, a cocaine-agonist medication strategy may be appropriate for a subgroup of cocaine-dependent patients with coexisting attention deficit-hyperactivity disorder.

Recent preclinical studies suggest utility for voltage-sensitive calcium channel blockers (VSCCBs) in the treatment of cocaine addiction. The following double-blind placebo-controlled study examined the role of the VSCCB nimodipine in attenuating cocaine craving in 66 recently abstinent cocaine-dependent patients on an inpatient substance abuse treatment unit utilizing an intensive 12-step milieu-oriented psychosocial therapy. While the medication was well tolerated, the dose of nimodipine used in this study (90 mg q.d.) was not superior to placebo in reducing background or cue-induced cocaine craving over the 3 weeks of the study. There was the suggestion that nimodipine might attenuate the severity of some cocaine-induced brain deficits, as detected by evaluation of smooth pursuit eye movement function. A rationale for evaluating higher doses of nimodipine for the treatment of cocaine addiction is presented. As nimodipine might have anticraving and mood-stabilizing properties and cardio- and neuroprotective properties in the face of cocaine intoxication and might possibly even reverse some cocaine-induced brain deficits, further investigation of the role of nimodipine (and other VSCCBs) in cocaine addiction appears an attractive avenue of future medication development.

NIDA's MDD is faced with the formidable task of identifying, characterizing, and developing new chemical entities to combat substance abuse. The primary challenge is to find one or more medications that will be useful in treating cocaine addiction, withdrawal, and abstinence. In addition, a treatment for cocaine overdose is in progress. Methodological approaches include testing compounds that alter endogenous neurotransmitters and compounds that suppress conditioned cues and stimuli. Compounds that appear efficacious in these tasks and that have a satisfactory safety profile will be studied in humans.

Assessments of the abuse potential of psychoactive drugs in preclinical and clinical studies are used in regulatory decision making process in the United States under the Controlled Substance Act (CSA) and the Federal Food, Drug, and Cosmetic Act (FD & C Act). Two types of drugs are evaluated in abuse potential studies, those being developed for a therapeutic indication by the pharmaceutical industry and illicitly manufactured 'street drugs' of abuse. Only the former will be considered here. In the case of drugs being pursued for marketing or are amendable to study in human subjects and are of scientific, medical, or regulatory interest, preclinical data may be inadequate for drug scheduling and marketing decisions. Preclinical data assessment can suggest hypotheses which must be validated in clinical studies. Moreover, there are limitations to the feasibility of evaluating certain drugs/dosage forms in preclinical studies. Thus, clinical studies are needed for the following scientific reasons: to validate preclinical hypotheses; to assess the time-course of subjective effects as a function of dose and route of administration; to evaluate the generalizability of drug liking in different human subject populations; and to evaluate the effects of drugs on cognitive and affective processes. Clinical studies are also needed if a claim is made regarding reduced or no abuse potential; and lack of additive or potentiative effects with alcohol.

The uptake of 3H-digitoxigenin (3H-DIGT), administered by intravenous infusion to conscious, unrestrained rats, increased with time in the medulla-pons, cerebellum, cerebral cortex, corpus striatum, hippocampus, hypothalamus, and midbrain coincident with the development of behavioral and motor disruption. At four minutes of infusion, during clonic convulsions, uptake appeared to follow reported differences in regional blood flow, ranging from 0.48 microgram/gm (hypothalamus) to 0.67 microgram/gm (cerebellum). After 5 1/2 minutes of infusion, rats still in clonic convulsions had no further increase in uptake; rats entering tonic convulsions had two- to three-fold increases in 3H-DIGT uptake, ranging from 1.00 microgram/gm (hypothalamus) to 1.65 microgram/gm (cerebellum). Electroshock-induced tonic convusions at 2 minutes of infusion increased 3H-DIGT uptake two- to three-fold in all regions, suggesting that the increased neuronal activity associated with the tonic convulsion enhanced the uptake of 3H-DIGT into all regions. The only significant monamine alteration was a slightly decreased medulla-pons serotonin level after 5 1/2 minutes of infusion.

EEG was recorded from several brain regions during the i.v. infusion of digitoxigenin to conscious, freely-moving rats. Two seizure episodes were recorded from the ventral hippocampus with the second, more severe seizure characterized by low-frequency (3-6/sec), high-amplitude (0.9-1.5 mV) discharges. Secondary activity was recorded from the mesencephalic and reticular formations. Pretreatment of rats with p-chlorophenylalanine or reserpine prevented the first seizure and markedly delayed the second seizure to appear after 1.85 mg or 4.66 mg digitoxigenin/kg, respectively, compared to 0.79 mg/kg in untreated rats. The pretreatments did not alter the frequency of the discharges but reduced their amplitude to 0.4 -0.75 mV. The results suggest a role for monoamines, and in particular serotonin, in the effect of digitoxigenin to cause hippocampal seizure discharge.

This study investigated modification of the tonic convulsive threshold to maximum electroshock in 15- and 30 day old rats treated with drugs which reduce steady-state concentrations of monoamines. On postnatal day 15, reduction of central catecholamine concentrations by 6-hydroxydopamine or of central serotonin concentrations by 5,7-dihydroxytryptamine or p-chloroamphetamine did not alter the tonic convulsive threshold. However, simultaneous depletion of catecholamines and serotonin by tetrabenazine was associated with a significant decrease in the tonic threshold. This effect could be reversed partially by simultaneous administration of the catecholamine and serotonin precursors, L-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively. On postnatal day 30, reduction of brain serotonin concentration, but not catecholamine concentrations, was associated with a significant decrease of the tonic convulsive threshold. In a previous study, in which 7-8 day old rats were used, a tetrabenazine-induced decrease in the tonic convulsive threshold prevented by L-dihydroxyphenylalanine but not 5-hydroxytryptophan. Furthermore, intracisternal 6-hydroxydopamine, but not 5,7-dihydroxyhyptamine, decreased the threshold on postnatal day 8. Therefore, the results of the present day study involving 15- and 30 day old rats, together with the earlier findings in 7-8 day old rats, [28] suggest an apparent developmental transition from catecholaminergic to serotonergic dominance in regulation of the tonic convulsive threshold during the first postnatal month.