All these effects are prevented by CB1 receptor blockade. The present results expand the pharmacological profile of URB597 to include the potentiation of stress-coping behaviors in the TST and FST, two widely used screens for antidepressant drugs, and point to the dual regulation of 5-HT and NE neurotransmission as a possible neural substrate for these actions. The 5-HT and NE systems of the midbrain serve important adaptive functions in the response to acute stress, and long-term alterations in their activity may contribute to the development of depression . Indeed, the ability to enhance monoaminergic transmission is a distinguishing feature shared by all antidepressant drugs, irrespective of their specific mechanism of action . Importantly, however, a dual 5-HT and NE activation reminiscent of that produced by URB597 is seen only with a restricted group of antidepressants, which include venlafaxine , nefazodone , and mirtazapine . Clinical evidence suggests that these ‘‘atypical’’ antidepressants display greater efficacy and faster onset of action compared with 5-HT reuptake inhibitors and improved side-effect profile compared with tricyclics and monoaminoxidase inhibitors . Our results indicate that URB597 may offer similar advantages, trim tray which might be further enhanced by the acute anxiolytic-like properties of this drug . The addictive properties of 9-THC are a major obstacle to the development of cannabinoid-based therapeutics. Thus, it is particularly important that URB597 does not mimic the hedonic and interoceptives states evoked by direct-acting cannabinoidagonists. This lack of cannabimimetic activity is consistent with the fact that URB597 does not elicit catalepsy, hypothermia, or other classical signs of CB1 activation .
Our experiments do not elucidate the neural substrates underlying the antidepressant-like properties of URB597. Indeed, although the results highlight a possible role of midbrain monoaminergic nuclei, the contribution of such nuclei and the sequence of events leading to their activation remain unknown. Despite these open questions, our findings provide a preclinical validation for URB597 as an antidepressant agent with dual 5-HT- and NE-enhancing activity.In the United States, over one million people are currently living with HIV. Substance use, including both alcohol and drug use, is a significant health challenge for people living with HIV as well as for those most at risk for acquiring HIV. Unhealthy alcohol and drug use is one of the major drivers of HIV acquisition and, among people already living with HIV, it contributes to low levels of engagement in HIV care, and is linked to poor medication adherence. A recent review found that only 60–79% of newly diagnosed people who inject drugs in the U.S. are linked to HIV care, with 24–59% retained in care, 20–49% on treatment, and 16–42% virally suppressed, rates that are well below the UNAIDS 90-90-90 goal. Other studies have found that substance-using PLHIV presented later for HIV testing and care; delayed linkage to HIV care and had poorer continuous engagement in HIV care; and reported lower levels of being prescribed with anti-retroviral therapy. Additional research has shown that PLHIV who use substances have lower rates of viral suppression than those who do not use substances, and PLHIV who inject drugs are more than twice as likely to discontinue antiretroviral therapy compared to those who do not. Despite this, many PLHIV continue to use alcohol and drugs. In a national survey of adult PLHIV, 27.9% reported binge drinking and 32.5% reported illicit substance use in the prior 30 days. Te relationship between unhealthy substance use and poor health outcomes along the HIV care continuum underscores the critical importance of identifying PLHIV engaged in harmful use and providing evidence-based addiction treatment. Te recent U.S. Surgeon General’s report on addiction calls for “integration across health care settings including primary care”.
A recent study showed, however, that among VA patients with alcohol use disorders, significantly fewer PLHIV received follow-up alcohol-related care compared to HIV-negative patients. HIV primary care clinics may be more effective sites for screening, assessment, and intervention among those who are engaged in care. In primary care, patients may present anywhere along the spectrum of substance involvement, from low risk behavior to an alcohol or substance use disorder, in recovery or during a relapse. As with other chronic illnesses, detection is an important first step, and screening can serve a dual purpose: as preventative care for those who may be at risk for problems associated with substance use, and as an opportunity for intervention for those already experiencing problems related to their substance use. Interventions may be brief counseling for those at low risk or, for those diagnosed with a substance use disorder, office-based medication-assisted treatment in the primary care setting or referral to specialty treatment by an addiction specialist. Prior studies also suggest that information technologies may be useful for improving access to behavioral interventions for substance use. One strategy that has been used in various health care settings to identify harmful substance use is screening, brief intervention, and referral to treatment. While SBIRT has been tested in a variety of settings and populations, evidence of its efficacy as a treatment methodology for alcohol and other substance use disorders is mixed. In one study conducted in four countries, SBIRT participants had lower levels of illicit substance use compared to non-SBIRT participants at follow-up, except in the United States. Another meta-analysis found little evidence that SBIRT increased patients’ receipt of care to reduce alcohol consumption. A more recent study found no association between a brief intervention and resolution of alcohol use disorder at follow-up in PLHIV patients of the VA. A qualitative study sought to identify facilitators and barriers to implementing SBIRT in primary care, and found general patient support for SBIRT, but also identified inconsistent implementation and provider lack of time as barriers. SBIRT is a potentially promising method for addressing substance use in primary care settings, and could be particularly effective in HIV primary care settings where rates of substance use are high.
Therefore, in an effort to examine SBIRT specifically in an HIV primary care setting, we developed and tested a two-arm approach to delivering SBIRT . We then measured changes in self-reported substance use over 6 months, using the Alcohol, Smoking and Substance Involvement Screening Test.We conducted a two-arm randomized trial to examine the effects of a self-administered, computerized SBIRT intervention compared to a clinician-administered SBIRT intervention in an HIV clinic. Te research protocol was approved by the Institutional Review Board of the University of California, San Francisco. Te study methods and rationale have been described in detail elsewhere. Based on low rates of participation in the computer-administered arm, we conducted an “as-treated” analysis to examine the observed changes in self-reported substance use over time in participants who received either SBIRT intervention .All participants underwent screening and assessment for tobacco, alcohol and other drug use with the Alcohol, Smoking and Substance Involvement Screening Test , which was developed by the WHO for use in primary care settings. Based on a participant’s ASSIST responses, Specific Substance Involvement Scores were generated for each of the drug classes assessed; tobacco, alcohol, cannabis, cocaine, amphetamines, inhalants, sedatives, hallucinogens, opioids and other substances. These scores were used as the basis for the Brief Intervention portion of the SBIRT. Whether self-administered on a computer or administered by a clinician, the ASSIST could be completed in about 10 min.After screening and assessment, participants received same-day feedback in the form of a WHO ASSIST guided feedback card that detailed their substance use risk severity and received a Brief Intervention tailored to the severity of their SSIS scores and based on the principles of motivational interviewing . Participants scoring at lower risk for health or other problems from their substance use received a firming, positive feedback, and safe behavior maintenance support. Participants with moderate- or high-risk SSIS scores engaged in a patient centered conversation that explored the pros and cons of continued drug use and readiness for change, and they reviewed information about specific substance use and its health complications. Action planning was offered to those participants, ebb and flow who were ready to make a change.Participants with high-risk SSIS scores also were offered appointments to meet with the clinic social worker, who had 4 h of protected time per week to meet with participants enrolled in the study. This social worker was a skilled behaviorist with expertise as a motivational interviewing trainer and extensive knowledge and experience providing referrals for different levels of substance use treatment. Treatment options ranged from office-based addiction pharmacotherapy and counseling at the HIV clinic to medically supervised withdrawal programs, intensive outpatient treatment, and inpatient residential treatment programs in the community. Participants randomized to the Clinician Group were to receive the screening and brief intervention procedures by a trained clinic staff member either the same day or within 1 week of study enrollment. These SBI clinicians included one Nurse and one Medical Assistant, who had more than 10 years combined experience in the HIV clinic, and who participated in two 4-h SBIRT training sessions that included how to administer and score the ASSIST, delivery of the Brief Intervention utilizing WHO ASSIST materials, and motivational interviewing principles and practice. Fidelity of the Clinician-administered intervention was monitored through documentation of each step in SBIRT delivery and through bi-weekly supervision meetings with senior study personnel.
Participants randomized to the Computer Group were to receive a self-administered SBIRT procedure embedded in the HIV clinic’s web-based personal health record. Study staff assisted participants in setting up their electronic patient portal accounts, if they had not done so already. Participants were instructed to complete the self-administered SBIRT from a computer in the clinic or from a remote computer either the same day or within one week of study enrollment. Developed by the HIV clinic’s lead social worker and senior study staff with SBIRT and motivational interviewing expertise, the web based SBIRT experience was designed to replicate the flow and components of SBIRT conducted by HIV clinic staff. This included interactive web-based screening and assessment using the ASSIST, motivational phrasing for delivery of the Brief Intervention , and links to substance use websites and patient resources, including referrals to in person appointments with the HIV clinic social worker— all preprogrammed into the electronic patient portal. We did not track visits to electronic resources.Study assessments were conducted by trained research assistants. Te baseline interview assessed patient demographics, including gender, sex, race/ethnicity, socioeconomic status, education, and year of HIV diagnosis, as well as frequency and severity of substance use . A urine specimen was collected for a urine drug screen, the results of which were not recorded in the patient’s medical record nor shared with clinic staff or providers. All measures except patient demographics were repeated at 1, 3 and 6 months. The WHO Alcohol, Smoking and Substance Involvement Screening Test is a self-report measure that consists of eight items to assess lifetime and recent non-medical substance use, including injection drug use, substance use related problems, dependency levels, and risk of current or future harm. From the ASSIST, Specific Substance Involvement Scores were calculated for each of the drug classes assessed; tobacco, alcohol, cannabis, cocaine, amphetamines, inhalants, sedatives, hallucinogens, opioids and other substances.It is the sum of responses to items 2–7: frequency of use in the past 3 months, strong desire or urge to use in the past 3 months, health, social, legal or financial problems due to use of a substance in the past 3 months, failing to do what was normally expected of you due to use of a substance in the past 3 months, anyone ever expressing concern over substance use, and ever trying and failing to control, cut down or stop using. Validated cut-off points stratify scores into lower risk to health and other problems , moderate risk to health and other problems , or high risk consistent with a diagnosis of substance dependence .Our primary outcome was change in mean SSIS between baseline and 6-month follow up. Substance use risk level was defined by the mean Specific Substance Involvement Scores assessed at baseline, 1-, 3-, and 6-month study assessments. We dichotomized risk level by previously validated cut-of points: lower risk , and collapsed moderate and high risk into a moderate– high risk category .