Dexmedetomidine HCL (BXCL501) as a potential treatment for alcohol use disorder and comorbid PTSD: A phase 1b, placebo-controlled crossover laboratory study.

BACKGROUND AND OBJECTIVES: Noradrenergic dysregulation is important in the pathophysiology of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD); pharmacotherapies targeting adrenergic function have potential as treatment for comorbidity. Dexmedetomidine (sublingual film formulation-BXCL501; IGALMI) is a highly potent, selective ⍺2-adrenergic receptor agonist and may be superior to other pharmacotherapeutic approaches. A within subjects, phase 1b safety laboratory study was conducted to evaluate adverse effects of BXCL501 when combined with alcohol; BXCL501's potential efficacy was also explored. METHODS: Heavy drinker participants with a diagnosis of or who were at risk for PTSD participated in three separate test days which included pretreatment with BXCL501 (40 µg, 80 µg or placebo) administered in a randomized, double-blind fashion, followed by three testing conditions: alcohol cue reactivity, trauma-induced reactivity, and IV ethanol administration. Safety outcomes included blood pressure (BP) and sedation. Exploratory outcomes included alcohol craving, trauma-induced anxiety and craving and subjective effects of alcohol. RESULTS: Ten of twelve randomized participants competed the entire study. BXCL501 (80 µg) was associated with expected mild changes in BP and sedation; administration with alcohol did not affect those parameters. There were no clinically significant adverse effects. BXCL501 attenuated trauma-induced anxiety and attenuated subjective effects of alcohol. DISCUSSIONS AND CONCLUSIONS: BXCL501 is safe for use in humans who may drink alcohol while undergoing treatment. BXCL501 may be explored as a potential treatment for PTSD and AUD. SCIENTIFIC SIGNIFICANCE: This is the first study to provide scientific support for BXCL501's potential to treat PTSD and comorbid AUD.

Progesterone Attenuates the Stress Response in Individuals with Alcohol Dependence and Post-Traumatic Stress Disorder - A Pilot Study.

OBJECTIVE: Evidence from laboratory studies suggests that progesterone may be effective in reducing stress and craving, and may improve cognitive performance in smokers and individuals with cocaine dependence. The objective of this study was to examine if progesterone would attenuate stress-induced craving, anxiety, affect and physiological measures, as well as improve stress-induced cognitive performance (processing speed and selective attention) in individuals diagnosed with alcohol use disorder (AUD) and post traumatic stress disorder (PTSD). METHODS: This laboratory study included (n = 13) participants who were diagnosed with current AUD and PTSD who were randomly assigned to recive either progesterone (200mg bid) or placebo in identical looking capsules for 3 days. On the fourth day they completed a laboratory session. In the morning of the test session, they received the last dose of medication and completed the rest of the laboratory procedures. The procedures included presentation in random order of personalized trauma and neutral scripts with relaxation in between. Main outcomes included measure of craving, anxiety, affect and cognitive performance. RESULTS: Consistent with other research, trauma scripts produced significantly greater increases in craving, anxiety and negative affect when compared with neutral scripts. Progesterone significantly reduced stress-induced symptoms of craving, anxiety, fear, anger and sadness but had no effect on positive emotions (joy, relaxation). Progesterone was effective in ameliorating stress-induced decreases in cognitive performance. CONCLUSIONS: The findings from this study demonstrate that progesterone can be effective in reducing stress-induced craving, anxiety and negative affect in a laboratory setting in individuals with comorbid AUD and PTSD. Interestingly, progesterone also improved cognitive performance. These findings require replication in a larger clinical trial and may have implications for treatment among individuals with AUD and PTSD.This study was registered as NCT02187224, at www.clinicaltrials.gov.

Analysis of Drugs in Saliva of US Military Veterans Treated for Substance Use Disorders Using Supported Liquid Extraction and Surface-Enhanced Raman Spectral Analysis.

According to the Center for Disease Control, there were more than 107,000 US drug overdose deaths in 2021, over 80,000 of which due to opioids. One of the more vulnerable populations is US military veterans. Nearly 250,000 military veterans suffer from substance-related disorders (SRD). For those seeking treatment, buprenorphine is prescribed to help treat opioid use disorder (OUD). Urinalysis is currently used to monitor buprenorphine adherence as well as to detect illicit drug use during treatment. Sometimes sample tampering occurs if patients seek to generate a false positive buprenorphine urine test or mask illicit drugs, both of which can compromise treatment. To address this problem, we have been developing a point-of-care (POC) analyzer that can rapidly measure both medications used for treatment and illicit drugs in patient saliva, ideally in the physi-cian's office. The two-step analyzer employs (1) supported liquid extraction (SLE) to isolate the drugs from the saliva and (2) surface-enhanced Raman spectroscopy (SERS) to detect the drugs. A prototype SLE-SERS-POC analyzer was used to quantify buprenorphine at ng/mL concentrations and identify illicit drugs in less than 1 mL of saliva collected from 20 SRD veterans in less than 20 min. It correctly detected buprenorphine in 19 of 20 samples (18 true positives, 1 true negative and 1 false negative). It also identified 10 other drugs in patient samples: acetaminophen, amphetamine, cannabidiol, cocaethylene, codeine, ibuprofen, methamphetamine, methadone, nicotine, and norbuprenorphine. The prototype analyzer shows evidence of accuracy in measuring treatment medications and relapse to drug use. Further study and development of the system is warranted.

Ghrelin Predicts Stimulant and Sedative Effects of Alcohol in Heavy Drinkers.

AIM: The aim of this study was to examine the relationship between ghrelin levels and the subjective effects of alcohol in heavy drinkers, and to compare them to healthy controls. METHODS: Ghrelin levels were collected as part of two laboratory studies. Both groups received either IV infusion of saline or high dose of alcohol (100 mg%). In the study of heavy drinkers, ghrelin was gathered on all subjects, but data was analyzed only for participants who received placebo (N=12). Healthy controls (N=20) came from another study that collected data on family history. Ghrelin levels and measures of alcohol effects (BAES, VAS, NDS, YCS [see manuscript for details]) were collected at 4 timepoints: baseline, before infusion, during infusion and after infusion. RESULTS: IV alcohol significantly reduced ghrelin levels and higher fasting ghrelin levels were associated with more intense subjective alcohol effects. There were no differences in fasting ghrelin levels or subjective effects between heavy drinkers and controls. However, while both groups showed similar decline in ghrelin levels following alcohol infusion, on the placebo day, ghrelin levels in the healthy subjects increased significantly and exponentially over time while for the heavy drinkers ghrelin levels remained flat. CONCLUSIONS: Our findings support the role of ghrelin in reward mechanisms for alcohol. Contrary to others, we found no differences in fasting ghrelin levels or subjective experiences of alcohol between heavy drinkers and healthy controls. However, the group differences on the IV placebo day may be a possible indication of ghrelin abnormalities in heavy drinkers.

Zonisamide as an Adjunctive Treatment to Cognitive Processing Therapy for Veterans With Posttraumatic Stress Disorder and Comorbid Alcohol Use Disorder: A Pilot Study.

BACKGROUND AND OBJECTIVES: There are high rates of comorbid alcohol use disorder (AUD) among those who have posttraumatic stress disorder (PTSD). Ideally, treatment for comorbidity should address both disorders simultaneously. Zonisamide, an anticonvulsant, may be effective in decreasing alcohol use and may attenuate symptoms of PTSD. Treatment strategies can include medication in combination with a proven evidence-based psychotherapy designed to treat PTSD, such as cognitive processing therapy (CPT). METHODS: This 12-week pilot study was designed to test feasibility, acceptability, and preliminary efficacy of zonisamide (400 mg) as an adjunct to CPT for veterans with PTSD and comorbid AUD. Veterans (n = 24) with PTSD and current alcohol dependence were randomized in a 3:1 ratio to receive zonisamide or placebo in a double-blind fashion. All subjects received CPT enhanced to include sessions addressing drinking behavior. RESULTS: Subjects overall reported a significant decrease in drinking outcomes, craving, and symptoms of PTSD. Zonisamide was well-tolerated and easily administered with CPT, which was also well-tolerated. Exploratory analysis of comparison of groups suggests there was no advantage of zonisamide vs placebo in drinking or PTSD outcomes. There was a numeric but nonsignificant higher rate of abstinence with zonisamide (50%) vs placebo (33%). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: The interpretation of the results is limited by the pilot nature of this study. The combination of psychosocial treatment with medication management mimics real-world treatment. In order to isolate the individual contributions of medication vs psychotherapy a much larger study would need to be conducted. (Am J Addict 2020;29:515-524).

Thiopental Does Not Produce Hyperalgesia: A Laboratory Study Using Two Human Experimental Pain Models.

OBJECTIVE: Past investigations assessing the effects of thiopental on pain are conflicting. Although several studies demonstrate hyperalgesia as a result of barbiturate administration, others show analgesia. Our objective was to assess the effects of an infusion of the GABAA agonist thiopental, compared with placebo, in healthy participants on two subjective experimental pain paradigms: noxious electrical stimulation and intradermal capsaicin. METHODS: For electrical stimulation, the milliamps required to achieve pain threshold and tolerance were recorded, and the percent change from baseline was determined for each infusion condition. In the intradermal capsaicin condition, the area of hyperalgesia was determined by von Frey technique pre- and postinfusion, and the percent change in the area of hyperalgesia was calculated. RESULTS: Though thiopental infusion resulted in an increase in the electrical stimulation current required to elicit pain threshold or reach pain tolerance when compared with baseline, this finding was not statistically significant. In the intradermal capsaicin condition, there was a statistically significant difference in overall pre- and postinfusion pain interpretation, as measured by the McGill Pain Questionnaire (P < 0.05), but there was no significant difference in area of hyperalgesia. CONCLUSIONS: In this human study of thiopental's effects on two experimental pain models, our results show that thiopental does not induce hyperalgesia.

Ghrelin is Related to Personality Differences in Reward Sensitivity and Impulsivity.

AIMS: Ghrelin, a feeding-related peptide mainly produced in the stomach, has been linked to reward mechanisms for food and drugs of abuse in addition to traits of impulsivity. This study is a secondary analysis of an existing data set designed to examine the direct relationships between fasting ghrelin levels and reward sensitivity/impulsivity in healthy social drinkers. METHODS: Participants (n = 20) were recruited from an original study examining the subjective effects of alcohol among social drinkers. Fasting ghrelin levels were collected at baseline. Personality measures (Behavioral Inhibition, Behavioral Activation, and Affective Response to Impending Reward and Punishment and Barratt Impulsiveness Scale) were administered at baseline to evaluate sensitivity to reward and punishment, and measure traits of impulsivity, respectively. RESULTS: Fasting ghrelin levels were significantly related to reward sensitivity and impulsivity traits. Specifically, those with higher ghrelin levels were more sensitive to reward and were more impulsive (have lower self-control). CONCLUSIONS: The results indicate that individuals with higher levels of ghrelin are more sensitive to reward. In addition, they are less able to exercise self-control and to an extent more likely to act without thinking. This is the first study to report on the direct relationship between fasting ghrelin levels and personality characteristics such as reward sensitivity and aspects of impulsivity among healthy social drinkers. SHORT SUMMARY: Individuals with higher levels of fasting ghrelin are more sensitive to reward, but less sensitive to punishment. Higher ghrelin levels are also related to some aspects of impulsivity such as decreased self-control and increased likelihood of acting without thinking.

Rapid Identification of Buprenorphine in Patient Saliva.

Buprenorphine is becoming the medication of choice to help patients withdraw from opioid addiction. However, treatment is compromised by the inability of physicians to assess patient usage during scheduled examinations. Here we describe the development of a point-of-care (POC) analyzer that can rapidly measure both illicit and treatment drugs in patient saliva, ideally in the physician's office, and with a degree of accuracy similar to chromatography. The analyzer employs a relatively simple supported liquid extraction to isolate the drugs from the saliva and surface-enhanced Raman spectroscopy (SERS) to detect the drugs. The SERS-based POC analyzer was used to identify buprenorphine and opioids in saliva samples by matching library spectra to samples collected from 7 veterans. The total analysis time, including sample preparation, was ~25 minutes. Buprenorphine concentration was estimated between 0 and 3 µg/mL. While no other prescription opioids were detected in any samples, heroin was identified in one sample; Δ-9 tetrahydrocannabinol (THC) was detected in 3 samples; and acetaminophen, caffeine, and nicotine were detected in several samples, none of which interfered with the measurements. The analysis was in very good agreement with urinalysis, correctly identifying the presence or absence of buprenorphine and THC in 13 of 14 measurements.

Ghrelin is Supressed by Intravenous Alcohol and is Related to Stimulant and Sedative Effects of Alcohol.

AIMS: Evidence indicates that feeding-related peptides, such as ghrelin, have a role in the rewarding properties of addictive substances like alcohol. Oral alcohol administration significantly suppresses ghrelin. This study was designed to evaluate the effects of two doses of alcohol on ghrelin and examine if ghrelin levels predict the subjective effects of alcohol. METHODS: Healthy social drinkers (N = 20) participated in three, randomly assigned, and counterbalanced laboratory sessions. During each session they received a continuous IV infusion of either placebo (saline), low dose (40 mg%) or high dose (100 mg%) of alcohol. Participants were given a standardized, light breakfast 90 min before the start of the infusion. Ghrelin levels [acyl ghrelin (AG) and total ghrelin (TG)] were collected at four time points before, during and after the infusion. Subjective effects of alcohol, using the BAES, were evaluated before, during and after alcohol infusion. RESULTS: IV alcohol significantly reduced AG but not TG levels with no difference between the two doses of alcohol. The percent change (%∆) in AG suppression was substantial in both high dose (43.4%∆), and low dose (39.5%∆) of alcohol. Also, fasting AG and TG levels were significant predictors of alcohol stimulant and sedative effects. Higher fasting ghrelin levels were associated with longer and more intense subjective effects. CONCLUSIONS: The results provide evidence that IV alcohol suppresses ghrelin levels similarly to oral alcohol. This study is the first to show that ghrelin predicts subjective effects of alcohol, suggesting that ghrelin may have a role in the rewarding mechanisms for alcohol. SHORT SUMMARY: Intravenous alcohol infusion (low dose and high dose of alcohol) when compared to placebo (saline) significantly suppresses ghrelin in healthy social drinkers. Fasting ghrelin levels also predict subjective behavioral effects of alcohol. Those with higher fasting ghrelin levels tend to experience alcohol effects longer and more intensely.

Effect of Intravenous Ethanol on Capsaicin-Induced Hyperalgesia in Human Subjects.

BACKGROUND: The objective of this study was to assess ethanol's (EtOH's) effects on capsaicin-induced hyperalgesia in healthy participants. Specifically, we investigated the change in area of capsaicin-induced hyperalgesia following 3 interventions: intravenous EtOH at 2 targeted breath alcohol concentrations (BrAC), or placebo. METHODS: Eighteen participants participated in 3 test days in a randomized order. Each test day, participants received an intradermal capsaicin injection on the volar surface of the forearm, followed by either infusion of high concentration EtOH (targeted BrAC = 0.100 g/dl), low concentration EtOH (targeted BrAC = 0.040 g/dl), or placebo. The area of hyperalgesia was determined by von Frey technique at 2 time points, prior to EtOH infusion, and again when target BrAC was reached. The primary outcome was the percent change in the area of capsaicin-induced hyperalgesia. Additional outcome measures included the visual analogue scale of mood states (VAS), which was administered at each time point. RESULTS: There was a marked 30% reduction in the area of capsaicin-induced hyperalgesia with infusion of a high concentration of EtOH (p < 0.05). Low concentration EtOH produced a 10% reduction in hyperalgesia area, although this finding did not reach significance. Further, participants reported significant feelings of euphoria and drowsiness at high concentrations of EtOH (p < 0.05), as measured by the VAS. CONCLUSIONS: In a human model examining pain phenomena related to central sensitization, this study is the first to demonstrate that capsaicin-induced hyperalgesia is markedly attenuated by EtOH. The capsaicin experimental pain paradigm employed provides a novel approach to evaluate EtOH's effects on pain processing. The antihyperalgesic effects of EtOH observed have important clinical implications for the converging fields of substance abuse and pain medicine and may inform why patients with chronic pain often report alcohol use as a form of self-medication.

Effects of family history of alcohol dependence on the subjective response to alcohol using the intravenous alcohol clamp.

BACKGROUND: Alcohol use disorders are well recognized to be common, debilitating, and the risk of developing them is influenced by family history (FH). The subjective response to alcohol may be determined familialy and related to the risk of developing alcoholism. The aim of this study was to evaluate differences between family history positive (FHP) and family history negative (FHN) individuals in their response to alcohol within the domains of subjective, coordination, and cognitive effects using an intravenous (IV) clamping method of alcohol administration. METHODS: Two groups of healthy subjects, those with an FHP (n = 65) versus those who were FHN (n = 115), between the ages of 21 to 30, participated in 3 test days. Subjects were scheduled to receive placebo, low-dose ethanol (EtOH) (target breath alcohol clamping [BrAC] = 40 mg%), and high-dose EtOH (target BrAC = 100 mg%) on 3 separate test days at least 3 days apart in a randomized order under double-blind conditions. Outcome measures included subjective effects, measures of coordination, and cognitive function. RESULTS: Both low- and high-dose alcohol led to dose-related stimulant and sedative subjective effects as measured the Biphasic Alcohol Effects Scale and subjective measures of "high" and "drowsy" measured on a visual analog scale. However, there were no effects of FH. Similar dose-related effects were observed on cognitive and coordination-related outcomes, but were not moderated FH. CONCLUSIONS: Results from this study showed that healthy individuals responded to an IV alcohol challenge in a dose-related manner; however, there were no significant differences on subjective response, or on EtOH-induced impairment of coordination or cognition, between individuals with a positive FH for alcoholism and those with a negative FH. Results suggest that FH may not be a specific enough marker of risk, particularly in individuals who are beyond the age where alcohol use disorders often develop.

Subjective Effects of Thiopental in Young Adults with and without a Family History of Alcoholism.

BACKGROUND: The development of alcohol use disorders is genetically influenced, and may be mediated through differences in the subjective response to alcohol. There is some evidence to suggest that response differences to alcohol could be conveyed by heritable differences in GABAA receptors. The purpose of this study was to investigate whether individuals with a family history positive (FHP) for alcohol dependence would experience alterations in response to the GABAA receptor agonist thiopental, in comparison to family history negative (FHN) subjects. METHODS: 73 subjects (24 FHP and 49 FHN) between the ages of 21 and 30 years were administered sub-anesthetic doses of the GABAA receptor agonist thiopental and placebo on two separate test days. Various alcohol-related measures were administered, including those examining subjective effects, coordination, and cognition. RESULTS: Sub-anesthetic doses of thiopental produced alcohol-like subjective effects, as well as alcohol-like impaired coordination and cognition in healthy subjects. While there were no significant main effects in subjective, coordination, or cognitive effects between FHP and FHN individuals, analysis of peak effects suggested FHP had blunted sedative, but not stimulant effects compared to FHN. CONCLUSION: Thiopental produced alcohol-like effects and perceived similarities to alcohol in healthy individuals. Subtle differences in sedative effects are consistent with reports of blunted FHP response to the negative but not stimulant effects of alcohol. Future studies are needed to better understand how this insight informs our understanding of the heritable risk for alcoholism and the treatment of alcohol use disorders.