Toward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: A critical review of preclinical research

Despite the lack of clinical research, marijuana and synthetic cannabinoids have been approved to treat posttraumatic stress disorder (PTSD) in several states in the United States. This review critically examines preclinical research on the endocannabinoid system (ECS) in order to evaluate three key questions that are relevant to PTSD: (1) Does ECS dysfunction impact fear extinction? (2) Can stress-related symptoms be prevented by ECS modulation? (3) Is the ECS a potential target for enhancing PTSD treatment? Disruption of the ECS impaired fear extinction in rodents, and ECS abnormalities have been observed in PTSD. Targeting fear memories via the ECS had mixed results in rodents, whereas augmented cannabinoid receptor activation typically facilitated extinction. However, the translational value of these findings is limited by the paucity and inconsistency of human research. Further investigation is necessary to determine whether incorporating cannabinoids in treatment would benefit individuals with PTSD, with cautious attention to risks

Impact of Cannabis Use on Treatment Outcomes among Adults Receiving Cognitive-Behavioral Treatment for PTSD and Substance Use Disorders

Background: Research has demonstrated a strong link between trauma, posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) in general and cannabis use disorders in particular. Yet, few studies have examined the impact of cannabis use on treatment outcomes for individuals with co-occurring PTSD and SUDs. Methods: Participants were 136 individuals who received cognitive-behavioral therapies for co-occurring PTSD and SUD. Multivariate regressions were utilized to examine the associations between baseline cannabis use and end-of-treatment outcomes. Multilevel linear growth models were fit to the data to examine the cross-lagged associations between weekly cannabis use and weekly PTSD symptom severity and primary substance use during treatment. Results: There were no significant positive nor negative associations between baseline cannabis use and end-of-treatment PTSD symptom severity and days of primary substance use. Cross-lagged models revealed that as cannabis use increased, subsequent primary substance use decreased and vice versa. Moreover, results revealed a crossover lagged effect, whereby higher cannabis use was associated with greater PTSD symptom severity early in treatment, but lower weekly PTSD symptom severity later in treatment. Conclusion: Cannabis use was not associated with adverse outcomes in end-of-treatment PTSD and primary substance use, suggesting independent pathways of change. The theoretical and clinical implications of the reciprocal associations between weekly cannabis use and subsequent PTSD and primary substance use symptoms during treatment are discussed

Effect of d-cycloserine on fear extinction training in adults with social anxiety disorder

© 2019 Hofmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Preclinical and clinical data have shown that D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor complex, augments the retention of fear extinction in animals and the therapeutic learning from exposure therapy in humans. However, studies with nonclinical human samples in de novo fear conditioning paradigms have demonstrated minimal to no benefit of DCS. The aim of this study was to evaluate the effects of DCS on the retention of extinction learning following de novo fear conditioning in a clinical sample. Eighty-one patients with social anxiety disorder were recruited and underwent a previously validated de novo fear conditioning and extinction paradigm over the course of three days. Of those, only 43 (53%) provided analyzable data. During conditioning on Day 1, participants viewed images of differently colored lamps, two of which were followed by with electric shock (CS+) and a third which was not (CS-). On Day 2, participants were randomly assigned to receive either 50 mg DCS or placebo, administered in a double-blind manner 1 hour prior to extinction training with a single CS+ in a distinct context. Day 3 consisted of tests of extinction recall and renewal. The primary outcome was skin conductance response to conditioned stimuli, and shock expectancy ratings were examined as a secondary outcome. Results showed greater skin conductance and expectancy ratings in response to the CS+ compared to CS- at the end of conditioning. As expected, this difference was no longer present at the end of extinction training, but returned at early recall and renewal phases on Day 3, showing evidence of return of fear. In contrast to hypotheses, DCS had no moderating influence on skin conductance response or expectancy of shock during recall or renewal phases. We did not find evidence of an effect of DCS on the retention of extinction learning in humans in this fear conditioning and extinction paradigm

Greater hippocampal volume is associated with PTSD treatment response

Previous research associates smaller hippocampal volume with posttraumatic stress disorder (PTSD). It is unclear, however, whether treatment affects hippocampal volume or vice versa. Seventy-six subjects, 40 PTSD patients and 36 matched trauma-exposed healthy resilient controls, underwent clinical assessments and magnetic resonance imaging (MRI) at baseline, and 10 weeks later, during which PTSD patients completed ten weeks of Prolonged Exposure (PE) treatment. The resilient controls and treatment responders (n=23) had greater baseline hippocampal volume than treatment non-responders (n=17) (p=0.012 and p=0.050, respectively), perhaps due to more robust fear-extinction capacity in both the initial phase after exposure to trauma and during treatment

PTSD remission after prolonged exposure treatment is associated with anterior cingulate cortex thinning and volume reduction

Background: Brain structures underlying posttraumatic stress disorder (PTSD) have been a focus of imaging studies, but associations between treatment outcome and alterations in brain structures remain largely unexamined. We longitudinally examined the relation of structural changes in the rostral anterior cingulate cortex (rACC), a previously identified key region in the PTSD fear network, to outcome of prolonged exposure (PE) treatment. Method: The sample included 78 adults (53 women): 41 patients with PTSD and 37 trauma-exposed healthy volunteers (TE-HCs). Patients underwent a 10-week course of PE treatment and completed pre- and posttreatment assessments and magnetic resonance imaging (MRI) structural scans. TE-HCs also underwent assessment and MRI at baseline and 10 weeks later. PE remitters (n = 11), nonremitters (n = 14), and TE-HCs, were compared at baseline on demographic and clinical characteristics and ACC structure. Remitters, nonremitters, and TE-HCs were compared for pre- to posttreatment clinical and structural ACC change, controlling for potential confounding variables. Results: There were no baseline differences in structure between PTSD and TE-HCs or remitters and nonremitters. Following treatment, PTSD remitters exhibited cortical thinning and volume decrease in the left rACC compared with PTSD nonremitters and TE-HCs. Conclusions: These results, while in need of replication, suggest that PE treatment for PTSD, by extinguishing maladaptive trauma associations, may promote synaptic plasticity and structure change in rACC. Future research should explore possible underlying mechanisms

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Scaling relative incentive value in anticipatory behavior

Papini and Pellegrini (Papini, M. R., & Pellegrini, S. Scaling relative incentive value in consummatory behavior. Learning and Motivation, in press) observed that, within limits, the level of consummatory responding of rats exposed to incentive downshifts in the concentration of sucrose solutions was similar when the ratio of test/training solutions was the same. For example,32 fi 4% and 16 fi 2% downshifts (1:8 test/training ratios) lead to similar levels of consummatorybehavior, despite differences in the absolute concentrations of the solutions involved in the downshift. This suggests the applicability of Weber’s law to spaced-trial, incentive-downshift situations. Experiment 1 extended these results to runway performance using food pellets as reward, and Experiment 2 to lever pressing performance, using an autoshaping procedure and sucrose solutions as rewards. The results conform well to the test/training ratio suggesting that Weber’s law is applicable to anticipatory behavior. A simple mathematical rule that can be easily incorporated into models based on linear operators describes the results of consummatory and anticipatory behavior experiments.Fil: Pellegrini, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Papini, Mauricio Roberto. Texas Christian University; Estados Unido

Scaling relative incentive value in consummatory behavior

Surprising downshifts from more preferred (training incentive) to less preferred incentives (test incentive) are usually accompanied by emotional activation and suppression of conditioned behavior in rats. Two experiments were designed to determine whether consummatory behavior is similarly affected by downshifts of equal proportions. Within limits, the degree of consummatory responding during incentive downshift was similar with equal ratios of test concentration to training concentration. Thus, 32% to 4% and 16% to 2% downshifts (1:8 test/training ratios) caused similar levels of consummatory behavior, despite differences in the absolute concentrations of the solutions involved in the downshift. An interpretation based on sensory contrast was discarded because of the long intervals between training and test solutions (40 min and 24 h in Experiments 1 and 2, respectively). It is suggested that Weber’s law regulates behavioral suppression after reward downshifts. A theoretical framework for the interpretation of these data is presented.Fil: Papini, Mauricio Roberto. Texas Christian University; Estados UnidosFil: Pellegrini, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Scaling relative incentive value: Different adjustments to incentive downshift in pigeons and rats

Previous research suggests that pigeons and rats show differences in their behavioral adjustments in spaced-trial, incentive-downshift situations. Also, Papini and Pellegrini [Papini, M.R., Pellegrini, S., 2006. Scaling relative incentive value in consummatory behavior. Learn. Motiv. 37, 357–378] and Pellegrini and Papini [Pellegrini, S., Papini, M.R., 2007. Scaling relative incentive value in anticipatory behavior. Learn. Motiv. 38, 128–154] showed that changes in the rat’s lever-pressing performance, runway running, and consumption of sucrose solutions after downshifts in incentive magnitude were a function of the ratio of postshift/preshift incentivemagnitudes. Here, two experiments using a Pavlovian autoshaping procedure studied the adjustment of pigeons and rats to changes in incentive magnitude. In Experiment 1, pigeons received light-food pairings, whereas in Experiment 2, rats received lever-sucrose pairings. As a result,key-pecking and lever-pressing developed in each experiment, respectively. Preshift incentivemagnitudes were downshifted so as to obtain postshift/preshift ratios of 0.125 and 0.25. Pigeons responded during the postshift phase according to the preshift incentive value and independently of the ratio value. However, rats showed ratio constancy, responding during the postshift in accordance with the postshift/preshift ratio, rather thanwith the absolutemagnitudes of either the preshift or postshift incentives. These results support the comparative hypothesis that the mechanisms underlying ratio constancy during incentive downshifts are unique to mammals.Fil: Pellegrini, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Lopez Seal, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Papini, Mauricio Roberto. Texas Christian University; Estados Unido

Opioid receptors modulate recovery from consummatory successive negative contrast

Three experiments explored the role of the opioid system in consummatory successive negative contrast. In Experiment 1, rats treated with the nonspecific opioid-receptor antagonist naloxone (2 mg/kg) exhibited increased suppression after a shift from 32% to 6% sucrose solution (32 → 6), relative to 6 → 6 unshifted controls. A similar but shorter effect was observed with the delta-opioid receptor antagonist naltrindole (1 mg/kg). In Experiment 2, naloxone increased suppression after a more conventional 32 → 4 sucrose shift. In Experiment 3, rats classified as expressing slow recovery from contrast (after a 32 → 4 sucrose downshift) were more sensitive to naloxone in an activity test than fast-recovery rats. Whereas it was previously known that contrast was reduced by the extrinsic administration of opioid agonists, the effects reported here with antagonists provide the first evidence that the opioid system is intrinsically engaged by situations involving surprising reward loss.Fil: Pellegrini, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Wood, Michael. Texas Christian University; Estados UnidosFil: Daniel, Alan M.. Texas Christian University; Estados UnidosFil: Papini, Mauricio Roberto. Texas Christian University; Estados Unido