Psychopharmacology最新文献

Rationale: Traumatically injured individuals can develop chronic negative psychological sequelae. Improved understanding of contributing, peri-traumatic risk factors is essential to reduce the risk of these consequences. Previous studies have found that peri-traumatic, circulating endocannabinoid concentrations are positively associated with development of post-traumatic stress disorder (PTSD), chronic pain and depression months later, particularly in members of racial/ethnic groups that have been historically marginalized.

Objectives: This replication study examined relationships among peri-trauma serum endocannabinoid concentrations and long-term consequences in a cohort comprised primarily of individuals from marginalized racial and ethnic groups.

Methods: Participants (n = 100; 81% from marginalized racial and ethnic groups) were traumatically injured adults presenting to the ED of an urban tertiary care hospital. Endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) were measured in serum collected within days (peri-trauma) and 6-10 months following injury (follow-up). Assessments, including PTSD, depression, pain and quality of life were completed. Statistical approaches, including multivariate, hierarchical regressions, were used to determine associations among serum endocannabinoid concentrations and long-term outcomes.

Results: Although it did not survive correction for multiple comparisons, peri-trauma serum 2-AG concentrations. Peri-trauma serum 2-AG concentrations were also positively associated with PTSD, pain severity, and functional engagement scores at follow-up. There were no significant associations between circulating 2-AG or AEA and depression.

Conclusions: These findings generally replicate earlier studies demonstrating that serum 2-AG concentrations are biomarkers of risk for PTSD and pain and uncover an additional association with poor functional quality of life. Further studies are needed to determine the underlying mechanisms of these relationships.

A hallmark of many psychiatric disorders is maladaptive and heightened fear responses to non-threatening stimuli. Adaptive defensive responses to threats involve transitions between passive behaviors, such as freezing, and active escape strategies, such as darting or fleeing. The endocannabinoid (eCB) system, particularly 2-arachidonoylglycerol (2-AG), plays a crucial role in modulating fear and stress responses. However, the extent to which 2-AG influences defensive behavioral state transitions to fear responses remains unclear. To address this, we investigated the role of 2-AG in shaping defensive behaviors to learned and innate threats using pharmacological manipulations in both the serial compound stimulus (SCS) and the looming shadow paradigm. During SCS, inhibition of 2-AG synthesis enhanced freezing to early cues and promoted active responses during cues associated with heightened threat imminence. In the looming shadow paradigm, 2-AG depletion biased defensive behavior toward freezing and increased time spent in a safe zone, suggesting a shift toward passive responses. These findings demonstrate that 2-AG signaling critically regulates the balance and transitions between passive and active defensive strategies in both learned and innate fear contexts. Thus, 2-AG plays a key role in the scaling of defensive response transitions and the promotion of active defensive responses to threats.

Rationale: Adverse childhood experiences (ACEs) have been identified as a major risk factor for psychiatric disorders from childhood to adult life along with the dysregulation of neuroendocrinological processes mediating stress and inflammation. The endocannabinoid system (ECS) has been found to play a putative role in the release of inflammatory cytokines.

Objective: We investigated the role of the ECS in the interplay between ACEs and interleukin 6 (IL-6) as an inflammatory marker.

Methods: We analysed ACEs (CTQ, Bernstein et al. 2003), plasma IL-6 and endocannabinoid concentrations (anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in a cohort comprising 48 female individuals diagnosed with borderline personality disorder (BPD) and 31 matched healthy controls (HCs).

Results: We found higher IL-6 levels in individuals with BPD compared to HCs and, across all study participants, observed significant positive correlations between AEA, 2-AG and IL-6 levels. CTQ sum scores correlated positively with IL-6 concentrations at a trend level (statistically significant for sexual abuse). Correlations between CTQ sum scores and IL-6 levels were particularly strong in participants with low endocannabinoid levels (lowest three quartiles; n = 57) while in the quartile with the highest endocannabinoid levels (n = 19), no correlations were evident. Furthermore, an exploratory analysis applying a median split for IL-6 levels revealed that the number of individuals with recent suicide attempts (< 1 month ago) was significantly higher in the high IL-6 levels group (OR = 0.22; 95%CI = 0.06-0.86).

Conclusion: Our findings support the bidirectional link between ACEs and immune system alterations and suggest that endocannabinoids may counteract the stress-inflammatory response.

Rationale: Chronic cannabis users frequently report stress relief as their primary reason for use. The endocannabinoid system is involved in the neuroendocrine stress response, and diurnal cortisol rhythms may be disrupted in chronic cannabis users.

Objectives: The objectives were to determine whether cannabis users demonstrate disruptions in diurnal stress rhythms and examine the acute effects of cannabis on stress-related outcomes in cannabis users' natural environments.

Methods: Eighty-two participants (39 cannabis users, 43 non-users) collected saliva samples to quantify cortisol concentrations and provided subjective stress ratings at 8 time points throughout the day. They wore a medical-grade wearable device for 24 h that recorded physiological indicators of stress (heart rate variability, electrodermal activity). Cannabis users collected additional saliva samples before and after cannabis use to examine acute effects of cannabis use.

Results: Cannabis users exhibited significant dysregulations in diurnal cortisol rhythms, including a blunted cortisol awakening response, flattened diurnal cortisol slope, and elevated afternoon cortisol concentrations. There were no differences in diurnal heart rate variability or electrodermal activity except for elevated evening heart rate in cannabis users. Finally, there were significant decreases in cortisol, subjective stress, and electrodermal activity following acute cannabis use in cannabis users' natural environment.

Conclusions: These results provide evidence of dysregulated diurnal cortisol rhythms in cannabis users that were related to later waking times and acute stress-relieving properties of cannabis use in naturalistic environments. Future research should examine the direction of the relationship between cannabis use and diurnal cortisol rhythms and potential implications for other psychological disorders.

Background: The endocannabinoid signaling system regulates stress and is implicated in depression, with altered circulating endocannabinoid concentrations frequently reported in adults with depression compared to without. Maternal depression is a well-established predictor of depressive symptoms in youth. However, few studies have examined the relationship between circulating endocannabinoids and susceptibility to psychiatric disorders during adolescence, a high-risk period for symptom onset. This study examines associations among adolescent depressive symptoms, maternal depressive symptoms, and circulating endocannabinoids in a heterogenous community sample of adolescents.

Methods: This study reports on 77 adolescents (M ± SD = 13.36 ± 2.19 years, 51.9% female; 41.6% White Non-Hispanic, 41.6% Black Non-Hispanic, 5.2% Hispanic, 9.0% biracial) and their biological mothers. Depressive symptoms were measured in mothers and adolescents using the Beck Depression Inventory and Children's Depression Inventory, respectively. Adolescent plasma concentrations of the endocannabinoids N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) were quantified using liquid chromatography-tandem mass spectrometry.

Results: Over half (58.4%) of adolescents and 15.6% of mothers exceeded clinically significant depression cut-offs. Maternal and adolescent depressive symptoms were not significantly associated (R² = 0.120, p = 0.053). However, maternal (but not adolescent) depressive symptoms were positively associated with adolescent AEA concentrations, adjusting for covariates (R² = 0.332, p < 0.001). This association was moderated by adolescent depressive symptoms (p = 0.004; B=-0.2557), particularly when maternal symptoms were low. Adolescent or maternal symptoms were not significantly associated with adolescent 2-AG concentrations (R² = 0.097, p = 0.670 and R² = 0.098, p = 0.611, respectively).

Conclusion: Higher AEA concentrations may serve as a monitoring marker of familial susceptibility for depression during adolescence, including among adolescents with subthreshold symptoms. These results suggest the endocannabinoid system as a potential target for identifying risk and developing interventions during adolescence.

Background: Exposure to childhood maltreatment (CM) has serious consequences on the health of affected individuals, potentially elevating vulnerability to various psychopathologies, including substance use disorders (SUDs). Recent investigations have implicated several biological signaling systems in vulnerability to SUD development following CM, including the kynurenine (KYN) pathway and endocannabinoid (eCB) system. Potential crosstalk between these systems has scarcely been explored.

Methods: The present exploratory analysis investigated the relationship between baseline and stress-induced changes in eCBs, KYN metabolites, inflammatory biomarkers, and cortisol across CM and SUD status (CM + SUD, CM only, SUD only, and healthy controls) using a factor analysis. Participants (N = 101) completed an acute laboratory stressor and blood samples were collected at five-timepoints throughout the task.

Results: Factor analysis revealed that KYN metabolites explained the majority of total variance in the dataset. The pro-inflammatory marker CRP was associated with neurotoxic KYN metabolites. Subsequent group-level analyses revealed that CM status significantly impacted a pro-inflammatory factor (baseline and stress-induced changes in CRP and IL-6). Additionally, CM and SUD status exhibited an interaction effect on a factor primarily comprised of 2-AG at baseline and throughout stress, such that in absence of CM, SUD was associated with significantly reduced levels of 2-AG.

Conclusions: Exposure to CM is associated with pro-inflammatory states at baseline and across stress exposure. Additionally, 2-AG may be a marker of SUD pathology in the absence of CM. However, no effect of CM or SUD status was found on KYN pathway metabolites. The mechanisms underlying elevated susceptibility to SUD following CM-exposure require further investigation.

Background: The endocannabinoid system, which regulates fear- and anxiety-related behaviors, is dysregulated in adults with posttraumatic stress disorder (PTSD), as indicated by higher circulating anandamide (AEA) concentrations. The C385A (rs324420) polymorphism in the fatty acid amide hydrolase (FAAH) gene, which catabolizes AEA, is linked to higher AEA concentrations and greater PTSD symptoms in adults. Given that adolescence is a critical period during which trauma and psychiatric disorders emerge, understanding this relationship in youth is essential. This study examines PTSD symptoms, AEA concentrations, and FAAH genotype in a diverse adolescent sample.

Methods: This study included 102 Detroit-area adolescents (M ± SD = 13.33 ± 2.21 years, 54.9% female) and their parents/guardians. The sample consisted of 40.2% White Non-Hispanic, 34.3% Black Non-Hispanic, 6.9% White Hispanic, 4.9% Asian/Pacific Islander, and 12.7% Biracial adolescents. Trauma exposure and PTSD symptoms were assessed using the UCLA PTSD Reaction Index for DSM-5. Plasma concentrations of AEA were measured by liquid chromatography-tandem mass spectrometry, and FAAH genotype was determined from saliva samples and high-throughput screening.

Results: The majority (90%) of adolescents reported trauma exposure, and 20% met PTSD criteria. Higher AEA concentrations were associated with more severe PTSD symptoms (p = 0.009), especially hyperarousal. The FAAH A-allele (present in 52.5% of participants) was associated with higher AEA concentrations (2.11 ± 0.69 pmol/ml, p = 0.013) and greater PTSD severity (22.65 ± 15.931, p = 0.027), particularly those with the reexperiencing cluster, compared to the CC genotype (1.79 ± 0.66 pmol/ml and 15.87 ±+ 13.043, respectively).

Conclusion: Elevated AEA concentrations and the FAAH A-allele were associated with greater PTSD symptom severity in urban adolescents. These findings suggest endocannabinoid dysregulation may play a role in adolescent PTSD, highlighting the need for further research and targeted interventions.

Rationale: Current treatment options for PTSD have unreliable efficacy, with many individuals unable to achieve complete remission. Cannabis and cannabinoids that act through the endogenous cannabinoid (endocannabinoid) system to help promote trauma recovery by means of enhanced extinction learning are potential therapeutic, pharmacological candidates. Using a preclinical model of translationally-relevant cannabis administration in rodents, we examined the impact of cannabis exposure on aversive memory.

Objectives: Our study investigated the effects of acute cannabis exposure prior to (1) fear conditioning and (2) fear extinction, as well as (3) chronic cannabis exposure prior to fear conditioning, on the behavioural representations of fear memory dynamics in a Pavlovian auditory conditioning paradigm.

Methods: Male and female Sprague Dawley rats were acutely or chronically exposed to THC-dominant cannabis extract or vehicle vapor as described above. We then assessed both passive (freezing) and active (darting) fear behaviours during conditioning, extinction, retrieval, and spontaneous recovery.

Results: Acute cannabis exposure prior to conditioning had no immediate effects on fear acquisition, but impaired fear recall in females 24 h later and prevented spontaneous recovery of conditioned fear following a two-week retrieval test in both male and female rats. Acute cannabis exposure prior to extinction training impaired extinction in females while enhancing extinction acquisition in males. Finally, chronic THC exposure prior to fear conditioning initially potentiated fear responses, predominately in females, but produced no differences in spontaneous recovery in a two-week retrieval test.

Conclusions: Cannabis exposure has complex dynamics on fear memory, however, acute cannabis exposure prior to fear learning appears to result in destabilization of the fear memory long term, which could have potential implications for PTSD.