Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use
Departments of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA
Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, Connecticut, USA
Department of Psychology, Yale University, New Haven, Connecticut, USA
Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, Connecticut, USA
Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
Departments of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA
Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, Connecticut, USA
Department of Psychology, Yale University, New Haven, Connecticut, USA
Abstract
Background
Metabotropic glutamate receptor 5 (mGlu5) dysregulation has been implicated in the pathophysiology of trauma-related psychopathology, and there are direct interactions between the endocannabinoid and glutamatergic systems. However, relationships between cannabis use (CU) and mGlu5 have not been directly investigated in trauma-related psychopathology.
Methods
Using positron emission tomography with [18F]FPEB, we examined relationships between CU status and mGlu5 availability in vivo in a cross-diagnostic sample of individuals with trauma-related psychopathology (n = 55). Specifically, we tested whether mGlu5 availability in frontolimbic regions of interest (ROIs; dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, hippocampus) differed as a function of CU status.
Results
Past-year CU (n = 22) was associated with 18.62%–19.12% higher mGlu5 availability in frontal and 14.24%–16.55% higher mGlu5 in limbic ROIs relative to participants with no recent CU. Similarly, past-month or monthly CU (n = 16) was associated with higher mGlu5 availability in frontal (18.05%–20.62%) and limbic (15.53%–16.83%) ROIs. mGlu5 availability in the orbitofrontal cortex and amygdala was negatively associated with depressive symptoms in the past-year CU group. In both CU groups, exploratory analyses showed negative correlations between mGlu5 availability and sadness across all ROIs and with perceptions of worthlessness and past failures (r’s = −.47 to .66, P’s = .006–.033) in the ventromedial prefrontal cortex. Participants with CU reported lower mean depressive symptoms (P’s = .006–.037) relative to those without CU.
Conclusions
These findings have substantial implications for our understanding of interactions between CU and glutamatergic neurotransmission in trauma-related psychopathology, underscoring the need for treatment development efforts to consider the effects of CU in this population.
Untitled section
Keywords: mGlu5, cannabis, trauma, PTSD, depression
Article notes
Untitled section
Received 2024 Jul 16; Accepted 2024 Sep 23; Collection date 2024 Oct.
Boxed Text
Effective pharmacological treatments for trauma-related psychopathology remain limited. Trauma-related psychopathology is often associated with high rates of medicinal and recreational cannabis use despite inconclusive evidence of cannabis’ effects in this population. Dysregulation of the glutamatergic system in the brain, specifically, metabotropic glutamate receptor 5 (mGlu5), has been observed in trauma-related psychopathology, and this system has direct interactions with brain systems affected by cannabis. However, these interactions have not been directly investigated in humans. In participants with trauma-related psychopathology, we demonstrated significant differences in mGlu5 in brain areas relevant to trauma-related psychopathology in cannabis users relative to non-users. mGlu5 was associated with depressive symptoms among cannabis users with trauma-related psychopathology. These findings add to our understanding of the interactions between the glutamatergic and endocannabinoid systems in the human brain and highlight the need for treatment development efforts aimed at mGlu5 to consider the effects of both medicinal and recreational cannabis use.
INTRODUCTION
In the United States, an estimated 80%–90% of individuals experience or are exposed to serious traumatic events (Kilpatrick et al., 2013). Defined as “exposure to actual or threatened death, serious injury, or sexual violence” (American Psychiatric Association, 2022), many individuals who experience these events go on to develop trauma-related psychopathology such as posttraumatic stress disorder (PTSD) or major depressive disorder (MDD). Large-scale studies have estimated that 8.1%–9.4% of trauma-exposed individuals will develop PTSD (Kilpatrick et al., 2013), and estimates of MDD following trauma exposure have ranged from 7.1% to 31% (Shih et al., 2010; Wanklyn et al., 2016). Research implicates trauma experience as a transdiagnostic risk factor for mental illness associated with almost 3 times higher likelihood of having a psychiatric illness (Hogg et al., 2023). Unfortunately, there are limitations to current pharmacotherapies for trauma-related psychopathology; fewer than 30% of individuals with PTSD achieve full remission with first-line pharmacological treatments (Kelmendi et al., 2016). Promisingly, neurobiological evidence has emerged supporting the therapeutic potential of a novel target in the glutamate system for trauma-related psychopathology, specifically, the metabotropic glutamate receptor 5 (mGlu5).
The mGlu5 receptor is located mostly post synaptically and on glia. It regulates glutamatergic neurotransmission (Asch et al., 2023a), serves as a mediator of synaptic plasticity, and plays key roles in cognitive functioning (e.g., fear learning and memory formation) (Tan and Kim, 2021; Hagena and Manahan-Vaughan, 2022; Xuan et al., 2023) and emotion regulation (Terbeck et al., 2015). Studies have demonstrated mGlu5 dysfunction in several clinical populations, including PTSD (Holmes et al., 2017, 2023; Esterlis et al., 2018; Davis et al., 2019). Critical to the current work, evidence suggests that mGlu5 plays a central role in the acquisition and formation of trauma-related memories (i.e., fear conditioning) (Rodrigues et al., 2002; Tronson et al., 2010; Asch et al., 2023a) and is implicated in PTSD-like behaviors in animal models (e.g., freezing, contextual fear memory, fear generalization) (Asch et al., 2023b, 2023c). In human studies using positron emission tomography (PET), higher mGlu5 availability was observed in individuals with PTSD compared with healthy adults (Holmes et al., 2017; Davis et al., 2019) and individuals with MDD (Davis et al., 2019). Moreover, the extent of mGlu5 dysregulation was associated with symptom severity, including avoidance (Holmes et al., 2017; Davis et al., 2019), anxiety and tension (Davis et al., 2019), and suicide ideation (Davis et al., 2019).
Findings of mGlu5 availability in MDD are mixed (DeLorenzo et al., 2015b; Abdallah et al., 2017; Davis et al., 2019; Holmes et al., 2023), although no study to our knowledge has examined the role of mGlu5 specifically in individuals who developed MDD in the wake of trauma exposure. Interestingly, administration of ketamine, a glutamate receptor antagonist, reduced mGlu5 availability in both mentally healthy adults and individuals with MDD (DeLorenzo et al., 2015a; Esterlis et al., 2018; Holmes et al., 2020), and the extent of mGlu5 reduction was associated with the anti-depressant response 24 hours post dose (Esterlis et al., 2018). The totality of this evidence implicates mGlu5 as a strong treatment target in trauma-related psychopathology that warrants further exploration.
Successful implementation of treatments targeting mGlu5 will require consideration of clinically relevant factors that can affect outcomes for individuals with trauma-related psychopathology. These considerations include substance use patterns, most notably, cannabis use (CU). Increasing evidence suggests that individuals with trauma-related psychopathology endorse high rates of CU (Cougle et al., 2011), and a large percentage of individuals report using cannabis to alleviate depressive symptoms (Sarris et al., 2020). Conflicting evidence exists for the potential utility of treating PTSD using various cannabis constituents (Ragen et al., 2015; Orsolini et al., 2019; Sarris et al., 2020; Steardo et al., 2021), and concerns have emerged surrounding the potential untoward side effects of medicinal CU (i.e., cannabis use disorder; psychosocial and cognitive difficulties) (Volkow et al., 2014). As such, current treatment guidelines do not recommend medicinal CU for the treatment of PTSD. Relevant to the present study, evidence from both human and preclinical studies implicate molecular relationships between cannabinoid pharmacological action and mGlu5. Clinical and preclinical evidence implicate mGlu5 as a key regulator of glutamate homeostasis via cannabinoid receptors (CB1) (Cristino et al., 2020), with the main psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC), being implicated in glutamate signaling (Colizzi et al., 2016). Specifically, review findings conclude that THC is capable of affecting glutamate release, enzyme activity, and expression and activity in receptors and transporters, as well as both agonizing and antagonizing CB1 receptors (Colizzi et al., 2016).
In light of widespread CU in trauma-related psychopathology and the changing landscape in the United States facilitating increased access to cannabis, novel treatment development efforts, including those targeting mGlu5 specifically, must consider the potential effects of CU. However, limited research on the neurobiological underpinnings of CU in trauma-related psychopathology is available, especially regarding its relationship to mGlu5. We thus aimed to address this significant gap in the literature by examining the relationships between CU and trauma-related psychopathology (PTSD; MDD with trauma exposure) in vivo for the first time using [18F]FPEB PET. We examined differences in mGlu5 availability in individuals with trauma-related psychopathology as a function of CU status and examined endophenotypic clinical correlates of mGlu5 availability in individuals with trauma-related psychopathology who use cannabis. First, we hypothesized that individuals with trauma-related psychopathology with past-month or monthly and past-year CU would demonstrate higher frontolimbic mGlu5 availability than those with trauma-related psychopathology and no past-month or past-year CU, respectively. Second, we hypothesized that endophenotypic clinical correlates (specifically, depressive symptoms) would be positively associated with mGlu5 availability in individuals with trauma-related psychopathology and past-month or monthly and past-year CU.
METHODS
Participants
Study participants (n = 55) were recruited from the local community and participated in PET scanning with [18F]FPEB. Table 1 contains the demographic details. All participants included in the study were required to meet criteria for PTSD or MDD with exposure to a traumatic event. There were no significant demographic differences between participants who met criteria for PTSD vs those who met criteria for MDD (i.e., sex, age, BMI, smoking status, or nicotine use status; all P >.05). Participants were divided based on CU status. Those who reported CU in the past calendar year (12 months) were included in the past-year CU group (past-year CU; n = 22). Those who reported no CU in the past 12 months were included in the no past-year CU group (no past-year CU; n = 31). To assess the effects of more recent CU, participants were further divided based on past-month use. These groups consisted of participants who either reported CU in the past month or a pattern of at least monthly use (past-month CU; n = 16) relative to those who reported no use in the past month or no monthly use (no past-month CU; n = 39).There were no significant diagnostic differences (i.e., PTSD vs MDD) in the CU groups relative to those in the no-CU groups. More detailed information can be found in Table 1.
| Past-Year CU | No Past-Year CUa | Statistical Test (T or chi2, P) | Past-Month CU | No Past-Month CU | Statistical Test (T or chi2, P) | |
|---|---|---|---|---|---|---|
| Demographics | n = 22 | n = 31 | n = 16 | n = 39 | ||
| Sex (M:F) (%F) | 12:10 (45.50) | 15:15b (50.00%) | 0.11, .75 | 12:4 (25.00%) | 15:23 b (60.50%) | 5.68, .02 |
| Age (y) | 31.00 (10.88) | 39.06 (11.61) | 2.56, .01 | 31.69 (11.74) | 36.64 (11.95) | 1.40, .17 |
| Weight (kg) | 74.28 (14.98) | 82.73 (19.88) | 1.59, .12 | 79.24 (14.23) | 77.87 (19.50) | 0.27, .81 |
| Medicated (% medicated) | 43.80% | 43.50% | 0.00,.99 | 41.70% | 46.40% | 0.08, .78 |
| Diagnostic status (% PTSD) | 50.00% | 41.90% | 0.34, .58 | 56.30% | 41.90% | 1.06, .30 |
| Nicotine use (% smoker) | 33.30% | 25.80% | 0.35, .56 | 33.30% | 25.60% | 1.06, .30 |
| BDI-II (M & SD) | 24.73 (8.26) | 23.65 (10.69) | 0.40, .69 | 23.69 (8.84) | 23.97 (10.14) | 0.10, .92 |
| CES-D (M & SD) | 27.94 (10.64) | 32.33 (11.81) | 1.21, .23 | 24.93 (10.05) | 32.73 (11.28) | 2.17, .037 |
| MADRS (M & SD) | 16.27 (5.69) | 22.19 (8.36) | 2.88, .006 | 14.19 (5.15) | 21.79 (7.66) | 3.64, <.001 |
| Injected dose of FPEB | 164.99 (19.95) | 156.75 (38.36) | 1.02, .32 | 161.18 (21.50) | 160.45 (35.11) | 0.09, .93 |
| Injected mass of FPEB (μg/kg) | .0052 (.003) | .0039 (.003) | 1.60, .13 | .0050 (.003) | .0041 (.003) | 0.97, .38 |
| Daily CU (% Y) | 27.30% | 0.00% | 9.53, .001 | 37.50% | 0.00% | 15.65, <.001 |
| Weekly CU (% Y) | 54.50% | 0.00% | 21.86, <.001 | 75.00% | 0.00% | 35.87, <.001 |
| Current Other Drug (% Y) | 0.00% | 03.22%^ | 0.72, .40 | 0.00% | 02.70%^ | 0.41, .51 |
Participants completed physical, psychiatric, and neurological examinations at an initial screening visit to establish diagnoses and rule out major medical or neurological illnesses. Screening tests included electrocardiography, hematology, chemistry, thyroid function, liver function, urinalysis and urine toxicology, and plasma pregnancy (for females).
Exclusion criteria included active suicide ideation; any severity of substance use disorder (past 6 months, except for CU in cannabis users) or moderate-to-severe substance use disorder (past 12 months moderate, lifetime for severe) except for nicotine and cannabis users; positive urine toxicology (except for cannabis in cannabis users) or pregnancy tests at screening or before any scan; history of loss of consciousness for more than 5 minutes; and contraindications to magnetic resonance imaging (MRI) scans. Individuals who tested positive for exclusionary substance use (such as opiates) on urine toxicology screen on either scan or screen day were excluded from participation. The study was approved by the Yale University Human Investigation Committee and the Radioactive Drug Research Committee. All participants provided written informed consent.
Psychiatric and Cannabis Use Assessments
All 55 participants had confirmed trauma-related psychopathology, determined using the Structured Clinical Interview for DSM-5 (First et al., 2015). Specifically, all participants met criteria of trauma exposure as defined by the DSM-5, specifically, having been exposed to “actual or threatened death, serious injury, or sexual violence (American Psychiatric Association, 2022).” To provide a comprehensive examination of current depressive symptoms, we used both clinician-rated (Montgomery-Åsberg Depression Rating Scale [MADRS]; Montgomery and Asberg, 1979) and self-report measures (Center for Epidemiological Studies Depression Scale [CES-D], Lewinsohn et al., 1997; and Beck Depression Inventory [BDI] II, Beck et al., 1996). CU status was determined by participants’ reports of frequency and recency of cannabis consumption.
MRI and PET Procedures
T1-weighted MRI scans were acquired for all participants on a 3T scanner (Trio, Siemens Medical Systems, Erlangen, Germany) to evaluate potential structural abnormalities and facilitate co-registration with PET data. High specific activity [18F]FPEB (674.99 ± 420.29 MBq/µg) was synthesized onsite at the Yale PET Center as previously described (Park et al., 2015). Radiotracer was injected i.v. using a bolus plus infusion paradigm with a Kbol = 190 minutes (total infusion = 120 minutes) (Sullivan et al., 2013; Park et al., 2015). There were no significant differences in the injected dose (160.66 ± 31.56 MBq) or mass (0.32 ± 0.19 µg) between groups (see Table 1). Emission data were acquired with a high-resolution research tomograph (Siemens/CTI) during the established equilibrium period of 90–120 minutes after the start of injection (Sullivan et al., 2013; Park et al., 2015). Head motion was tracked using the Polaris Vicra optical tracking system (Vicra, NDI System Waterloo, CA). A 6-minute transmission scan was obtained for attenuation correction. Dynamic scan data were reconstructed with corrections for attenuation, normalization, randoms, scatter, dead time, and motion using the ordered-subset expectation maximization-based MOLAR algorithm (Carson et al., 2003). The high-resolution research tomograph has an intrinsic spatial resolution of approximately 2.5 mm full width at half maximum. Venous sampling was conducted throughout scanning for calculation of the metabolite-corrected venous input function as previously validated (Park et al., 2015; Abdallah et al., 2017).
PET images were co-registered to each participant’s T1-weighted MRI images using a 6-parameter mutual information algorithm (FSL 3.2, Analysis Group, FMRIB, Oxford, UK), which was then co-registered to the MRI template by nonlinear transformation using Bioimagesuite (version 2.5). Regions of interest (ROIs) were delineated using the Anatomical Automatic Labeling atlas (Rolls et al., 2020). Gray matter segmentation was conducted using FSL-FAST, and a gray matter mask was applied to the ROIs. Given the lack of a reference region for mGlu5 targets (Patel et al., 2007), volume of distribution (VT: the ratio of radioligand concentration in ROI to the concentration in plasma at equilibrium) was used as the outcome measure. The equilibrium analysis method described previously (Sullivan et al., 2013) and a venous plasma input function (Park et al., 2015) were used to calculate VT.
Statistical Analyses
Statistical analyses were completed using SPSS Statistics v29 (IBM Corp., Armonk, NY, USA). Independent-samples t tests, chi-square, correlational analyses, and 1-way analysis of variance (ANOVA) were used to assess demographic differences across groups. ROIs included frontal (dorsolateral prefrontal cortex [dlPFC], orbitofrontal cortex [OFC], ventromedial PFC [vmPFC]) and limbic (amygdala, hippocampus) regions relevant to trauma-related psychopathology. Group differences in the relationship between CU status and mGlu5 availability were assessed using multivariate ANOVAs (MANOVA). CU status was entered as the fixed factor, with mGlu5 availability in study ROIs as dependent variables. For both past-year CU/no CU and past-month CU/no CU groups, we conducted 2 MANOVAs. The first model evaluated the differences in mGlu5 availability in frontal ROIs, and the second model evaluated differences in mGlu5 availability in limbic ROIs. Percent differences were computed to quantify the magnitude of differences in mGlu5 availability across groups. Pearson bivariate correlations examined potential clinical correlates of mGlu5 availability in individuals with trauma-related psychopathology and CU.
RESULTS
To include as much of the available sample and conserve statistical power, groups were not demographically matched 1-to-1. Instead, we evaluated differences between group means; variables that differed between groups were considered as covariates. Independent samples t tests demonstrated that the past-year CU participants were significantly younger than the no past-year CU participants (t(51) = 2.56, P =.014). The past-month CU group had a higher proportion of males relative to the no past-month CU group (chi-square = 5.68, P = .017). Independent samples t tests and chi-square analyses indicated that groups did not differ significantly with respect to other potentially relevant variables (i.e., weight, medication status; nicotine use status; diagnostic status [MDD/PTSD]; Table 1). MGlu5 availability did not differ as a function of biological sex. Age was negatively correlated with mGlu5 in the vmPFC (r = −.33, P = .014). Significant findings were followed up with additional analyses adjusting for sex and age.
Assumption checks revealed that ROIs were highly correlated with one another (r’s = .86–95), and Box’s test of equality of covariance matrices was significant for analyses examining frontal ROIs in CU (P’s < .001). However, Levene tests for individual F tests revealed homogeneity of variances, and all ROIs were normally distributed. As such, we used Pillai trace to interpret the multivariate analyses. One outlier (SD ≥3 relative to subgroup mean) was excluded from analyses. Finally, 15 participants included in the no past-year CU group and 21 included in the no past-month CU group had histories of distal cannabis use. The t tests demonstrated no significant differences in mGlu5 availability in participants who had used cannabis over a year before the scan relative to those who had never used cannabis (all P = .36–.64). Thus, we opted to include these participants to increase statistical power. Planned analyses used Bonferroni corrections for multiple comparisons.
Main Analyses
Past-Year Cannabis Use
The MANOVA examining the effects of past-year CU on frontal ROI mGlu5 was significant (F(3,49) = 3.47, P =.023, ηp2 = 0.18; Figure 1). Post-hoc univariate analyses evaluating specific ROIs revealed significantly higher mGlu5 availability in the past-year CU group relative to the no past-year CU group in the OFC (F(1,51) = 10.36, P = .002, d = 0.89), vmPFC (F(1,51) = 9.64, P =.003, d = 0.85), and dlFPC (F(1,51) = 9.02, P = .004, d = 0.83). Post-hoc analyses survived corrections for multiple comparisons. While the overall model was no longer significant after controlling for sex and age (P = .058), univariate analyses for individual ROIs remained significant (P’s = .006–.020).
The MANOVA examining limbic ROIs was significant (F(2,49) = 4.53, P = .016, ηp2 = 0.12; Figure 1), with post-hoc analyses revealing higher mGlu5 availability in the hippocampus (F(1,50) = 8.31, P = .006, d = 0.80) and amygdala (F(1,50) = 5.74, P = .02, d = 0.67) in the past-year CU group compared with the no past-year CU. Post-hoc analyses survived corrections for multiple comparisons. Controlling for sex and age did not alter the findings (F(2,45) = 3.41, P = .042, ηp2 = 0.13).
Past-Month or Monthly Cannabis Use
The MANOVA examining the effects of past-month CU on frontal ROIs was significant (F(3,51) = 3.44, P = .024, ηp2 = 0.17; Figure 2). Post-hoc tests demonstrated significantly higher mGlu5 availability in the OFC (F(1,53) = 10.57, P = .002, d = 0.90), vmPFC (F(1,53) = 8.04, P = .006, d = 0.79), and dlPFC (F(1,53) = 9.78, P = .003, d = 0.88) in the past-month CU group relative to the no past-month CU group. Post-hoc analyses survived corrections for multiple comparisons. Follow-up analyses showed significant effects after controlling for sex and age (F(3,47) = 3.60, P = .020, ηp2 = 0.19).
The MANOVA examining the effects of past-month CU on limbic ROIs was significant (F(2,51) = 3.88, P = .027, ηp2 = 0.13; Figure 2). Specifically, we observed higher mGlu5 availability in the amygdala (F(1,52) = 6.35, P = .015, d = 0.71) and hippocampus (F(1,52) = 7.79, P = .007 d = 0.79) in the past-month CU group relative to the no past-month CU group. Post-hoc analyses survived corrections for multiple comparisons. Follow-up analyses showed that controlling for sex and age (F(2,47) = 6.38, P = .004, ηp2 = 0.21) did not alter these findings.
Figure 3 provides parametric images of mGlu5 availability in a representative participant endorsing past-month CU relative to a participant with no CU in the past year.
Secondary Analyses
Clinical Correlations and Secondary Analyses
In the past-year CU group, mGlu5 availability was not significantly associated with scan day self-reported depression (BDI-II or CES-D; r’s = −.15 to .38; all P >.05). On the other hand, clinician-rated depression scores (MADRS) scores were negatively associated with mGlu5 availability in the OFC (r = −.45, P = .037) and amygdala (r = −.44, P = .043; Figure 4). Controlling for age and sex did not alter findings for the amygdala (r = −.51, P = .046); however, findings for the vmPFC became marginally significant (r = −.49, P = .052). Additional, negative correlations were observed between CES-D scores and mGlu5 availability in the amygdala (r = −.51, P = .044) and vmPFC, (r = −.51, P = .046) and between the vmPFC and BDI scores (r = −.60, P = .015) when controlling for age and sex. Additionally, correlations did not survive Bonferroni corrections for multiple comparisons. In the past-month CU group, there were no significant correlations between ROIs and scores on any depression measures (r’s = −.13 to .43, all P >.05). No significant correlations were observed between mGlu5 availability and depression measures in the no-CU groups.
Exploratory Analyses
To examine associations between mGlu5 availability and specific depressive symptoms, we conducted exploratory correlational analyses. In the past-year CU group, reported sadness on the BDI-II was negatively correlated with mGlu5 availability in all frontal and limbic ROIs (r’s = −.47 to 52, P’s = .012-.033), and mGlu5 availability in the vmFPC was negatively correlated with perceptions of past failures (r = −.52, P = .014) and feelings of worthlessness (r = −.56, P = .007). Controlling for sex and age did not alter these findings (r’s = −.51 to 71, P’s = .002–.046). Similarly, in the past-month CU group, reported sadness was negatively correlated with mGlu5 availability across all ROI (r’s = −.57 to .66, P’s = .006–.025), and perceptions of past failures (r = −.55, P = .027) and worthlessness (r = −.58, P = .019) were negatively correlated with mGlu5 availability in the vmPFC (Figure 4). Controlling for sex and age did not alter these findings (r’s = −.58 to .82, P’s = .001–.49). Notably, none of these associations were significant in participants without CU.
Given observed relationships between mGlu5 availability and depressive severity within the CU groups, we conducted additional exploratory analyses to examine differences in depressive symptom severity as a function of CU status (i.e., CU vs non-CU; Table 1 shows mean scores on depression measures). Past-year CU was entered as a fixed factor into a MANOVA with CES-D, MADRS, and BDI-II scores as dependent variables. The model demonstrated a significant effect of past-year CU depressive symptoms (F(3,35) = 5.52, P = .003, ηp2 = 0.32). Specifically, MADRS scores were significantly lower for past-year CU relative to no past-year CU (F(1,37) = 4.77, P = .035, d = 0.71). BDI-II and CES-D scores did not differ between groups. The overall model remained significant when controlling for sex and age (F(3,32) = 4.14, P = .014, ηp2 =.28). However, univariate analyses revealed that differences in MADRS score no longer reached statistical significance (P = .068), potentially due to reduced statistical power. Similarly, a MANOVA examined the effects of past-month or monthly CU on depressive symptoms. Past-month or monthly CU was entered as a fixed factor, and the 3 depression measures were entered as dependent variables. The overall model was significant (F(3,36) = 7.72, P < .001, ηp2 = 0.39), with MADRS (F(1,38) = 8.53, P = .006, d = 0.69) and self-report CES-D scores (F(1,38) = 4.69, P = .037, d = 0.73) being significantly lower in the past-month CU group relative to the no past-month CU group. BDI-II scores did not differ between groups. The overall model remained significant when controlling for age and sex (F(3,33) = 5.32, P = .004, ηp2 = 0.33), although CES-D scores no longer differed significantly between groups (P = .211).
Finally, for exploratory purposes, we compared our study sample with a large existing group of healthy controls (HC; n = 52; nonpsychiatric, no CU use) who participated in the same scanning procedures. There were no significant differences between HCs and clinical groups regarding age (M = 37.83, SD = 14.47) or sex (53.1% male; all P > .05). For past-year CU, mGlu5 was significantly higher in the trauma-related psychopathology group in the dlPFC (P = .034) and marginally in the hippocampus (P = .051) relative to HC. For the past-month CU group, mGlu5 was significantly higher in the OFC (P = .039), dlPFC (P = .015), and hippocampus (P = .034) relative to HCs. No differences were observed between the HC and trauma-related psychopathology groups without CU; this may have been due to the heterogeneity of the HC sample.
DISCUSSION
To our knowledge, this was the first in vivo study to examine relationships between mGlu5 and CU specifically among individuals with trauma-related psychopathology. Consistent with our first hypothesis, we demonstrated significant associations between CU and mGlu5 availability in regions of the brain relevant to the pathophysiology of trauma-related psychopathology. Specifically, we observed higher mGlu5 availability in frontal and limbic brain regions in comparing both (1) participants who had used cannabis in the past year relative to individuals with no past-year cannabis use (14%–19%); and (2) participants who had used cannabis in the past month relative to individuals with no past month use (15%–20%), with large effect sizes.
The interpretation of these results and their clinical implications requires consideration of the relationship between the glutamatergic and cannabinoid systems. The observed between-group differences may be the result of mGlu5 upregulation via CU, as cannabis and THC have widespread effects on neural glutamate transmission (Colizzi et al., 2016). Specifically, the majority of preclinical models have demonstrated that THC binding to CB1 inhibits glutamate release and leads to long-term synaptic depression of glutamatergic neurotransmission (Brown et al., 2003; Fan et al., 2010). . Animal studies have demonstrated that after chronic exposure to THC and other CB1 agonists, there is a reduction in the number and function of CB1 receptors (Oviedo et al., 1993; Breivogel et al., 1999, 2003; Sim-Selley, 2003; Sim-Selley et al., 2006; McKinney et al., 2008). Additionally, repeated treatments with THC induce reduced glutamate transmission in animals (Fan et al., 2010). Magnetic resonance spectroscopy studies show that THC administration is associated with decreases in glutamate levels (Chang et al., 2006; Prescot et al., 2011, 2013; Chun et al., 2022). It is possible that CU attenuates presynaptic glutamate release, leading to less glutamate binding to mGlu5 and subsequent compensatory upregulation of mGlu5 (i.e., higher mGlu5 availability). However, it is worth noting that some preclinical studies have demonstrated links between CB1 activation in adolescence and decreased mGlu5 (Gleason et al., 2012). One possible explanation for these divergent findings may be differential effects of CU in adolescence relative to adulthood. Overall, future work is necessary to elucidate the neurobiological underpinnings of cannabis’ effects on mGlu5 in trauma-related psychopathology; our findings provide a starting place for such investigations.
A fuller understanding of the interactions between the cannabinoid and glutamatergic systems in trauma-related psychopathology has implications for treatment development. Past research has demonstrated higher mGlu5 availability in PTSD relative to HCs and to individuals with MDD (Holmes et al., 2017; Davis et al., 2019), adding to evidence supporting a role for mGlu5 in the pathophysiology of trauma-related conditions. Past research has also shown that mGlu5 antagonists produce anxiolytic effects (Krystal et al., 2010), and the action of mGlu5 is implicated in animal models of trauma (Asch et al., 2023b, 2023c), as well as trauma-related memories and fear conditioning in PTSD (Rodrigues et al., 2002; Tronson et al., 2010; Tan and Kim, 2021; Asch et al., 2023a). Given the intricate relationships between endocannabinoid function and mGlu5 combined with high rates of CU in trauma-related psychopathology, self-medication through CU may be an attempt to regulate the mGlu5 disruption observed in this population. These preliminary findings showing differences in mGlu5 availability as a function of CU underscore the relevance of considering this factor in trauma-related psychopathology treatment development of mGlu5 drugs.
Notably, not all hypotheses were sustained. Based on prior work, our second hypothesis maintained that mGlu5 would positively correlate with endophenotypic clinical features in individuals with trauma-related psychopathology and CU. This hypothesis was not supported; negative associations were observed between past-year CU and clinician-rated depressive symptoms. Exploratory analyses revealed negative correlations between mGlu5 availability and sadness, perceptions of failure and worthlessness in the CU groups. The relationships between mGlu5 availability and these symptoms were not significant in the non-CU groups. Additional exploratory analyses revealed that relative to the non-CU groups, individuals with past-year and past-month CU had significantly lower scores on a clinician-rated measure of depression, although differences on self-reported depression measures were more variable.
The findings may have diverged from our hypotheses for several reasons. First, the observed higher mGlu5 in participants with CU may suggest more severe baseline symptom presentations in these individuals relative to non-cannabis users, prompting initial CU as a form of self-medication. Specifically, individuals with more severe trauma-related symptoms may show mGlu5 upregulation and more severe endocannabinoid deficits (Neumeister et al., 2013), increasing the likelihood of CU in an attempt to regulate these systems and relieve symptoms. Indeed, individuals report CU to treat depression (Sarris et al., 2020). Alternatively, there may be symptom-specific relationships between mGlu5, CU, and trauma-related psychopathology. It may be crucial to identify symptom profiles of individuals with trauma-related psychopathology who will clinically benefit from medicinal cannabis, as well as identifying those at highest risk for adverse side effects. For instance, recent findings demonstrate mixed results regarding the effects of CU in PTSD, ranging from a worsening of symptoms (Orsolini et al., 2019), no differences relative to a placebo condition (Bonn-Miller et al., 2021), to reductions in hyperarousal (Ragen et al., 2015; Steardo et al., 2021), suicide ideation (Steardo et al., 2021), anxiety, depressive symptoms, and improvements in sleep quality (Orsolini et al., 2019).
Despite the potential cross-diagnostic relevance of cannabis in trauma-related psychopathology, many questions remain. Longitudinal work examining mGlu5 availability in individuals with trauma-related psychopathology before and after the initiation of CU is clearly needed to begin to clarify the relationships between mGlu5, stress-related pathology, and CU. Future research on the effects of cannabis constituents is critically needed to inform the development of effective, safe treatment protocols that maximize benefits and minimize risks. Findings suggest that such treatments may be relevant not only to individuals diagnosed with PTSD but also to those with stress and trauma-related psychopathology cross-diagnostically. The development of transdiagnostic treatment targets is essential and consistent with movements in the field of psychiatry toward dimensional approaches to psychopathology (Koudys et al., 2019; Levin-Aspenson and Greene, 2024).
Limitations
Limitations include the study’s cross-sectional nature, precluding a determination of causality between any of the variables assessed. There was variability in the data collected, limiting the specificity with which we could examine participants’ cannabis use. For instance, we were unable to consider relevant factors that could have affected findings related to CU, such as the dose, duration, and method of use, as these data were not available for all participants. There was also considerable variability in the frequency of cannabis use among participants, especially in the past-year CU group. Consequently, the analyses are preliminary and should be interpreted with caution. Similarly, mGlu5 and trauma-related psychopathology both have notable relevance to anxiety symptoms: however, we examined depressive symptoms only. Future research should consider assessing anxiety symptoms. Additionally, circadian factors can affect mGlu5 availability (Ahnaou et al., 2015; Aguilar et al., 2020); thus, participants were scanned at similar times of day. We could not control for individual differences in circadian biology, however, no significant differences were observed in injection times for the CU vs non-CU groups (P’s = .32–.47). Finally, there is no neural region entirely devoid of mGlu5 (DeLorenzo et al., 2011; Kagedal et al., 2013); thus, our primary outcome measure, VT includes specific and nonspecific binding.
CONCLUSIONS
In summary, this study was the first, to our knowledge, to explore the differential relationships between mGlu5 availability, CU, and mood symptoms in a cross-diagnostic sample of individuals with trauma-related psychopathology. Consistent with hypotheses, we found that the subsample of individuals who reported CU (both past-year and past-month or monthly use) had significantly higher mGlu5 availability in key frontolimbic regions relative to individuals with no recent CU. Furthermore, the relationships between mGlu5 availability and psychiatric symptoms varied as a function of CU, with exploratory analyses demonstrating negative correlations between mGlu5 and mood symptoms only among participants in the CU subsample. Additional exploratory analyses revealed significantly lower depressive symptoms for individuals reporting CU. Overall, these data underscore the importance of examining CU in individuals with trauma-related psychopathology and suggest that mGlu5 may be differentially implicated as a function of CU status. Novel treatment development targeting mGlu5 in individuals with trauma-related psychopathology must consider the impact of both recreational and medicinal CU.
Acknowledgments
The authors thank the staff of the Yale PET Center for their assistance and our participants for their time and effort.
Contributor Information
Emily R Weiss, Departments of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA.
Margaret T Davis, Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA; U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, Connecticut, USA; Department of Psychology, Yale University, New Haven, Connecticut, USA.
Ruth H Asch, Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.
Deepak Cyril D’Souza, Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA; U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
Ryan Cool, Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.
Irina Esterlis, Departments of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA; Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA; U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, Connecticut, USA; Department of Psychology, Yale University, New Haven, Connecticut, USA.
Untitled section
This work was supported by the National Institute of Mental Health (grant nos. NIMH 1-K08-MH117351-01 to M.T.D., 1 R01 MH116657-01A1 and 1R01MH104459-01 to I.E.); National Center for Advancing Translational Science (grant no. KL2TR001862 to R.H.A.); the National Institute on Drug Abuse (grant no. T32 DA 22975-15 to E.R.W.); and the VA National Center for PTSD (to I.E.).
Interest Statement
D.C.D. currently receives research funding administered through Yale University from the US National Institute on Drug Abuse, US Dept. of Veteran Affairs, Wallace Foundation and Boehringer Ingelheim. He has received funding in the past 3 years from Takeda and Biogen. In the past year he has served as a consultant to Atai, the France Foundation and Inverready. None of the other authors declared potential conflicts of interest.
Data Availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.
REFERENCES
Untitled section
References
- Abdallah CG, Hannestad J, Mason GF, Holmes SE, DellaGioia N, Sanacora G, Jiang L, Matuskey D, Satodiya R, Gasparini F, Lin X, Javitch J, Planeta B, Nabulsi N, Carson RE, Esterlis I (2017) Metabotropic glutamate receptor 5 and glutamate involvement in major depressive disorder: a multimodal imaging study. Biol Psychiatry Cogn Neurosci Neuroimaging 2:449–456.
- Aguilar DD, Strecker RE, Basheer R, McNally JM (2020) Alterations in sleep, sleep spindle, and EEG power in mGluR5 knockout mice. J Neurophysiol 123:22–33.
- Ahnaou A, Raeymaekers L, Steckler T, Drinkenbrug WH (2015) Relevance of the metabotropic glutamate receptor (mGluR5) in the regulation of NREM-REM sleep cycle and homeostasis: evidence from mGluR5 (-/-) mice. Behav Brain Res 282:218–226.
- American Psychiatric Association (2022) Diagnostic and statistical manual of mental disorders (DSM-5-TR®): ®American Psychiatric Pub.
- Asch RH, Hillmer AT, Baldassarri SR, Esterlis I (2023a) The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders. Int Rev Neurobiol 168:265–310.
- Asch RH, Fowles K, Pietrzak RH, Taylor JR, Esterlis I (2023b) Examining mGlu5 receptor availability as a predictor of vulnerability to PTSD: an [(18)F]FPEB and PET study in male and female rats. Chronic Stress 7:24705470231215001.
- Asch RH, Pothula S, Toyonaga T, Fowles K, Groman SM, Garcia-Milian R, DiLeone RJ, Taylor JR, Esterlis I (2023c) Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [(18)F]FPEB and positron emission tomography study in rats. Neuropsychopharmacology 48:489–497.
- Beck AT, Steer RA, Brown GK (1996) Beck depression inventory-II (BDI-II). San Antonio, TX: Psychological Corporation.
- Bonn-Miller MO, Sisley S, Riggs P, Yazar-Klosinski B, Wang JB, Loflin MJE, Shechet B, Hennigan C, Matthews R, Emerson A, Doblin R (2021) The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: A randomized cross-over clinical trial. PLoS One 16:e0246990.
- Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Vogt LJ, Sim-Selley LJ (1999) Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem 73:2447–2459.
- Breivogel CS, Scates SM, Beletskaya IO, Lowery OB, Aceto MD, Martin BR (2003) The effects of delta9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors. Eur J Pharmacol 459:139–150.
- Brown TM, Brotchie JM, Fitzjohn SM (2003) Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake. J Neurosci 23:11073–11077.
- Carson RE, Barker WC, Liow J-S, Johnson CA (2003) Nuclear science symposium conference record; October 19–25, 2003; Portland, OR. In: IEEE, 3281–3285.
- Chang L, Cloak C, Yakupov R, Ernst T (2006) Combined and inde-pendent effects of chronic marijuana use and HIV on brain metabolites. J Neuroimmune Pharmacol 1:65–76.
- Chun S, Zuo KAD, Scott EL (2022) Lower dACC glutamate in cannabis users during early phase abstinence. Neuropsychopharmacology 47:1969–1975.
- Colizzi M, McGuire P, Pertwee RG, Bhattacharyya S (2016) Effect of cannabis on glutamate signalling in the brain: a systematic review of human and animal evidence. Neurosci Biobehav Rev 64:359–381.
- Cougle JR, Bonn-Miller MO, Vujanovic AA, Zvolensky MJ, Hawkins KA (2011) Posttraumatic stress disorder and cannabis use in a nationally representative sample. Psychol Addict Behav 25:554–558.
- Cristino L, Bisogno T, Di Marzo V (2020) Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16:9–29.
- Davis MT, Hillmer A, Holmes SE, Pietrzak RH, DellaGioia N, Nabulsi N, Matuskey D, Angarita GA, Carson RE, Krystal JH, Esterlis I (2019) In vivo evidence for dysregulation of mGluR5 as a biomarker of suicidal ideation. Proc Natl Acad Sci U S A 116:11490–11495.
- DeLorenzo C, Milak MS, Brennan KG, Kumar JS, Mann JJ, Parsey RV (2011) In vivo positron emission tomography imaging with [(1)(1)C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons. Eur J Nucl Med Mol Imaging 38:1083–1094.
- DeLorenzo C, DellaGioia N, Bloch M, Sanacora G, Nabulsi N, Abdallah C, Yang J, Wen R, Mann JJ, Krystal JH, Parsey RV, Carson RE, Esterlis I (2015a) In vivo ketamine-induced changes in [(1)(1)C]ABP688 binding to metabotropic glutamate receptor subtype 5. Biol Psychiatry 77:266–275.
- DeLorenzo C, Sovago J, Gardus J, Xu J, Yang J, Behrje R, Kumar JS, Devanand DP, Pelton GH, Mathis CA, Mason NS, Gomez-Mancilla B, Aizenstein H, Mann JJ, Parsey RV (2015b) Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [(1)(1)C]ABP688. Transl Psychiatry 5:e693.
- Esterlis I, DellaGioia N, Pietrzak RH, Matuskey D, Nabulsi N, Abdallah CG, Yang J, Pittenger C, Sanacora G, Krystal JH, Parsey RV, Carson RE, DeLorenzo C (2018) Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [(11)C]ABP688 and PET imaging study in depression. Mol Psychiatry 23:824–832.
- Fan N, Yang H, Zhang J, Chen C (2010) Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivoΔ9‐THC exposure‐impaired hippocampal synaptic plasticity. J Neurochem 112:691–702.
- First M, Williams J, Karg R, Spitzer R (2015) Structured clinical interview for DSM-5 disorders, clinician version (SCID-5-CV). Arlington, VA: American Psychiatric Association.
- Gleason KA, Birnbaum SG, Shukla A, Ghose S (2012) Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia. Transl Psychiatry 2:e199.
- Hagena H, Manahan-Vaughan D (2022) Role of mGlu5 in persistent forms of hippocampal synaptic plasticity and the encoding of spatial experience. Cells 11:3352.
- Hogg B, Gardoki-Souto I, Valiente-Gomez A, Rosa AR, Fortea L, Radua J, Amann BL, Moreno-Alcazar A (2023) Psychological trauma as a transdiagnostic risk factor for mental disorder: an umbrella meta-analysis. Eur Arch Psychiatry Clin Neurosci 273:397–410.
- Holmes SE, Girgenti MJ, Davis MT, Pietrzak RH, DellaGioia N, Nabulsi N, Matuskey D, Southwick S, Duman RS, Carson RE, Krystal JH, Esterlis I, Traumatic Stress Brain Study G (2017) Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. Proc Natl Acad Sci U S A 114:8390–8395.
- Holmes SE, Gallezot JD, Davis MT, DellaGioia N, Matuskey D, Nabulsi N, Krystal JH, Javitch JA, DeLorenzo C, Carson RE, Esterlis I (2020) Measuring the effects of ketamine on mGluR5 using [(18)F]FPEB and PET. J Cereb Blood Flow Metab 40:2254–2264.
- Holmes SE, Asch RH, Davis MT, DellaGioia N, Pashankar N, Gallezot JD, Nabulsi N, Matuskey D, Sanacora G, Carson RE, Blumberg HP, Esterlis I (2023) Differences in quantification of the metabotropic glutamate receptor 5 across bipolar disorder and major depressive disorder. Biol Psychiatry 93:1099–1107.
- Kagedal M, Cselenyi Z, Nyberg S, Raboisson P, Stahle L, Stenkrona P, Varnas K, Halldin C, Hooker AC, Karlsson MO (2013) A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 - estimating occupancy in the absence of a reference region. Neuroimage 82:160–169.
- Kelmendi B, Adams TG, Yarnell S, Southwick S, Abdallah CG, Krystal JH (2016) PTSD: from neurobiology to pharmacological treatments. Eur J Psychotraumatol 7:31858.
- Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM, Friedman MJ (2013) National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress 26:537–547.
- Koudys JW, Traynor JM, Rodrigo AH, Carcone D, Ruocco AC (2019) The NIMH Research Domain Criteria (RDoC) initiative and its implications for research on personality disorder. Curr Psychiatry Rep 21:37.
- Krystal JH, Mathew SJ, D’Souza DC, Garakani A, Gundaz-Bruce H, Charney DS (2010) Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 24:669–693.
- Levin-Aspenson HF, Greene AL (2024) Rethinking trauma-related psychopathology in the Hierarchical Taxonomy of Psychopathology (HiTOP). J Trauma Stress 37:361–371.
- Lewinsohn PM, Seeley JR, Roberts RE, Allen NB (1997) Center for Epidemiological Studies-Depression Scale (CES-D) as a screening instrument for depression among community-residing older adults. Psychol Aging 12:277–287.
- McKinney DL, Cassidy MP, Collier LM, Martin BR, Wiley JL, Selley DE, Sim-Selley LJ (2008) Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to delta9-tetrahydrocannabinol. J Pharmacol Exp Ther 324:664–673.
- Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389.
- Neumeister A, Normandin MD, Pietrzak RH, Piomelli D, Zheng MQ, Gujarro-Anton A, Potenza MN, Bailey CR, Lin SF, Najafzadeh S, Ropchan J, Henry S, Corsi-Travali S, Carson RE, Huang Y (2013) Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry 18:1034–1040.
- Orsolini L, Chiappini S, Volpe U, Berardis D, Latini R, Papanti GD, Corkery AJM (2019) Use of medicinal Cannabis and synthetic Cannabinoids in Post-Traumatic Stress Disorder (PTSD): a systematic review. Medicina (Kaunas) 55:525.
- Oviedo A, Glowa J, Herkenham M (1993) Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain Res 616:293–302.
- Park E, Sullivan JM, Planeta B, Gallezot J-D, Lim K, Lin S-F, Ropchan J, McCarthy TJ, Ding Y-S, Morris ED, Williams WA, Huang Y, Carson RE (2015) Test–retest reproducibility of the metabotropic glutamate receptor 5 ligand [18F] FPEB with bolus plus constant infusion in humans. Eur J Nucl Med Mol Imaging 42:1530–1541.
- Patel S, Hamill TG, Connolly B, Jagoda E, Li W, Gibson RE (2007) Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F] F-PEB. Nucl Med Biol 34:1009–1017.
- Prescot AP, Locatelli AE, Renshaw PF, Yurgelun-Todd DA (2011) Neurochemical alterations in adolescent chronic marijuana smokers:a proton MRS study. Neuroimage 57:69–75.
- Prescot AP, Renshaw PF, Yurgelun-Todd DA (2013) c-Aminobutyric acid and glutamate abnormalities in adolescent chronic marijuanasmokers. Drug and Alcohol Dependence 129:232–239.
- Ragen BJ, Seidel J, Chollak C, Pietrzak RH, Neumeister A (2015) Investigational drugs under development for the treatment of PTSD. Expert Opin Investig Drugs 24:659–672.
- Rodrigues SM, Bauer EP, Farb CR, Schafe GE, LeDoux JE (2002) The group I metabotropic glutamate receptor mGluR5 is required for fear memory formation and long-term potentiation in the lateral amygdala. J Neurosci 22:5219–5229.
- Rolls ET, Huang C-C, Lin C-P, Feng J, Joliot M (2020) Automated anatomical labelling atlas 3. Neuroimage 206:116189.
- Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J (2020) Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review. BMC Psychiatry 20:24.
- Shih RA, Schell TL, Hambarsoomian K, Belzberg H, Marshall GN (2010) Prevalence of posttraumatic stress disorder and major depression after trauma center hospitalization. J Trauma 69:1560–1566.
- Sim-Selley LJ (2003) Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 15:91–119.
- Sim-Selley LJ, Schechter NS, Rorrer WK, Dalton GD, Hernandez J, Martin BR, Selley DE (2006) Prolonged recovery rate of CB1 receptor adaptation after cessation of long-term cannabinoid administration. Mol Pharmacol 70:986–996.
- Steardo L Jr, Carbone EA, Menculini G, Moretti P, Steardo L, Tortorella A (2021) Endocannabinoid system as therapeutic target of PTSD: a systematic review. Life (Basel) 11:214.
- Sullivan JM, Lim K, Labaree D, Lin S-f, McCarthy TJ, Seibyl JP, Tamagnan G, Huang Y, Carson RE, Ding Y-S (2013) Kinetic analysis of the metabotropic glutamate subtype 5 tracer [18F] FPEB in bolus and bolus-plus-constant-infusion studies in humans. J Cereb Blood Flow Metab 33:532–541.
- Tan SZK, Kim JH (2021) mGlu5: a double-edged sword for aversive learning related therapeutics. Neuroanatomy Behav 3:e16.
- Terbeck S, Akkus F, Chesterman LP, Hasler G (2015) The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies. Front Neurosci 9:86.
- Tronson NC, Guzman YF, Guedea AL, Huh KH, Gao C, Schwarz MK, Radulovic J (2010) Metabotropic glutamate receptor 5/Homer interactions underlie stress effects on fear. Biol Psychiatry 68:1007–1015.
- Volkow ND, Baler RD, Compton WM, Weiss SR (2014) Adverse health effects of marijuana use. N Engl J Med 370:2219–2227.
- Wanklyn SG, Pukay-Martin ND, Belus JM, St. Cyr K, Girard TA, Monson CM (2016) Trauma types as differential predictors of posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and their comorbidity. Can J Behav Sci 48:296–305.
- Xuan SM, Su YW, Liang YM, Gao ZJ, Liu CY, Fan BF, Shi YW, Wang XG, Zhao H (2023) mGluR5 in amygdala modulates fear memory generalization. Front Behav Neurosci 17:1072642.
Associated Data
Data Availability Statement
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.