Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2026 Feb 15.
Published in final edited form as: Psychopharmacology (Berl). 2024 Oct 16;243(2):235–250. doi: 10.1007/s00213-024-06702-w

Dose-dependent effect of acute THC on extinction memory recall and fear renewal: a randomized, double-blind, placebo-controlled study

Nicole L Zabik 1,2,3, Allesandra Iadipaolo 3, Craig A Peters 3, Samantha L Baglot 4,5, Matthew N Hill 4,5, Christine A Rabinak 1,2,3,6
PMCID: PMC12000385  NIHMSID: NIHMS2046481  PMID: 39412674

Abstract

Rationale

Prior work from our lab and others demonstrates that the endocannabinoid system is a promising avenue for improving fear memory deficits in posttraumatic stress disorder (PTSD). Specifically, 7.5 mg of delta-9-tetrahydrocannabinol (THC) decreases fear responding in healthy adults and increases prefrontal cortex activation during extinction learning and fear renewal in adults with PTSD.

Objectives

The present study will determine whether there is a dose-dependent effect of THC on short-term (24 h) and long-term (one week) fear learning and memory in adults with PTSD.

Methods

Using a randomized, double-blind, placebo-controlled design, N = 36 adults with PTSD completed the study and were randomized to receive placebo (PBO, n = 11), 5 mg of THC (n = 11), or 10 mg of THC (n = 14) prior to fear extinction learning. Participants completed a Pavlovian conditioning paradigm with extinction recall and fear renewal occurring 24 h and one week later, where we measured concurrent functional imaging and behavioral responses.

Results

Twenty-four hours after drug administration, individuals with PTSD given 5 mg of THC exhibited greater anterior cingulate cortex and prefrontal cortex activation during early fear renewal. One week later, individuals given 10 mg of THC exhibited greater hippocampus activation during extinction recall and prefrontal cortex activation during fear renewal.

Conclusions

These data suggest that dosing and timing are critical for facilitating fear memory processes in PTSD, and that low-dose oral THC prior to extinction learning can affect brain indices of fear learning and memory both acutely and one week after administration.

Keywords: PTSD, Cannabinoids, Fear conditioning, fMRI, Anterior cingulate cortex, Hippocampus

Introduction

Posttraumatic stress disorder (PTSD) is a complex and debilitating mental health condition that can develop after exposure to a traumatic event (e.g., assault, motor vehicle accident, etc.; (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders 2013). First-line treatment for PTSD addresses its core dysfunction—poor extinction memory retention—via prolonged exposure therapy (Foa 2011). Exposure therapies rely on repeated presentation of trauma-related cues to promote extinction of fear and prevent renewal of fear (Foa et al. 2007). Despite their overall successes, nearly half of patients are left with lingering symptoms, due to poor extinction recall, or relapse within a year due to fear renewal (Foa et al. 1999; Hembree et al. 2003; Rothbaum et al. 2005). There is a great need to improve exposure therapy outcomes by (1) facilitating extinction learning and recall and (2) preventing later fear renewal.

Extinction of learned fear is dependent on the concerted effort of the amygdala and hippocampus to store the new, safe information that the event cue or reminder no longer predicts danger (Chhatwal et al. 2006; Ji and Maren 2007; Pape and Pare 2010). Extinction memory retention and recall, however, is primarily driven by the prefrontal cortex (PFC) and hippocampus (Berretta et al. 2005; Ji and Maren 2008; Milad and Quirk 2002; Paré and Smith 1993). In healthy humans, successful extinction memory recall is associated with hippocampus and vmPFC activation (Milad et al. 2007; Milad, Wright, Milad et al. 2007a, b). Adults with PTSD, however, have poor extinction memory retention and exhibit lesser activation of the PFC and hippocampus, and greater anterior cingulate cortex and amygdala activation, compared to healthy controls (Milad et al. 2008, 2009). Improving extinction retention and preventing fear renewal may therefore require pharmacological interventions that can target fear processes and their associated neural network.

Compelling evidence over the last two decades posits that the endocannabinoid (eCB) system is essential for extinction learning and recall. In rodents, blocking type-1 cannabinoid receptor (CB1R) transmission, the primary receptor of the eCB system, impairs fear extinction learning and later recall (Marsicano et al. 2002). Inhibiting the breakdown of eCBs, and therefore increasing eCB transmission and CB1R activation, improves fear extinction recall in rodents (Bitencourt et al. 2008; Chhatwal et al. 2005; Gunduz-Cinar et al. 2013; Pamplona et al. 2008). Systemic or intra-amygdala, -PFC, or -hippocampus administration of a CB1R agonist facilitates extinction learning and later recall (Kuhnert et al. 2013; Segev and Akirav 2011). In healthy humans, low dose, oral THC (7.5 mg) facilitates extinction recall and increases vmPFC and hippocampus activation during an extinction recall test (24 h later; (Rabinak et al. 2013, 2014). Likewise, we recently demonstrated that 7.5 mg THC increases vmPFC activation during extinction learning and 24 h later during fear renewal in adults with PTSD, compared to controls (Zabik et al. 2023). However, based on these data, it is unclear whether the dose used in prior studies (e.g., (Rabinak et al. 2013, 2014) is sufficient for maximizing gains related to extinction learning and retention, as well as preventing fear renewal.

To extend our prior work in adults with PTSD given low dose, oral THC, we report on a randomized, double-blind, placebo-controlled study to determine whether THC has a dose-dependent effect on extinction retention and fear renewal. Specifically, we aimed to determine whether increasing doses of THC in individuals with PTSD causes a linear, dose-dependent: (1) decrease in self-report measures of fear during a test of extinction recall or fear renewal and (2) increase in hippocampus and/or decrease in amygdala activation. Additionally, we determined whether the proposed effects would impact whole brain activation and be retained at a 1-week follow-up.

Materials & methods

Participants

Participants were recruited from the community via flyers, online postings, etc. (Detroit, MI) to complete a study testing the effects of a cannabinoid-based drug on fear memory in those with PTSD. Eligible participants were aged 18–60, right-handed, fluent in English, had at least a high school diploma or equivalent education, and had exposure to a Criterion A event defined by DSM-5 (detailed below). Participants were free of any MRI contraindications (e.g., ferrous metal in the body) and any neurocognitive impairment (including traumatic brain injury with current cognitive impairment). Participants who were pregnant or breast-feeding or were unable to tolerate small, enclosed spaces without anxiety (e.g., claustrophobia) were excluded. Participants with a current or past allergic or adverse reaction or known sensitivity to cannabinoid-like substances (dronabinol/marijuana/cannabis/THC, cannabinoid oil, sesame oil, gelatin, glycerin, and titanium dioxide) were also excluded from the study. Participants completed a novel, immersive reality Pavlovian fear conditioning paradigm that contained a snake stimulus; therefore, participants were screened for excessive fear of snakes (i.e., possible snake phobia) via the Snake Avoidance Questionnaire prior to participation (SNAQ; (Klorman et al. 1974). Potential participants with scores ≥ 24 on the SNAQ were excluded, following Fredrikson (Fredrikson 1983). All participants were required to test negative on a seven-panel urine drug screen and alcohol breathalyzer. Participants also could not have a psychotic or related disorder, could not pose a risk of harm to themselves or others, and could not be taking a medication with a level 1 (severe) drug-drug interaction with dronabinol.

In total, n = 139 participants were screened to complete the present study. Of those participants, n = 21 withdrew their consent, n = 28 were lost to follow-up prior to randomization, n = 23 were ineligible and did not complete the screening interview, n = 1 tested positive on a drug screen, n = 4 were not enrolled due to validity concerns with their interview. All participants completed the Life Events Checklist for DSM-5 to determine exposure to traumatic events in the participant’s lifetime (Weathers et al. 2013). A total of n = 62 participants endorsed a traumatic event that met Criterion A per DSM-5 criteria for PTSD (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders 2013). Of those that endorsed a Criterion A event, n = 44 met criteria for PTSD, by either meeting Clinician Administered PTSD Scale-5 (CAPS-5) diagnosis or having a total CAPS-5 severity score ≥ 25 (Weathers et al. 2018). Of note, the CAPS-5 is a structured interview designed to assess symptoms of post-traumatic stress disorder (PTSD) according to DSM-5 criteria. It is considered the gold-standard for PTSD diagnosis and severity assessment. The n = 18 who did not meet these criteria were excluded from analyses. The CAPS-5 was administered by AI, CP, or NLZ after standardized CAPS-5 training with a licensed clinician; diagnoses were confirmed by CAR.

In addition to determining trauma exposure, psychiatric comorbidities were identified based on a computerized version (NetSCID-4, TeleSage) of the Structured Clinical Interview for DSM-IV (SCID-IV; (First et al. 2002) or the Mini International Neuropsychiatric Interview (MINI version 6.0.0; (Sheehan et al. 1998). Participants with a primary comorbid mood or anxiety disorder more debilitating and clinically salient than PTSD or with current substance or alcohol abuse or dependence were excluded; See Supplemental Data section S1.1 for more details. N = 44 adults met screening eligibility for PTSD and were randomized. Of those that met eligibility criteria, n = 8 were excluded, leaving N = 36. Reasons for exclusion include: lost to follow-up (n = 1) and incomplete functional magnetic resonance imaging (fMRI) data due to either technical errors or participant request to cease scanning (n = 7). See Fig. 1 for details about the recruitment pipeline.

Fig. 1.

Fig. 1

Open in a new tab

Recruitment pipeline for the study after randomization. Forty-four individuals were randomized to receive a capsule of: PBO (n = 13), 5 mg THC (n = 16), or 10 mg THC (n = 15). Of the 44 randomized, 8 were excluded for the following reasons: 1 was lost to follow-up and 7 had incomplete imaging data. In all, N = 36 participants were included in the analyses. PBO = placebo; THC = delta-9-tetrahydrocannabinol

The study protocols were approved by the Wayne State University Institutional Review Board, and all participants provided written informed consent prior to completing study procedures. Participants were compensated for their time. This study is a registered clinical trial investigating the effects of THC on fear extinction in participants with PTSD (NCT03008005).

Pavlovian conditioning paradigm

Participants underwent a well-validated, 3-day Pavlovian conditioning paradigm originally developed by Milad and colleagues (Milad et al. 2007). We previously reported on the modified version of this paradigm (Zabik et al. 2023; Zabik, Rabinak, Zabik et al. 2023a, b). Two different 3D environments consisting of different colors, textures, sounds (ambient noise related to context), and background scenes, constituted the contexts. The fear conditioning context (‘danger’ context, CXT + or A) is separate from the ‘safety’ context where fear is extinguished (CXT− or B). An extinction recall test occurs in the safety context (CXT−), while fear renewal occurs in the danger context (CXT+). The CSs were messenger bags in three colors of maximum discriminability for those with colorblindness. The unconditioned stimulus (US) was a 3D virtual snake darting out of a bag of a specific color [conditioned stimulus (CS); varying colors] and striking towards the participant’s point of view, paired with a snake hiss sound (800 ms, 50 dB, 60% reinforcement). This US was chosen as an evocative and ecologically threatening stimulus (Öhman 2005). Fear conditioning (~ 13.8 min) occurred outside the MRI scanner on a 24” LCD computer monitor in a standard lab office using a VR head-mounted Oculus Rift. They were presented with two CS + s (e.g., red bag and blue bag) that opened to reveal the snake and hissing sound during reinforced trials; in total, participants saw the bag for 4.5 s, where the final 0.8 s included presentation of the US. A third CS (e.g., yellow bag) was presented but never paired with the US (CS−); that is, the bag opened but no US occurred. CS + s had 8 non-reinforced presentations that were intermixed with an additional 12 presentations of each CS + that co-terminated with the US, and 20 presentations of the CS−. The next day, participants completed an extinction learning phase (~ 9.2 min) in the fMRI scanner. One CS + was presented in the absence of the US (CS + E, e.g., red bag). The other CS + was not presented (CS + U, e.g., blue bag). Extinction learning consisted of 20 CS + E and 20 CS − trials presented in the extinction context (CXT−; Fig. 2). Twenty-four hours later, participants returned to the MRI for an extinction recall test phase (~ 13.8 min) in CXT − and a fear renewal test phase (~ 13.8 min) in CXT+, where 20 presentations each of the CS + E, CS + U, and CS − were displayed. The US was not presented during extinction recall or fear renewal. One week later, participants returned to complete an additional test of extinction recall and fear renewal that was identical to the previous tests, which we denote as extinction recall or fear renewal ‘follow-up’. Fear extinction learning, extinction recall, and fear renewal were displayed using Vizard (WorldViz Version 5.0, WorldViz, Santa Barbara, CA, USA) on a screen viewed behind the scanner using a mirror affixed to the headcoil. Assignment of the CSs to the three colored bags was randomized for each participant. All stimuli were presented within the conditioning context (CXT+) during fear conditioning (Fig. 2). The designation of colored bags as CSs and the virtual environment as CXT + or CXT− was randomized across participants. The order of trials was also pseudo-randomized, so no more than 2 presentations of the same color bag occurred in a row.

Fig. 2.

Fig. 2

Open in a new tab

Pavlovian conditioning paradigm occurs over three days: Day 1 contains fear conditioning, Day 2 (24 h later) contains fear extinction learning, and Day 3 (24 h later) contains extinction recall and fear renewal. Participants came back 1 week later for a follow-up, where they repeated extinction recall and fear renewal. Participants received a capsule of PBO, 5 mg THC, or 10 mg THC 120 min prior to extinction learning on Day 2. All days, except Day 1, occurred in the functional imaging scanner. Icons sourced from Flaticon.com; PBO = placebo; THC = delta-9-tetrahydrocannabinol.

Drug randomization and administration

Participants were randomized to receive an acute oral dose of THC (dronabinol, 5 or 10 mg capsule; Ascend Laboratories, LLC, Parsippany, NJ) or dextrose (PBO) using covariate adaptive randomization where a new participant was sequentially allocated to a drug group (PBO, 5 mg THC, 10 mg THC) by accounting for baseline characteristics (i.e., CAPS-5 total severity score, age, sex, and race). In this approach, the current distribution of participants across covariate is assessed and the marginal balance distance is calculated for each covariate to determine the imbalance between groups. The biased coin method with a probability of 0.7 was used to assign the next participant to the group that would minimize the imbalance. If both groups were equally balanced, then the participant was assigned to either group with a probability of 0.5 (Lin et al. 2015). The principal investigator (CAR) randomized participants, wherein participants and study personnel were blinded to the capsule content and drug group assignments.

Approximately 120 min prior to extinction learning, participants ingested a capsule of PBO (n = 11), 5 mg THC (n = 11), or 10 mg THC (n = 14). This administration corresponds to peak drug effects of orally ingested THC (Wachtel et al. 2002).

US expectancy ratings

Participants were instructed to rate (indicate) whether they thought they would encounter the US (see a snake popping out of the bag). Participants were instructed to make a rating of: “Yes, I do think [US] will occur”, “No, I do not think [US] will occur”, or “I don’t know”. This rating happened each time they saw the CS, as soon as they saw the CS. Responses were registered using a computer keyboard on Day 1 and an MR-compatible 4-button response device on Days 2 and 3.

Drug effects questionnaire

We collected data on subjective drug effects from participants during the drug day visit (Day 2) using the Drug Effects Questionnaire (DEQ; (Johanson and Uhlenhuth 1980). The DEQ included the following questions: (1) “Do you FEEL a drug effect right now?”, (2) “Are you HIGH right now?”, (3) “Do you DISLIKE any of the effects you are feeling right now?”, (4) “Do you LIKE any of the effects you are feeling right now?”, and (5) “Would you like MORE of the drug you took, right now?”. Participants rated their response on a 100 mm visual analog scale, from “not at all” to “extremely”. DEQ ratings were collected at baseline (prior to capsule administration) and at approximately 30, 60, 90, 180, and 240 min after capsule ingestion. We also collected DEQ ratings at approximately 120 and 150 min after capsule ingestion while participants were in the fMRI scanner.

Serum levels of THC

We collected blood plasma samples from participants on Day 2 (Extinction Learning) before and after they entered the MRI scanner. Serum samples were collected and processed as previously reported by Baglot and colleagues (Baglot et al. 2021). See Supplemental Information Section S1.1 for methodological details, and Section S2.3 for reported serum levels.

Functional imaging

Data collection and preprocessing

Blood-oxygen level-dependent (BOLD) fMRI data were collected from 66 axial, 2-mm-thick slices (set to the manufacturer-minimum gap size) using a T2*-sensitive gradient echo EPI acquisition sequence (repetition time = 2,000 ms; echo time = 30 ms; 128 × 128 × 66 matrix; field of view = 256 mm; flip angle = 73°; 2.0 × 2.0 × 2.0 mm voxels; multiband acceleration factor = 3). A T1-weighted anatomical image (repetition time = 1,820 ms; echo time = 3.52 ms; 256 × 256 × 120 matrix; field of view = 240 mm; flip angle = 8°; 0.94 × 0.94 × 1.5 mm voxels) and field map image (repetition time = 2,412 ms; echo time = 51 ms; 128 × 128 × 66 matrix; field of view = 256 mm; flip angle = 90°; multiband acceleration factor = 3) were collected within the same scan session for coregistration and distortion correction. Participants were inside the scanner for approximately 13 min prior to beginning the task to reduce the novelty of the scanning environment (5 min for T1-weight anatomical scan and 8 min for resting state).

FMRI data were analyzed using SPM8 software (Wellcome Department of Cognitive Neurology, London, UK; http://www.fil.ion.ucl.ac.uk/spm). The following preprocessing steps were applied sequentially: (a) distortion correction, (b) realignment to first image, (c) slice timing correction, (d) coregistration, (e) normalization to MNI space, (f) reslicing, and (g) spatial smoothing (6-mm FWHM Gaussian kernel). Participants with high quality data and scan stability (minimum motion correction) were included in the analyses. See Supplemental Information Section S1.2 for details on motion-related quality control.

First-level model

After preprocessing, a general linear model was applied to the time series and convolved with the canonical hemodynamic response function (HRF) with a 128-s high-pass filter (Worsley and Friston 1995). Individual statistical parametric maps were calculated using this general linear model for each participant, for each condition type during fear extinction learning (CS + E, CS−) and extinction recall/fear renewal (CS + E, CS + U, CS−). To reduce the impact of motion-related artifacts, the following variables were included in the first-level model as nuisance regressors: the six movement parameters obtained during realignment, the derivatives of the movement parameters, and the quadratic terms for both the movement parameters and their derivatives. Volumes with excess motion (i.e., > 0.8 mm framewise displacement) were also added as nuisance regressors in the models.

Second-level model

First-level contrasts were submitted to second-level analyses in a random-effects statistical model in SPM8 (Friston et al. 1998). Previous animal work, as well as meta-analyses from human data, suggests that activation of fear-related brain regions is strongest during early phases of learning (e.g., extinction recall; see (Fullana et al. 2018; Milad et al. 2007b; Milad and Quirk 2002)). Therefore, fear extinction learning, extinction recall, and fear renewal were split into early and late, defined as the average of the first and second halves of each phase, respectively (10 trials per CS for early and 10 trials per CS for late).

Regions of interest (ROIs)

ROIs included anatomically defined bilateral amygdala and hippocampus, based on the AAL atlas (Tzourio-Mazoyer et al. 2002).

Whole brain analysis

In addition to small-volume, ROI-based analysis, we included whole-brain analyses in SPM12.

Statistical analyses

The primary focus of this study was to determine whether THC has dose-dependent effects on fear-related measures during Pavlovian conditioning in adults with PTSD, with a primary interest in short-erm (24 h) and long-term (1 week) extinction recall and fear renewal. Unless otherwise stated, data were analyzed using SPSS software (IBM SPSS Statistics 29).

US expectancy ratings

For analysis of US expectancy ratings, early fear conditioning is defined as the second trial, while early extinction learning, extinction recall, and fear renewal are defined as the first trials of each stimulus following prior work (Zabik et al. 2022; Zabik, Peters, Zabik et al. 2023a, b). Late trials for all phases are defined as the last trials of each stimulus per phase. Several stimuli had zero responses for a given category, likely due to small drug x trauma sample sizes. To address this issue for statistical analyses, we collapsed responses into two categories: ‘Yes/I don’t know’ and ‘No’.

During each phase, binary logistic regressions assessed the probability of participants responding ‘Yes/I don’t know’ vs. ‘No’. During fear conditioning, our aim was to validate that participants conditioned and differentiated between stimuli. We conducted time (early, late) x stimulus (CS + E, CS + U, CS−) binary logistic regression; we also conducted a prospective drug group (PBO, 5 mg, 10 mg) x time (early, late) x stimulus (CS + E, CS + U, CS−) binary logistic regression. During extinction learning, we conducted a drug group (PBO, 5 mg, 10 mg) x time (early, late) x stimulus (CS + E, CS−) binary logistic regression. Fear conditioning and extinction learning results are presented in Supplemental Information Sect. 2.1. During extinction recall and fear renewal (and 1-week follow-ups), we conducted a drug (PBO, 5 mg, 10 mg) x time (early, late) x stimulus (CS + E, CS + U, CS−) binary logistic regression. Across all phases, results are considered significant with the omnibus test (χ2), where direction of the effect is determined by either B-weights with 95% confidence intervals that do not include one, or estimated marginal means with 95% confidence intervals that do not include zero. Data were analyzed using SPSS software (IBM SPSS Statistics 27) and considered significant at α = 0.05; Bonferroni correction was applied to main effects and interactions for extinction learning, extinction recall, and fear renewal, where the corrected α-level = 0.017. Bonferroni correction was also applied to estimated marginal means within the SPSS software.

Drug effects Questionnaire

For each question on the Drug Effect Questionnaire (feeling a drug effect, feeling high, disliking effects, liking effects, wanting more), we ran a time (0, 30, 60, 90, 120, 150, 180 min) x drug group (PBO, 5 mg, 10 mg) 7 RM-ANOVA. Significance was determined at α = 0.05 for each question, with follow-up t-tests Bonferroni-corrected within the SPSS software. We report the results of these analyses in Supplemental Section S2.4.

Functional activation

Our primary hypothesis of interest was determining whether THC had a linear, dose-dependent effect on functional brain activation in a priori ROIs during a Pavlovian conditioning paradigm. To test this, drug group (PBO, 5 mg, 10 mg), stimulus, and time (early, late) were predictors of functional activation in a RM-ANOVA in SPM12. For each a priori region of interest during extinction learning, a drug group x stimulus (CS + E, CS−) x time mixed factorial ANOVA was performed. For each a priori region of interest during extinction recall and fear renewal (and 1-week follow-ups), a drug group x stimulus (CS + E, CS + U) x time mixed factorial ANOVA was performed. Results were considered significant within bilateral amygdala and hippocampus ROIs using: (1) F-statistic of mixed factorial ANOVA with small volume family wise error correction α = 0.05 [applied via Gaussian random field theory for small volumes] and (2) voxel threshold k = 10 (Lieberman and Cunningham 2009; Worsley et al. 1996). Results were considered significant for whole-brain activation using (1) F-statistic of mixed factorial ANOVA with cluster level α = 0.05 and (2) a voxel threshold (k) = 70. Direction of significant effects were determined by post-hoc t-tests using TukeyHSD in R Studio (Version 2023.12.0).

Results

Participants

Participants varied in racial/ethnic makeup consistent with the recruitment area (Detroit, Michigan. USA; See Table 1 for details).

Table 1.

Participant demographics

PBO
(n = 11)		 5 mg
(n = 11)		 10 mg
(n = 14)		 Total p-value
Age, mean years (SD) 23.1 (5.3) 25.6 (10.8) 24.8 (6.7) 24.5 (7.7) N.S.
Sex, nfemale (%) 11 (100%) 7 (64%) 12 (86%) 30 N.S.
Race, n
 African American/Black 2 3 5 10 N.S.
 Asian 3 1 1 5
 Caucasian/White 5 7 7 19
 More than 1, Other 1 0 1 2
Hispanic or Latino, n 0 0 0 0 —
PTSD Severity (CAPS-5)
 Total severity score, mean (SD) 33.4 (9.5) 38.4 (10.0) 36.1 (12.5) 36.0 (10.8) N.S.
 Number of clinically significant symptoms, mean (SD) 11.7 (2.5) 13.6 (2.4) 12.8 (3.6) 12.8 (3.0) N.S.
Open in a new tab
*

denotes significance between treatment groups at p < 0.05 and N.S. denotes non-significance for multiple comparisons using t-test or chi-square tests. 5 or 10 mg refers to dose of THC (delta-9-tetrahydrocannabinol); PBO = placebo; CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; Clinically significant symptoms refer to the number of symptoms that met the minimum threshold to meet Criteria A-E in the CAPS-5

US ratings

Extinction recall

Drug group, stimulus, and time effects were submitted to a binary logistic regression to predict the likelihood of a ‘Yes/I don’t know’ response to CS + E, CS + U, and CS− during extinction recall. Due to the matrix being singular, early and late stimuli were placed into separate models. In the early stimuli model, no main effects or interactions were detected [drug x stimulus interaction: χ2(4) = 6.837, p = 0.145]. The late stimuli model was still singular and is not reported herein. See Fig. 3 for details.

Fig. 3.

Fig. 3

Open in a new tab

US expectancy ratings during extinction recall and fear renewal. Y-axis indicates percentage of responses for a given category in extinction recall (top panel) and fear renewal (bottom panel). Stacked bars represent responses, from top to bottom: ‘No, ‘I don’t know’, and ‘Yes. PBO = placebo; THC = delta-9-tetrahydrocannabinol

Fear renewal

Drug group, stimulus, and time effects were submitted to a binary logistic regression to predict the likelihood of a ‘Yes/I don’t know’ response to CS + E, CS + U, and CS− during fear renewal. Due to the matrix being singular, early and late stimuli were placed into separate models. In the early stimuli model, no main effects or interactions were detected [drug x stimulus interaction: χ2(4) = 8.521, p = 0.074]. The late stimuli model was still singular and is not reported herein. See Fig. 3 for details.

Extinction recall 1-week follow-up

Drug group, stimulus, and time effects were submitted to a binary logistic regression to predict the likelihood of a ‘Yes/I don’t know’ response to CS + E, CS + U, and CS− during extinction recall follow-up. Due to the matrix being singular, early and late stimuli were placed into separate models. In the early stimuli model, no main effects or interactions were detected [drug x stimulus interaction: χ2(4) = 1.327, p = 0.857]. The late stimuli model was still singular and is not reported herein. See Fig. 4 for details.

Fig. 4.

Fig. 4

Open in a new tab

US expectancy ratings during extinction recall and fear renewal at a 1-week follow-up. Y-axis indicates percentage of responses for a given category in extinction recall (top panel) and fear renewal (bottom panel). Stacked bars represent responses, from top to bottom: ‘No, ‘I don’t know’, and ‘Yes. PBO = placebo; THC = delta-9-tetrahydrocannabinol

Fear renewal 1-week follow-up

Drug group, stimulus, and time effects were submitted to a binary logistic regression to predict the likelihood of a ‘Yes/I don’t know’ response to CS + E, CS + U, and CS− during fear renewal follow-up. Due to the matrix being singular, early and late stimuli were placed into separate models. No significant main effects or interactions could be detected, as the models were still singular and are not reported herein. See Fig. 4 for details.

Functional activation

Extinction recall

In a drug x stimulus x time model, we found no main effects or interactions in the amygdala or hippocampus. However, we found a drug x stimulus x time interaction in the right putamen (108 voxels, p = 0.018, Z = 3.65, xyz = 22, 16, −4). Follow-up t-tests revealed that individuals given 5 mg THC had lesser putamen activation during early presentations of CS + E, compared with those given PBO (p = 0.015) (See Fig. 5). We also found that individuals given PBO exhibited higher putamen activation during early CS + E presentations, compared to late CS + E presentations.

Fig. 5.

Fig. 5

Open in a new tab

BOLD fMRI activation of the putamen during extinction recall in adults with PTSD given varying doses of THC. $Individuals with PTSD given 5 mg THC exhibited lower putamen activation compared to those given PBO during early presentations of CS + E. *Individuals with PTSD given PBO exhibited higher putamen activation during early CS + E, compared to late CS + E. Bar graph values represent peak eigenvariate for significant cluster. PBO = placebo

Fear renewal

In a stimulus x time x drug model, we did not find any main effects or interactions in the amygdala or hippocampus. We found a drug x stimulus x time interaction in the subgenual ACC, dorsolateral PFC, vmPFC, dorsomedial PFC, pregenual ACC, and right putamen (subgenual ACC: 216 voxels, p = 0.002, Z = 4.27, xyz = −22, 24, −12; dorsolateral PFC: 181 voxels, p = 0.005, Z = 4.18, xyz = −34, 14, 54; 127 voxels, p = 0.014, Z = 3.73, xyz = 28, 20, 42; vmPFC: 187 voxels, p = 0.004, Z = 4.25, xyz = −42, 34, −12; dorsomedial PFC: 249 voxels, p = 0.001, Z = 3.62, xyz = 10, 42, 36; pregenual ACC: 610 voxels, p < 0.001, Z = 3.76, xyz = −10, 38, −2; right putamen: 76 voxels, p = 0.049, Z = 3.34, xyz = 24, 2, 8; See Fig. 6). Follow-up t-tests revealed that only the 5 mg THC group exhibited differences in activation. In the subgenual ACC, individuals given 5 mg THC had higher subgenual ACC activation during early, compared to late, presentations of CS + E (p = 0.010). Additionally, individuals given 5 mg THC had higher subgenual ACC activation during early CS + E presentations, compared to activation to late CS + U in individuals given PBO (p = 0.011). In the dorsolateral PFC, individuals given 5 mg THC exhibited greater dorsolateral PFC activation during early CS + E presentations, compared to late CS + E (p = 0.004) and early CS + U (p = 0.002). Individuals given 5 mg THC also exhibited higher dorsolateral PFC activation during late CS + U, compared to late CS + E (p = 0.020) and early CS + U (p = 0.010). In the vmPFC, individuals given 5 mg THC exhibited greater vmPFC activation during early CS + E, compared to late CS + E (p = 0.010) and early CS + U (p = 0.017). In the dorsomedial PFC, individuals given 5 mg THC had higher dorsomedial PFC activation during early CS + E, compared to early CS + U (p = 0.001). Additionally, those given 5 mg THC had lesser dorsomedial PFC activation during late CS + E, compared to early CS + U (p = 0.004). In the pregenual ACC, individuals given 5 mg THC had higher pregenual ACC activation during CS + U late, compared to CS+E late (p = 0.010). In the right putamen, follow-up t-tests did not detect significant differences (p’s > 0.05).

Fig. 6.

Fig. 6

Open in a new tab

BOLD fMRI activation of the subgenual ACC, dorsolateral PFC, and ventromedial PFC during fear renewal in adults with PTSD given varying doses of THC. $Individuals with PTSD given 5 mg THC exhibited higher subgenual ACC activation during early CS + E, compared to those given PBO (CS + U late). *Individuals with PTSD given 5 mg THC exhibited: higher subgenual ACC activation during early, compared to late CS + E (left); higher dorsolateral PFC activation during early (vs. late) CS + E and CS + U (middle); and higher ventromedial PFC during early CS + E (vs. late CS + E or early CS + U) (right). Bar graph values represent peak eigenvariate for significant cluster. PBO = placebo; ACC + anterior cingulate cortex; PFC = prefrontal cortex

Extinction recall 1-week follow-up

In a stimulus x time x drug model, we found a drug x time interaction in the hippocampus (14 voxels, p = 0.046, Z = 3.71, xyz = −26, −22, −10; See Fig. 7). Follow-up t-tests revealed that individuals given 10 mg THC exhibited higher left hippocampus activation during late extinction recall, compared to those given 5 mg (p < 0.001). Individuals given 10 mg THC also had greater left hippocampus activation during late, compared to early, extinction recall (p = 0.027).

Fig. 7.

Fig. 7

Open in a new tab

BOLD fMRI activation of the hippocampus during extinction recall follow-up in adults with PTSD given varying doses of THC. $Individuals with PTSD given 5 mg THC exhibited lower hippocampus activation compared to those given 10 mg THC during late extinction recall. *Individuals with PTSD given 10 mg THC exhibited higher hippocampus activation during late extinction recall, compared to early. Bar graph values represent peak eigenvariate for significant cluster. PBO = placebo.

We also found a drug x stimulus interaction in the left postcentral gyrus (329 voxels, p < 0.001, Z = 3.88, xyz = −46, −22, 54); however, follow-up t-tests did not reveal any significant differences.

Fear renewal 1-week follow-up

In a stimulus x time x drug model, we found no main effects or interactions in the amygdala and hippocampus. We found drug x stimulus interactions in the rostromedial PFC (98 voxels, p = 0.033, Z = 3.70, xyz = −2, 54, 6) and dorsomedial PFC (194 voxels, p = 0.005, Z = 3.55, xyz = −8, 38, 26) (See Fig. 8). Follow-up t-tests revealed that only individuals given 10 mg THC exhibited differences in activation; specifically, those given 10 mg THC had greater rostromedial PFC (p = 0.011) and dorsomedial PFC (p = 0.013) activation during CS + E, compared to CS + U.

Fig. 8.

Fig. 8

Open in a new tab

BOLD fMRI activation of the rostromedial and dorsolateral prefrontal cortex during fear renewal at a 1-week follow-up in adults with PTSD given varying doses of THC. *Individuals with PTSD given 10 mg THC exhibited higher rostromedial PFC (top) and dorsomedial PFC (bottom) activation during CS + E. Bar graph values represent peak eigenvariate of the significant cluster. PBO = placebo; PFC = prefrontal cortex

Discussion

The present study investigated the effects of increasing doses of delta-9-tetrahydrocannabinol (THC) on fear learning and memory in adults with posttraumatic stress disorder (PTSD). Our primary interest was determining whether increasing doses of THC would (1) decrease self-report ratings of fear and (2) impact brain activation, in a randomized, double-blind, placebo-controlled sample. We did not find an effect of THC dose on fear (expectancy) ratings but found that different doses of THC impacted neural activation. Specifically, individuals given 5 mg THC had greater prefrontal cortex (PFC) activation during fear renewal, while individuals given 10 mg THC had greater hippocampus and PFC activation at a 1-week follow-up. These findings from a small sample of adults with PTSD suggest that both low and high doses of acute THC, which targets the cannabinoid-1 receptor, can impact fear memory neural activation and extend decades of promising data showing the endocannabinoid (eCB) system as a putative target for fear-based disorder interventions (Mayo et al. 2022; Rabinak and Phan 2014).

The first major study finding was that adults with PTSD given 5 mg of THC exhibited greater PFC and anterior cingulate cortex (ACC) activation during early fear renewal. Fear renewal represents a unique, and understudied, phase of Pavlovian conditioning paradigms, as preventing fear renewal is a cornerstone of first-line therapies for PTSD (Foa 2011). Recent work highlights the dynamic roles of the PFC and ACC in fear renewal. Specifically, the ACC is involved in expression of fear during fear conditioning, but activation of the ACC is also involved in preventing fear renewal (Corcoran and Quirk 2007; Vasquez et al. 2019). Similarly, the dorsomedial and ventromedial PFC are necessary for both extinguishing fear and preventing its renewal. In healthy humans, activation of the dorsomedial PFC mediates lesser fear expression during fear renewal (Åhs et al. 2015). Activation of the ventromedial PFC is most often associated with successful extinction recall, but activation during fear renewal is now recognized as an integral component of preventing fear renewal. Greater resting-state functional connectivity of the ventromedial PFC is predictive of lesser fear renewal, suggesting that greater task-based activation of the ventromedial PFC may also reflect lesser fear renewal in our sample of adults with PTSD (Lissek and Tegenthoff 2021). We previously reported that administering 7.5 mg of THC in adults with PTSD also increases ventromedial PFC activation during fear renewal (Zabik et al. 2023). The PFC has a high density of CB1Rs (Burns et al. 2007; Marsicano and Lutz 1999; Tsou et al. 1998). Low doses of THC, like those administered in the present study, preferentially bind to, and therefore inhibit, glutamatergic neurons that mediate fear and anxiety responses (Rey et al. 2012; Steindel et al. 2013). Thus, the activation reported in the present study may reflect prevailing activation of neurons associated with non-fear responses. Notably, the difference in activation we report is within those given 5 mg of THC, 24 h after drug administration. Dynamic engagement of brain regions during fear renewal is important for processing the context and stimuli, which were previously associated with an unconditioned stimulus (US; snake). Thus, while no differences were detected between drug groups, activation differences in the PFC suggests that those given 5 mg of THC were likely displaying lesser fear renewal. We did not find differences in expectancy ratings, which may reflect the different processes captured by expectancy ratings (cognitive appraisal) and neuroimaging data (emotional and cognitive processes). However, those given 5 mg of THC, overall, had qualitatively lesser fear expectancy during fear renewal. Together, greater activation of the ACC and PFC during fear renewal in those given 5 mg of THC suggests that low dose THC can decrease fear renewal outside of an acute drug state.

The second major study finding was that adults with PTSD given 10 mg of THC exhibited greater hippocampus and PFC activation at a one-week follow-up visit. Specifically, those given 10 mg of THC exhibited greater hippocampus during late extinction recall and greater PFC activation to the previously extinguished cue during fear renewal. Extinction recall is highly dependent on activation of the hippocampus, and administration of THC into the hippocampus facilitates extinction recall (Segev and Akirav 2011). Interestingly, individuals given 10 mg of THC had greater hippocampus activation compared to those given 5 mg of THC, suggesting that higher doses of THC may be more beneficial for longer-term changes in the hippocampus. Assessing brain activation within 24 h and one-week of acute THC administration revealed a unique finding: individuals given 10 mg of THC showed greater PFC activation at the one-week follow-up, which contrasts with those given 5 mg of THC showing greater PFC activation within 24 h of administration. This represents an important time- and dose-dependent brain response, where lower doses of THC may be beneficial for acute brain changes, while higher doses of THC may be more beneficial for sustained brain changes. Recent preclinical research also shows a similar time-dependent behavioral pattern: animals given vaped THC prior to fear conditioning display no fear renewal two weeks later (Lightfoot et al., n.d.). While administering THC at a different time, these data further suggest the importance of determining the impact of THC on fear learning and memory beyond a 24-hour window. The differential brain response related to timing and dosing reported herein has implications for THC-assisted psychotherapy: lower doses of THC could facilitate corticolimbic brain changes when there are shorter times between psychotherapy sessions, while higher doses would facilitate brain changes when there are longer times between psychotherapy sessions. Further, the time- and dose-dependent brain responses reported in this study highlight the importance of investigating drug interventions beyond the acute effects of the drug, especially as it relates to fear memory processes.

Limitations of this study warrant mention. First, the study sample size was modest. The present study is one of the first to test a dose-dependent response of THC in adults with PTSD using a Pavlovian conditioning paradigm. Thus, these results are an important step towards larger studies that may have greater power to detect more differences between drug groups, as our study only detected differences within drug groups. Second, we collected blood concentrations of THC but were unable to collect enough data to test secondary hypotheses relating THC blood concentrations to fear expectancy and/or brain activation during the task. In healthy adults and those with PTSD, increased eCB levels predict extinction recall success (Crombie et al. 2021; Mayo et al. 2020a; Mayo, Asratian, Mayo et al. 2020a, b). However, the relation between blood concentration of THC and extinction recall success has not yet been determined. Future work will benefit from collecting blood samples, not only to determine a THC-extinction relation, but also to prevent individual metabolic variability from influencing behavioral or neural outcomes (Dean and Kane 2020; Wall et al. 1983). Finally, we report on a single acute dose of THC and its effects on fear learning and memory over a 1-week period. In clinical application, it would be more likely that patients with PTSD would receive multiple doses of THC throughout their therapeutic intervention (i.e., prior to each therapy session). While we report tolerable effects of acute, oral doses of THC in this report and prior work (Rabinak et al. 2013, 2014; Zabik et al. 2023b), it is unclear whether these doses would be tolerable in successive exposure therapy sessions. Our group is currently testing the effect of repeated, oral, low-dose THC (7.5 mg) prior to exposure therapy in adults with PTSD (NCT04080427).

These findings suggest that an oral, low dose of THC impacts corticolimbic activation in adults with PTSD beyond the acute effects of THC. Our results extend prior data, in healthy adults and those with PTSD, demonstrating that low dose THC can affect neural activation both shortly after an acute dose of THC, and up to one-week afterwards. Overall, these data further add to the literature that cannabinoid-based interventions for trauma-related disorders may have promising, positive effects on exposure-based therapies by facilitating activation of corticolimbic brain regions necessary for extinction recall and preventing fear renewal.

Supplementary Material

Supplemental

Acknowledgements

The authors thank all the individuals who generously shared their time and effort to participate in this research. We thank Kaitlyn Clough, a 3D artist (https://kmclough.artstation.com), for helping C.A.R. and C.P. create the contextual environments and discrete stimuli (messenger bags and animated snake) for the Pavlovian conditioning paradigm. N.L.Z and C.A.R. greatly thank Dr. Ana M. Daugherty for her statistical guidance in the early phases of the project.

Funding

This work was supported by the National Institute of Mental Health awarded to CAR (Award #R61MH111935). NLZ is supported by the National Institute of Mental Health (Award #F31MH124279). This work was also supported by the “Mental Health Initiative in Stress and Trauma” chair program at the University of Calgary to MNH.

Footnotes

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00213-024-06702-w.

Conflicts of interest None to disclose.

References

  1. Åhs F, Kragel PA, Zielinski DJ, Brady R, LaBar KS (2015) Medial prefrontal pathways for the contextual regulation of extinguished fear in humans. NeuroImage 122:262–271. 10.1016/j.neuroimage.2015.07.051 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (5th ed.) (2013) American Psychiatric Association. 10.1016/B978-0-12-809324-5.05530-9 [DOI] [Google Scholar]
  3. Baglot SL, Hume C, Petrie GN, Aukema RJ, Lightfoot SHM, Grace LM, Zhou R, Parker L, Rho JM, Borgland SL, McLaughlin RJ, Brechenmacher L, Hill MN (2021) Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats. Sci Rep 11(1):23990. 10.1038/S41598-021-03242-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berretta S, Pantazopoulos H, Caldera M, Pantazopoulos P, Paré D (2005) Infralimbic cortex activation increases c-Fos expression in intercalated neurons of the amygdala. Neuroscience 132(4):943–953. 10.1016/j.neuroscience.2005.01.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bitencourt RM, Pamplona FA, Takahashi RN (2008) Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur Neuropsychopharmacol 18(12):849–859. 10.1016/j.euroneuro.2008.07.001 [DOI] [PubMed] [Google Scholar]
  6. Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Hargreaves RJ (2007) [18F] MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci USA 104(23):9800–9805. 10.1073/PNAS.0703472104 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chhatwal JP, Davis M, Maguschak KA, Ressler KJ (2005) Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30(3):516–524. 10.1038/sj.npp.1300655 [DOI] [PubMed] [Google Scholar]
  8. Chhatwal JP, Stanek-Rattiner L, Davis M, Ressler KJ (2006) Amygdala BDNF signaling is required for consolidation but not encoding of extinction. Nat Neurosci 9(7):870–872. 10.1038/nn1718 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Corcoran KA, Quirk GJ (2007) Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J Neuroscience: Official J Soc Neurosci 27(4):840–844. 10.1523/JNEUROSCI.5327-06.2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Crombie KM, Sartin-Tarm A, Sellnow K, Ahrenholtz R, Lee S, Matalamaki M, Almassi NE, Hillard CJ, Koltyn KF, Adams TG, Cisler JM (2021) Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: preliminary evidence from a randomized controlled trial. Psychoneuroendocrinology 132:105355. 10.1016/j.psyneuen.2021.105355 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dean L, Kane M (2020) Dronabinol therapy and CYP2C9 genotype. Med Genet Summ [PubMed] [Google Scholar]
  12. First MB, Spitzer RL, Gibbon ML, Williams JBW (2002) Structured clinical interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition [Google Scholar]
  13. Foa EB (2011) Prolonged exposure therapy: past, present, and future. Depress Anxiety 28(12):1043–1047. 10.1002/da.20907 [DOI] [PubMed] [Google Scholar]
  14. Foa EB, Dancu CV, Hembree EA, Jaycox LH, Meadows EA, Street GP (1999) A comparison of exposure therapy, stress inoculation training, and their combination for reducing posttraumatic stress disorder in female assault victims. J Consult Clin Psychol 67(2):194–200. 10.1037/0022-006X.67.2.194 [DOI] [PubMed] [Google Scholar]
  15. Foa EB, Hembree EA, Rothbaum BO (2007) Prolonged exposure therapy for PTSD: Emotional processing of traumatic experiences: Therapist guide. In Treatments that work [Google Scholar]
  16. Fredrikson M (1983) Reliability and validity of some specific fear questionnaires. Scand J Psychol 24(1):331–334. 10.1111/j.1467-9450.1983.tb00507.x [DOI] [PubMed] [Google Scholar]
  17. Friston KJ, Fletcher P, Josephs O, Holmes A, Rugg MD, Turner R (1998) Event-related fMRI: characterizing differential responses. NeuroImage 7(1):30–40. 10.1006/nimg.1997.0306 [DOI] [PubMed] [Google Scholar]
  18. Fullana MA, Albajes-Eizagirre A, Soriano-Mas C, Vervliet B, Cardoner N, Benet O, Radua J, Harrison BJ (2018) Fear extinction in the human brain: a meta-analysis of fMRI studies in healthy participants. Neuroscience and Biobehavioral Reviews, vol 88. Elsevier Ltd, pp 16–25. 10.1016/j.neubiorev.2018.03.002 [DOI] [PubMed] [Google Scholar]
  19. Gunduz-Cinar O, MacPherson KP, Cinar R, Gamble-George J, Sugden K, Williams B, Godlewski G, Ramikie TS, Gorka AX, Alapafuja SO, Nikas SP, Makriyannis A, Poulton R, Patel S, Hariri AR, Caspi A, Moffitt TE, Kunos G, Holmes A (2013) Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18(7):813–823. 10.1038/MP.2012.72 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hembree EA, Foa EB, Dorfan NM, Street GP, Kowalski J, Tu X (2003) Do patients Drop out prematurely from exposure therapy for PTSD? J Trauma Stress 16(6):555–562. 10.1023/B:JOTS.0000004078.93012.7d [DOI] [PubMed] [Google Scholar]
  21. Ji J, Maren S (2007) Hippocampal involvement in contextual modulation of fear extinction. Hippocampus 17(9):749–58 10.1002/hipo.20331 [DOI] [PubMed] [Google Scholar]
  22. Ji J, Maren S (2008) Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear. Learn Memory 15(4):244–251. 10.1101/lm.794808 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Johanson CE, Uhlenhuth EH (1980) Drug preference and mood in humans: diazepam. Psychopharmacology 71(3):269–273. 10.1007/BF00433061 [DOI] [PubMed] [Google Scholar]
  24. Klorman R, Weerts TC, Hastings JE, Melamed BG, Lang PJ (1974) Psychometric description of some specific-fear questionnaires. Behav Ther 5(3):401–409. 10.1016/S0005-7894(74)80008-0 [DOI] [Google Scholar]
  25. Kuhnert S, Meyer C, Koch M (2013) Involvement of cannabinoid receptors in the amygdala and prefrontal cortex of rats in fear learning, consolidation, retrieval and extinction. Behav Brain Res 250:274–284. 10.1016/j.bbr.2013.05.002 [DOI] [PubMed] [Google Scholar]
  26. Lieberman MD, Cunningham WA (2009) Type I and type II error concerns in fMRI research: re-balancing the scale. Soc Cognit Affect Neurosci 4(4):423–428. 10.1093/scan/nsp052 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lightfoot SHM, Nastase AS, Lenz Cesar C, Gom G, Teskey RCC, G., Hill MN (under review ). Acute and chronic cannabis vapor produces immediate and delayed impacts on phases of fear learning in a sex specific manner. Psychopharmacology [DOI] [PubMed] [Google Scholar]
  28. Lin Y, Zhu M, Su Z (2015) The pursuit of balance: an overview of covariate-adaptive randomization techniques in clinical trials. Contemp Clin Trials 45:21–25. 10.1016/j.cct.2015.07.011 [DOI] [PubMed] [Google Scholar]
  29. Lissek S, Tegenthoff M (2021) Higher functional connectivity between prefrontal regions and the dorsal attention network predicts absence of renewal. Behav Brain Res 412:113413. 10.1016/J.BBR.2021.113413 [DOI] [PubMed] [Google Scholar]
  30. Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11(12):4213–4225. 10.1046/j.1460-9568.1999.00847.x [DOI] [PubMed] [Google Scholar]
  31. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascioll MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418(6897):530–534. 10.1038/nature00839 [DOI] [PubMed] [Google Scholar]
  32. Mayo LM, Asratian A, Lindé J, Holm L, Nätt D, Augier G, Stensson N, Vecchiarelli HA, Balsevich G, Aukema RJ, Ghafouri B, Spagnolo PA, Lee FS, Hill MN, Heilig M (2020a) Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Mol Psychiatry 25(5):993–1005. 10.1038/s41380-018-0215-1 [DOI] [PubMed] [Google Scholar]
  33. Mayo LM, Asratian A, Lindé J, Morena M, Haataja R, Hammar V, Augier G, Hill MN, Heilig M (2020b) Elevated anandamide, enhanced Recall of fear extinction, and attenuated stress responses following inhibition of fatty acid Amide Hydrolase: a Randomized, controlled Experimental Medicine Trial. Biol Psychiatry 87(6):538–547. 10.1016/j.biopsych.2019.07.034 [DOI] [PubMed] [Google Scholar]
  34. Mayo LM, Rabinak CA, Hill MN, Heilig M (2022) Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation? Biol Psychiatry 91(3):262–72 10.1016/j.biopsych.2021.07.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420(6911):70–74. 10.1038/nature01138 [DOI] [PubMed] [Google Scholar]
  36. Milad MR, Quirk GJ, Pitman RK, Orr SP, Lischl B, Rauch SL (2007a) A role for the Human Dorsal Anterior Cingulate Cortex in fear expression. Biol Psychiatry 62(10):1191–1194. 10.1016/j.biopsych.2007.04.032 [DOI] [PubMed] [Google Scholar]
  37. Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL (2007b) Recall of fear extinction in humans activates the Ventromedial Prefrontal Cortex and Hippocampus in Concert. Biol Psychiatry 62(5):446–454. 10.1016/j.biopsych.2006.10.011 [DOI] [PubMed] [Google Scholar]
  38. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK (2008) Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res 42(7):515–520. 10.1016/j.jpsychires.2008.01.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP, Rauch SL (2009) Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry. 10.1016/j.biopsych.2009.06.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Öhman A (2005) The role of the amygdala in human fear: automatic detection of threat. Psychoneuroendocrinology 30(10):953–958. 10.1016/j.psyneuen.2005.03.019 [DOI] [PubMed] [Google Scholar]
  41. Pamplona FA, Bitencourt RM, Takahashi RN (2008) Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats. Neurobiol Learn Mem 90(1):290–293. 10.1016/j.nlm.2008.04.003 [DOI] [PubMed] [Google Scholar]
  42. Pape H-C, Pare D (2010) Plastic synaptic networks of the Amygdala for the Acquisition, expression, and extinction of conditioned fear. Physiol Rev 90(2):419. 10.1152/PHYSREV.00037.2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Paré D, Smith Y (1993) The intercalated cell masses project to the central and medial nuclei of the amygdala in cats. Neuroscience 57(4):1077–1090. 10.1016/0306-4522(93)90050-P [DOI] [PubMed] [Google Scholar]
  44. Rabinak CA, Phan K (2014) Cannabinoid modulation of fear extinction brain circuits: a novel target to advance anxiety treatment. Curr Pharm Design 20(13):2212–2217. 10.2174/13816128113199990437 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rabinak CA, Angstadt M, Sripada CS, Abelson JL, Liberzon I, Milad MR, Phan KL (2013) Cannabinoid facilitation of fear extinction memory recall in humans. Neuropharmacology 64(1):396–402. 10.1016/j.neuropharm.2012.06.063 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rabinak CA, Angstadt M, Lyons M, Mori S, Milad MR, Liberzon I, Phan L,K (2014) Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. Neurobiol Learn Mem 113:125–134. 10.1016/j.nlm.2013.09.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rey AA, Purrio M, Viveros MP, Lutz B (2012) Biphasic effects of cannabinoids in anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacol 2012 37(12):2624–2634. 10.1038/npp.2012.123. 37 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rothbaum BO, Astin MC, Marsteller F (2005) Prolonged exposure versus Eye Movement Desensitization and Reprocessing (EMDR) for PTSD rape victims. J Trauma Stress 18(6):607–616. 10.1002/jts.20069 [DOI] [PubMed] [Google Scholar]
  49. Segev A, Akirav I (2011) Differential effects of cannabinoid receptor agonist on social discrimination and contextual fear in amygdala and hippocampus. Learn Memory 18(4):254–259. 10.1101/lm.2110511 [DOI] [PubMed] [Google Scholar]
  50. Sheehan DV, Lecrubier Y, Sheehan H, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): The Development and Validation of a Structured Diagnostic Psychiatric Interview for DSM-IV and ICD-10. J Clin Psychiatry [PubMed] [Google Scholar]
  51. Steindel F, Lerner R, Häring M, Ruehle S, Marsicano G, Lutz B, Monory K (2013) Neuron-type specific cannabinoid-mediated G protein signalling in mouse hippocampus. J Neurochem 124(6):795–807. 10.1111/JNC.12137 [DOI] [PubMed] [Google Scholar]
  52. Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83(2):393–411. 10.1016/S0306-4522(97)00436-3 [DOI] [PubMed] [Google Scholar]
  53. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15(1):273–289. 10.1006/nimg.2001.0978 [DOI] [PubMed] [Google Scholar]
  54. Vasquez JH, Leong KC, Gagliardi CM, Harland B, Apicella AJ, Muzzio IA (2019) Pathway specific activation of ventral hippocampal cells projecting to the prelimbic cortex diminishes fear renewal. Neurobiol Learn Mem 161:63. 10.1016/J.NLM.2019.03.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wachtel S, ElSohly M, Ross S, Ambre J, De Wit H (2002) Comparison of the subjective effects of Δ9-tetrahydrocannabinol and marijuana in humans. Psychopharmacology 161(4):331–339. 10.1007/s00213-002-1033-2 [DOI] [PubMed] [Google Scholar]
  56. Wall ME, Sadler BM, Brine D, Taylor H, Perez-Reyes M (1983) Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther 34(3):352–363. 10.1038/CLPT.1983.179 [DOI] [PubMed] [Google Scholar]
  57. Weathers FW, Blake DD, Schnurr PP, Kaloupek DG, Marx BP, Keane TM (2013) Life Events Checklist for DSM-5 (LEC-5) [Google Scholar]
  58. Weathers FW, Bovin MJ, Lee DJ, Sloan DM, Schnurr PP, Kaloupek DG, Keane TM, Marx BP (2018) The clinician-administered ptsd scale for DSM-5 (CAPS-5): development and initial psychometric evaluation in military veterans. Psychol Assess. 10.1037/pas0000486 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Worsley KJ, Friston KJ (1995) Analysis of fMRI time-series revisited—again. NeuroImage 2(3):173–181. 10.1006/nimg.1995.1023 [DOI] [PubMed] [Google Scholar]
  60. Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ, Evans AC (1996) A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 4(1):58–73. https://pubmed.ncbi.nhn.nih.gov/20408186/ [DOI] [PubMed] [Google Scholar]
  61. Zabik NL, Iadipaolo AS, Marusak HA, Peters C, Burghardt K, Rabinak CA (2022) A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults. J Neurosci Res 100(3):744–761. 10.1002/jnr.24860 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Zabik NL, Peters C, Iadipaolo A, Marusak HA, Rabinak CA (2023a) Comparison of behavioral and brain indices of fear renewal during a standard vs. novel immersive reality pavlovian fear extinction paradigm in healthy adults. Behav Brain Res 437. 10.1016/j.bbr.2022.114154 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Zabik NL, Rabinak CA, Peters CA, Iadipaolo A (2023b) Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder. Neurobiol Learn Mem 201. 10.1016/J.NLM.2023.107758 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental
NIHMS2046481-supplement-Supplemental.docx (2.3MB, docx)

RESOURCES