A single dose of cannabidiol modulates medial temporal and striatal function during fear processing in people at clinical high risk for psychosis

 Translational Psychiatry“Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe.

Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach.

During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups.

These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.”

https://pubmed.ncbi.nlm.nih.gov/32921794/

“This study is the first to demonstrate that a single dose of CBD modulates activation of the medial temporal cortex and striatum during fear processing in CHR patients. In showing that CBD modulates function of the neural circuitry directly implicated in psychosis onset, these results add to previous evidence that CBD may be a promising novel therapeutic for patients at CHR. Our results also support further investigation of the potential utility of CBD outside of the CHR field in other populations, such as in those with anxiety.”

https://www.nature.com/articles/s41398-020-0862-2

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Endocannabinoid-Epigenetic Cross-Talk: A Bridge toward Stress Coping

ijms-logo“There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive.

Environmental stress challenges individuals’ equilibrium, enhancing homeostatic request in the attempt to steer down arousal-instrumental molecular pathways that underlie hypervigilance and anxiety.

A relevant homeostatic pathway is the endocannabinoid system (ECS).

In this review, we summarize recent discoveries unambiguously listing ECS as a stress coping mechanism.

As stress evokes huge excitatory responses in emotional-relevant limbic areas, the ECS limits glutamate release via 2-arachydonilglycerol (2-AG) stress-induced synthesis and retrograde cannabinoid 1 (CB1)-receptor activation at the synapse. However, ECS shows intrinsic vulnerability as 2-AG overstimulation by chronic stress rapidly leads to CB1-receptor desensitization.

In this review, we emphasize the protective role of 2-AG in stress-response termination and stress resiliency. Interestingly, we discuss ECS regulation with a further nuclear homeostatic system whose nature is exquisitely epigenetic, orchestrated by Lysine Specific Demethylase 1.

We here emphasize a remarkable example of stress-coping network where transcriptional homeostasis subserves synaptic and behavioral adaptation, aiming at reducing psychiatric effects of traumatic experiences.”

https://pubmed.ncbi.nlm.nih.gov/32872402/

https://www.mdpi.com/1422-0067/21/17/6252

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Meet Your Stress Management Professionals: The Endocannabinoids

Trends in Molecular Medicine (@TrendsMolecMed) | Twitter“The endocannabinoid signaling system (ECSS) is altered by exposure to stress and mediates and modulates the effects of stress on the brain.

Considerable preclinical data support critical roles for the endocannabinoids and their target, the CB1 cannabinoid receptor, in the adaptation of the brain to repeated stress exposure.

Chronic stress exposure increases vulnerability to mental illness, so the ECSS has attracted attention as a potential therapeutic target for the prevention and treatment of stress-related psychopathology.

We discuss human genetic studies indicating that the ECSS contributes to risk for mental illness in those exposed to severe stress and trauma early in life, and we explore the potential difficulties in pharmacological manipulation of the ECSS.”

https://pubmed.ncbi.nlm.nih.gov/32868170/

https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(20)30177-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1471491420301775%3Fshowall%3Dtrue

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Effects of ∆ 9-tetrahydrocannabinol on aversive memories and anxiety: a review from human studies

Medscape | BMC Psychiatry - Content Listing“Posttraumatic stress disorder (PTSD) may stem from the formation of aberrant and enduring aversive memories. Some PTSD patients have recreationally used Cannabis, probably aiming at relieving their symptomatology.

Here, we seek to review and discuss the effects of THC on aversive memory extinction and anxiety in healthy humans and PTSD patients.

Results: At low doses, THC can enhance the extinction rate and reduce anxiety responses. Both effects involve the activation of cannabinoid type-1 receptors in discrete components of the corticolimbic circuitry, which could couterbalance the low “endocannabinoid tonus” reported in PTSD patients. The advantage of associating CBD with THC to attenuate anxiety while minimizing the potential psychotic or anxiogenic effect produced by high doses of THC has been reported. The effects of THC either alone or combined with CBD on aversive memory reconsolidation, however, are still unknown.

Conclusions: Current evidence from healthy humans and PTSD patients supports the THC value to suppress anxiety and aversive memory expression without producing significant adverse effects if used in low doses or when associated with CBD. Future studies are guaranteed to address open questions related to their dose ratios, administration routes, pharmacokinetic interactions, sex-dependent differences, and prolonged efficacy.”

https://pubmed.ncbi.nlm.nih.gov/32842985/

“Altogether, the findings encourage future controlled studies evaluating the effects of low doses of THC to attenuate aversive/traumatic memory expression in PTSD patients.”

https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-020-02813-8

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Experiences With Medical Cannabis in the Treatment of Veterans With PTSD: Results From a Focus Group Discussion

 European Neuropsychopharmacology“Posttraumatic stress disorder (PTSD) is an often chronic condition for which currently available medications have limited efficacy.

Medical cannabis is increasingly used to treat patients with PTSD; however, evidence for the efficacy and safety of cannabinoids is scarce. To learn more about patients’ opinions on and experiences with medical cannabis, we organized a focus group discussion among military veterans (N = 7) with chronic PTSD who were treated with medical cannabis. Afterwards, some of their partners (N = 4) joined the group for an evaluation, during which they shared their perspective on their partner’s use of medical cannabis.

Both sessions were audio-recorded, transcribed verbatim, and analyzed by means of qualitative content analysis. Five overarching themes were identified. The first four themes related to the different phases of medical cannabis use – namely, 1) Consideration; 2) Initiation; 3) Usage; and 4) Discontinuation. The fifth theme related to several general aspects of medical cannabis use.

Patients used medical cannabis to manage their symptoms and did not experience an urge to “get high.” They used a variety of different cannabis strains and dosages and reported several therapeutic effects, including an increased quality of sleep. Furthermore, discussions about the experienced stigma surrounding cannabis generated insights with implications for the initiation of medical cannabis use.

These results underscore the value of qualitative research in this field and are relevant for the design of future clinical trials on the use of medical cannabis for the treatment of PTSD.”

https://pubmed.ncbi.nlm.nih.gov/32576481/

“Reported therapeutic effects ranged from reduced anger and irritability to increased sleep quality and reductions in nightmares and night sweats.”

https://www.sciencedirect.com/science/article/pii/S0924977X20301280?via%3Dihub

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Cannabidiol Disrupts Conditioned Fear Expression and Cannabidiolic Acid Reduces Trauma-Induced Anxiety-Related Behaviour in Mice

Behavioural Pharmacology (journal) - Wikipedia“The major phytocannabinoid cannabidiol (CBD) has anxiolytic properties and lacks tetrahydrocannabinol-like psychoactivity. Cannabidiolic acid (CBDA) is the acidic precursor to CBD, and this compound appears more potent than CBD in animal models of emesis, pain and epilepsy. In this short report, we aimed to examine whether CBDA is more potent than CBD in disrupting expression of conditioned fear and generalised anxiety-related behaviour induced by Pavlovian fear conditioning. Mice underwent fear conditioning and 24 h later were administered CBD and CBDA before testing for fear expression and generalized anxiety-like behaviour. We found that CBD and CBDA had dissociable effects; while CBD but not CBDA disrupted cued fear memory expression, CBDA but not CBD normalized trauma-induced generalized anxiety-related behaviour. Neither phytocannabinoid affected contextual fear expression. Our findings form the basis for future experiments examining whether phytocannabinoids, alone and in combination, are effective in these mouse models of fear and anxiety.”

https://pubmed.ncbi.nlm.nih.gov/32483052/

https://journals.lww.com/behaviouralpharm/Abstract/9000/Cannabidiol_disrupts_conditioned_fear_expression.99176.aspx

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Chronic Psychosocial Stress Causes Increased Anxiety-Like Behavior and Alters Endocannabinoid Levels in the Brain of C57Bl/6J Mice.

View details for Cannabis and Cannabinoid Research cover image“Chronic stress causes a variety of physiological and behavioral alterations, including social impairments, altered endocrine function, and an increased risk for psychiatric disorders. Thereby, social stress is one of the most effective stressful stimuli among mammals and considered to be one of the major risk factors for the onset and progression of neuropsychiatric diseases.

Although the chronic social defeat stress model has been extensively studied, little is known about the effects of repeated or chronic social defeat stress on the endocannabinoid system (ECS).

The present study aimed to understand the effects of chronic social stress on anxiety behavior and the levels of endocannabinoids (ECs) and two N-acylethanolamines (NAEs) in different brain regions of mice.

 

The current study confirms that the ECS plays an essential role in stress responses, whereby its modulation seems to be brain region dependent.”

https://www.ncbi.nlm.nih.gov/pubmed/32322676

https://www.liebertpub.com/doi/10.1089/can.2019.0041

“Deficiency in endocannabinoid signaling in the nucleus accumbens induced by chronic unpredictable stress.” https://www.ncbi.nlm.nih.gov/pubmed/20664582

“Cannabinoids ameliorate impairments induced by chronic stress to synaptic plasticity and short-term memory.” https://www.ncbi.nlm.nih.gov/pubmed/23426383

“Blunted stress reactivity in chronic cannabis users.”  https://link.springer.com/article/10.1007/s00213-017-4648-z?no-access=true

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Cannabinoids as therapeutics for PTSD.

Pharmacology & Therapeutics“Post-traumatic stress disorder (PTSD) is a complex disorder that involves dysregulation of multiple neurobiological systems. The traumatic stressor plays a causal role in producing psychological dysfunction and the pattern of findings suggests that the hypothalamic-pituitary-adrenal (HPA) axis, which is instrumental for stress adaptation, is critically dysfunctional in PTSD. Given the lack of understanding of the basic mechanisms and underlying pathways that cause the disorder and its heterogeneity, PTSD poses challenges for treatment.

Targeting the endocannabinoid (ECB) system to treat mental disorders, and PTSD in particular, has been the focus of research and interest in recent years. The ECB system modulates multiple functions, and drugs enhancing ECB signaling have shown promise as potential therapeutic agents in stress effects and other psychiatric and medical conditions.

In this review, we focus on the interaction between the ECB-HPA systems in animal models for PTSD and in patients with PTSD. We summarize evidence supporting the use of cannabinoids in preventing and treating PTSD in preclinical and clinical studies. As the HPA system plays a key role in the mediation of the stress response and the pathophysiology of PTSD, we describe preclinical studies suggesting that enhancing ECB signaling is consistent with decreasing PTSD symptoms and dysfunction of the HPA axis.

Overall, we suggest that a pharmacological treatment targeted at one system (e.g., HPA) may not be very effective because of the heterogeneity of the disorder. There are abnormalities across different neurotransmitter systems in the pathophysiology of PTSD and none of these systems function uniformly among all patients with PTSD. Hence, conceptually, enhancing ECB signaling may be a more effective avenue for pharmacological treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/32311373

https://www.sciencedirect.com/science/article/abs/pii/S0163725820300796?via%3Dihub

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2-Arachidonoylglycerol Modulation of Anxiety and Stress Adaptation: From Grass Roots to Novel Therapeutics.

Biological Psychiatry Home“Over the past decade there has been a surge of interest in the development of endocannabinoid-based therapeutic approaches for the treatment of diverse neuropsychiatric conditions. Although initial preclinical and clinical development efforts focused on pharmacological inhibition of fatty acid amide hydrolase to elevate levels of the endocannabinoid anandamide, more recent efforts have focused on inhibition of monoacylglycerol lipase (MAGL) to enhance signaling of the most abundant and efficacious endocannabinoid ligand, 2-arachidonoylglycerol (2-AG). We review the biochemistry and physiology of 2-AG signaling and preclinical evidence supporting a role for this system in the regulation of anxiety-related outcomes and stress adaptation. We review preclinical evidence supporting MAGL inhibition for the treatment of affective, trauma-related, and stress-related disorders; describe the current state of MAGL inhibitor drug development; and discuss biological factors that could affect MAGL inhibitor efficacy. Issues related to the clinical advancement of MAGL inhibitors are also discussed. We are cautiously optimistic, as the field of MAGL inhibitor development transitions from preclinical to clinical and theoretical to practical, that pharmacological 2-AG augmentation could represent a mechanistically novel therapeutic approach for the treatment of affective and stress-related neuropsychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32197779

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(20)30049-4/fulltext

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Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study.

 SpringerLink“Excessive fear and anxiety, coupled with corticolimbic dysfunction, are core features of stress- and trauma-related psychopathology, such as posttraumatic stress disorder (PTSD).

Interestingly, low doses of ∆9-tetrahydrocannabinol (THC) can produce anxiolytic effects, reduce threat-related amygdala activation, and enhance functional coupling between the amygdala and medial prefrontal cortex and adjacent rostral cingulate cortex (mPFC/rACC) during threat processing in healthy adults.

Together, these findings suggest the cannabinoid system as a potential pharmacological target in the treatment of excess fear and anxiety. However, the effects of THC on corticolimbic functioning in response to threat have not be investigated in adults with trauma-related psychopathology.

OBJECTIVE:

To address this gap, the present study tests the effects of an acute low dose of THC on corticolimbic responses to threat in three groups of adults: (1) non-trauma-exposed healthy controls (HC; n = 25), (2) trauma-exposed adults without PTSD (TEC; n = 27), and (3) trauma-exposed adults with PTSD (n = 19).

METHODS:

Using a randomized, double-blind, placebo-controlled, between-subjects design, 71 participants were randomly assigned to receive either THC or placebo (PBO) and subsequently completed a well-established threat processing paradigm during functional magnetic resonance imaging.

RESULTS:

In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling.

CONCLUSIONS:

These preliminary data suggest that THC modulates threat-related processing in trauma-exposed individuals with PTSD, which may prove advantageous as a pharmacological approach to treating stress- and trauma-related psychopathology.”

https://www.ncbi.nlm.nih.gov/pubmed/32162103

https://link.springer.com/article/10.1007%2Fs00213-020-05499-8

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