Category Archives: Post-Traumatic Stress Disorder (PTSD)

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

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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

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

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 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

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

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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

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

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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

Cannabinoids as therapeutics for PTSD.

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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

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

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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

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

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 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

Possible therapeutic applications of cannabis in the neuropsychopharmacology field.

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European Neuropsychopharmacology“Cannabis use induces a plethora of actions on the CNS via its active chemical ingredients, the so-called phytocannabinoids.

These compounds have been frequently associated with the intoxicating properties of cannabis preparations. However, not all phytocannabinoids are psychotropic, and, irrespective of whether they are psychotropic or not, they have also shown numerous therapeutic properties.

These properties are mostly associated with their ability to modulate the activity of an intercellular communication system, the so-called endocannabinoid system, which is highly active in the CNS and has been found altered in many neurological disorders.

Specifically, this includes the neuropsychopharmacology field, with diseases such as schizophrenia and related psychoses, anxiety-related disorders, mood disorders, addiction, sleep disorders, post-traumatic stress disorder, anorexia nervosa and other feeding-related disorders, dementia, epileptic syndromes, as well as autism, fragile X syndrome and other neurodevelopment-related disorders.

Here, we gather, from a pharmacological and biochemical standpoint, the recent advances in the study of the therapeutic relevance of the endocannabinoid system in the CNS, with especial emphasis on the neuropsychopharmacology field. We also illustrate the efforts that are currently being made to investigate at the clinical level the potential therapeutic benefits derived from elevating or inhibiting endocannabinoid signaling in animal models of neuropsychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32057592

https://www.sciencedirect.com/science/article/abs/pii/S0924977X20300365?via%3Dihub

Nightmares and the Cannabinoids.

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“The cannabinoids, δ9 tetrahydrocannabinol and its analogue, nabilone, have been found to reliably attenuate the intensity and frequency of post-traumatic nightmares.

This essay examines how a traumatic event is captured in the mind after just a single exposure and repeatedly replicated during the nights that follow.

The adaptive neurophysiological, endocrine and inflammatory changes that are triggered by the trauma and that alter personality and behavior are surveyed. These adaptive changes, once established, can be difficult to reverse. But cannabinoids, uniquely, have been shown to interfere with all of these post-traumatic somatic adaptations.

While cannabinoids can suppress nightmares and other symptoms of the post-traumatic stress disorder, they are not a cure. There may be no cure.

The cannabinoids may best be employed, alone, but more likely in conjunction with other agents, in the immediate aftermath of a trauma to mitigate or even abort the metabolic changes which are set in motion by the trauma and which may permanently alter the reactivity of the nervous system. Steps in this direction have already been taken.”

https://www.ncbi.nlm.nih.gov/pubmed/31934840

http://www.eurekaselect.com/178302/article

Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus.

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Image result for Springer Link“The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals.

OBJECTIVES:

This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception.

METHODS:

A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH.

RESULTS:

The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH.

CONCLUSION:

These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.”

https://www.ncbi.nlm.nih.gov/pubmed/31919563

https://link.springer.com/article/10.1007%2Fs00213-019-05435-5

“panicolytic: That reduces the flight reflex in animals when faced with danger. Any drug that has this effect.” https://en.wiktionary.org/wiki/panicolytic