Potential Utility of Cannabidiol in Stress-Related Disorders

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“Background: The endocannabinoid (eCB) system plays an important role in homeostatic regulation of anxiety and stress responses; however, the eCB system can be disrupted following traumatic stressors. Additionally, traumatic or chronic stressors that occur during adulthood or early life can cause long-lasting disturbances in the eCB system. These alterations interfere with hypothalamic-pituitary-adrenal axis function and may be involved in lifelong increased fear and anxiety behaviors as well as increased risk for development of post-traumatic stress disorder (PTSD). 

Methods: This review focuses on the implications of trauma and significant stressors on eCB functionality and neural pathways, both in adolescence and into adulthood, as well as the current state of testing for CBD efficacy in treating pediatric and adult patients suffering from stress-induced eCB dysregulation. Articles were searched via Pubmed and included studies examining eCB modulation of stress-related disorders in both clinical settings and preclinical models. 

Conclusion: Given the potential for lifelong alterations in eCB signaling that can mediate stress responsiveness, consideration of pharmaceutical or nutraceutical agents that impact eCB targets may improve clinical outcomes in stress-related disorders. However, caution may be warranted in utilization of medicinal cannabinoid products that contain delta-9-tetrahydrocannabinol due to pronounced euphorigenic effects and potential to exacerbate stress-related behaviors. Other cannabinoid products, such as cannabidiol (CBD), have shown promise in reducing stress-related behaviors in pre-clinical models. Overall, pre-clinical evidence supports CBD as a potential treatment for stress or anxiety disorders resulting from previously stressful events, particularly by reducing fearful behavior and promoting extinction of contextual fear memories, which are hallmarks of PTSD. However, very limited clinical research has been conducted examining the potential effectiveness of CBD in this regard and should be examined further.”

https://pubmed.ncbi.nlm.nih.gov/36409719/

https://www.liebertpub.com/doi/10.1089/can.2022.0130

Regulation of DNA Methylation by Cannabidiol and Its Implications for Psychiatry: New Insights from In Vivo and In Silico Models

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“Cannabidiol (CBD) is a non-psychotomimetic compound present in cannabis sativa. Many recent studies have indicated that CBD has a promising therapeutic profile for stress-related psychiatric disorders, such as anxiety, schizophrenia and depression. Such a diverse profile has been associated with its complex pharmacology, since CBD can target different neurotransmitter receptors, enzymes, transporters and ion channels. However, the precise contribution of each of those mechanisms for CBD effects is still not yet completely understood. Considering that epigenetic changes make the bridge between gene expression and environment interactions, we review and discuss herein how CBD affects one of the main epigenetic mechanisms associated with the development of stress-related psychiatric disorders: DNA methylation (DNAm). Evidence from in vivo and in silico studies indicate that CBD can regulate the activity of the enzymes responsible for DNAm, due to directly binding to the enzymes and/or by indirectly regulating their activities as a consequence of neurotransmitter-mediated signaling. The implications of this new potential pharmacological target for CBD are discussed in light of its therapeutic and neurodevelopmental effects.”

https://pubmed.ncbi.nlm.nih.gov/36421839/

https://www.mdpi.com/2073-4425/13/11/2165

Cannabinoid Treatments for Anxiety: A Systematic Review and Consideration of the Impact of Sleep Disturbance

Neuroscience & Biobehavioral Reviews

“Cannabidiol’s (CBD) safety profile and broad action has made it a popular treatment option for anxiety and co-occurring sleep disturbance. However, its efficacy in healthy and clinical populations, treatment duration, formulation and doses for optimal therapeutic benefits remains unclear. Selected databases were examined from inception to October 2022. Study selection, data extraction and Cochrane Risk of Bias assessments were conducted according to PRISMA guidelines and registered on the PROSPERO database (CRD42021247476) with 58 full-text studies meeting the eligibility criteria and administered CBD only or with Δ-9-tetrahydrocannabinol (THC) across healthy and clinical populations. In healthy populations and certain non-cannabis using clinical populations, CBD had greater anxiolytic effects without prominent effects on sleep. An inverted U-shaped dose relationship, and CBD ratio to THC in combined treatments likely moderated these effects. Mechanistically, observed CBD effects occurred via primary modulation of the endocannabinoid system and secondary regulation of neuroendocrine function. Additional research is needed to understand CBD mechanisms of action across diverse groups.”

https://pubmed.ncbi.nlm.nih.gov/36370842/

https://www.sciencedirect.com/science/article/abs/pii/S0149763422004304?via%3Dihub

Clinical and cognitive improvement following full-spectrum, high-cannabidiol treatment for anxiety: open-label data from a two-stage, phase 2 clinical trial

Communications Medicine

“Background: Evidence suggests cannabidiol (CBD) has anxiolytic properties, indicating potential for novel treatment strategies. However, few clinical trials of CBD-based products have been conducted, and none thus far have examined the impact of these products on cognition.

Methods: For the open-label stage of clinical trial NCT02548559, autoregressive linear modeling assessed efficacy and tolerability of four-weeks of 1 mL t.i.d. treatment with a full-spectrum, high-CBD sublingual solution (9.97 mg/mL CBD, 0.23 mg/mL Δ-9-tetrahydrocannabinol) in 14 outpatients with moderate-to-severe anxiety, defined as ≥16 on the Beck Anxiety Inventory (BAI) or ≥11 on the Overall Anxiety Severity and Impairment Scale (OASIS).

Results: Findings suggest significant improvement on primary outcomes measuring anxiety and secondary outcomes assessing mood, sleep, quality of life, and cognition (specifically executive function) following treatment. Anxiety is significantly reduced at week 4 relative to baseline (BAI: 95% CI = [-21.03, -11.40], p < 0.001, OASIS: 95% CI = [-9.79, -6.07], p < 0.001). Clinically significant treatment response (≥15% symptom reduction) is achieved and maintained as early as week 1 in most patients (BAI = 78.6%, OASIS = 92.7%); cumulative frequency of treatment responders reached 100% by week 3. The study drug is well-tolerated, with high adherence/patient retention and no reported intoxication or serious adverse events. Minor side effects, including sleepiness/fatigue, increased energy, and dry mouth are infrequently endorsed.

Conclusions: Results provide preliminary evidence supporting efficacy and tolerability of a full-spectrum, high-CBD product for anxiety. Patients quickly achieve and maintain symptom reduction with few side effects. A definitive assessment of the impact of this novel treatment on clinical symptoms and cognition will be ascertained in the ongoing double-blind, placebo-controlled stage.”

https://pubmed.ncbi.nlm.nih.gov/36352103/

“Cannabidiol (CBD) is a compound found within the Cannabis sativa plant. Previous studies suggest CBD may reduce anxiety. In this clinical trial, 14 patients with anxiety were treated for four-weeks with a cannabis-derived study product with high levels of CBD, administered under their tongue 3 times each day. All patients knew that they were being given CBD. Following four weeks of treatment, patients reported reduced anxiety as well as improvements in mood, sleep, quality of life, and measures reflecting their self-control and ability to think flexibly. Patients did not experience any serious negative effects during the trial. The impact of this product is now being evaluated in more patients with anxiety.”

https://www.nature.com/articles/s43856-022-00202-8

” Flower Power”: Controlled Inhalation of THC-Predominant Cannabis Flos Improves Health-Related Quality of Life and Symptoms of Chronic Pain and Anxiety in Eligible UK Patients

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“In November 2018, the UK’s Home Office established a legal route for eligible patients to be prescribed cannabis-based products for medicinal use in humans (CBPMs) as unlicensed medicines. These include liquid cannabis extracts for oral administration (“oils”) and dried flowers for inhalation (“flos”). Smoking of CBPMs is expressly prohibited. To date, THC-predominant cannabis flowers remain the most prescribed CBPMs in project Twenty21 (T21), the first multi-center, prospective, observational UK cannabis patient registry. This observational, prospective data review analyzes patient-reported outcome measures (PROMS) collected by T21 associated with the inhalation of KHIRON 20/1, the most prescribed CBPM in the project. PROMS collected at baseline and at subsequent 3-month follow-up included health-related quality of life (HRQoL), general mood, and sleep. Condition-specific measures of illness severity were performed with the Brief Pain Inventory Short Form (BPI-SF) and the Generalized Anxiety Disorder 7-Item Scale (GAD-7). Participants (N = 344) were mostly males (77.6%, average age = 38.3) diagnosed mainly with chronic pain (50.9%) and anxiety-related disorders (25.3%). Inhalation of KHIRON 20/1 was associated with a marked increase in self-reported HRQoL, general mood, and sleep (N = 344; p < 0.001). Condition-specific assessments showed significant improvements in pain severity (T = 6.67; p < 0.001) and interference (T = 7.19; p < 0.001) in patients using KHIRON 20/1 for chronic pain (N = 174). Similar results were found for patients diagnosed with anxiety-related disorders (N = 107; T = 12.9; p < 0.001). Our results indicate that controlled inhalation of pharmaceutical grade, THC-predominant cannabis flos is associated with a significant improvement in patient-reported pain scores, mood, anxiety, sleep disturbances and overall HRQoL in a treatment-resistant clinical population.”

https://pubmed.ncbi.nlm.nih.gov/36289837/

“Our results indicate that controlled inhalation of pharmaceutical grade, THC-predominant cannabis flos was associated with a robust improvement in patient-reported pain scores, general mood, anxiety, sleep, and overall HRQoL in a treatment-resistant clinical population.”

https://www.mdpi.com/2227-9059/10/10/2576/htm

The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence

“Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10-50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether “low-dose” CBD products confer any therapeutic benefits. This is an important question to answer, as low-dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ9 -tetrahydrocannabinol content greater than 2.0%.

Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300-400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti-addiction effects in drug-dependent individuals. More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., <300 mg/day) oral doses of CBD.”

https://pubmed.ncbi.nlm.nih.gov/36259271/

https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.13425

Cannabidiol as a personalized treatment for anxiety: clinical cases in Mexico

Drugs in Context

“Anxiety-related disorders are one of the most common mental health issues worldwide. Mexico has reported an increase in the prevalence of these ailments secondary to the confinement derived from the COVID-19 pandemic. Given the limitations of commonly used treatments for these disorders, a need arises to develop new pharmacological treatments for these patients. This paper has the primary objective of evaluating the efficacy and safety of cannabidiol isolate in drug compounding used as a personalized treatment in patients with anxiety disorders through the presentation of four clinical cases.”

https://pubmed.ncbi.nlm.nih.gov/36188636/

Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats

Psychological Medicine

“Background: Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses.

Methods: As socially stressful events pose particular challenges at developmental stages, this research applied the resident-intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms.

Results: Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling.

Conclusions: Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD’s relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.”

https://pubmed.ncbi.nlm.nih.gov/36065905/

https://www.cambridge.org/core/journals/psychological-medicine/article/abs/social-stress-under-bingelike-alcohol-withdrawal-in-adolescence-evidence-of-cannabidiol-effect-on-maladaptive-plasticity-in-rats/0A68E4159FDCAF5592BD10DEC4DAC9F8

Cannabidiol impairs fear memory reconsolidation in female rats through dorsal hippocampus CB1 but not CB2 receptor interaction

European Neuropsychopharmacology

“Women present increased susceptibility to anxiety- and stress-related disorders compared to men. A potentially promising pharmacological-based strategy to regulate abnormal aversive memories disrupts their reconsolidation stage after reactivation and destabilization.

Male rodent findings indicate that cannabidiol (CBD), a relatively safe and effective treatment for several mental health conditions, can impair the reconsolidation of aversive memories. However, whether and how CBD influences it in females is still unknown.

The present study addressed this question in contextually fear-conditioned female rats.

We report that systemically administered CBD impaired their reconsolidation, reducing freezing expression for over a week. This action was restricted to a time when the reconsolidation presumably lasted (< six hours post-retrieval) and depended on memory reactivation/destabilization. Moreover, the impairing effects of CBD on memory reconsolidation relied on the activation of cannabinoid type-1 but not type-2 receptors located in the CA1 subregion of the dorsal hippocampus.

CBD applied directly to this brain area was sufficient to reproduce the effects of systemic CBD treatment. Contextual fear memories attenuated by CBD did not show reinstatement, an extinction-related feature. By demonstrating that destabilized fear memories are sensitive to CBD and how it hinders mechanisms in the DH CA1 that may restabilize them in female rats, the present findings concur that reconsolidation blockers are viable and could be effective in disrupting abnormally persistent and distressing aversive memories such as those related to posttraumatic stress disorder.”

https://pubmed.ncbi.nlm.nih.gov/36049316/

https://www.sciencedirect.com/science/article/abs/pii/S0924977X22008367?via%3Dihub

Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice

SpringerLink

“The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis.

In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models.

This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice’s chronic consumption of a high-refined carbohydrate (HC) diet.

BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF).

The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet.

Our data reinforced the harmful effects of the HC diet’s chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.”

https://pubmed.ncbi.nlm.nih.gov/36040711/

https://link.springer.com/article/10.1007/s11011-022-01071-9