Category Archives: Anxiety

Cannabidiol abrogates cue-induced anxiety associated with normalization of mitochondria-specific transcripts and linoleic acid in the nucleus accumbens shell

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“Anxiety disorders are one of the top contributors to psychiatric burden worldwide. Recent years have seen a dramatic rise in the potential anxiolytic properties ascribed to cannabidiol (CBD), a non-intoxicating constituent of the Cannabis Sativa plant.

This has led to several clinical trials underway to examine the therapeutic potential of CBD for anxiety disorders. Yet, CBD’s anxiolytic effects are mixed with some studies reporting little to no impact on trait anxiety but significant reductions in pathological anxiety with suggestions that CBD’s effect may relate to triggered or cue-induced behavior.

Here, we studied the effects of CBD on cued and non-cued behaviors and related neurobiological underpinnings. To investigate the effect of CBD on cue-induced anxiety, male rats underwent a fear conditioning protocol (odor associated with shock) followed by assessments of avoidance behavior. CBD (10 mg/kg) was administered 1 h prior to anxiety assessments. To understand molecular mechanisms associated with behavior, we investigated the transcriptome and lipid profile of the nucleus accumbens shell (NAcSh), a structure implicated in cue-mediated behaviors and aversion.

Administration of CBD significantly reduced avoidance behavior, but only in animals repeatedly exposed to a shock-paired cue. CBD did not affect behavior in animals exposed to neutral cue or encoding of the cue behavioral response. RNA sequencing revealed substantial impact of the shock-paired cue in control animals, recruiting mechanisms ranging from cytoskeletal dynamics to mitochondria dysfunction. The shock-paired cue also resulted in elevated linoleic acid in vehicle animals which correlated with anxiety-like behavior. CBD either reversed or normalized these cue-induced molecular phenotypes. CBD also recruited lipid networks which correlated with transcripts involved in synaptic plasticity, signaling, and epigenetic mechanisms.

These results suggest that CBD may specifically alleviate salient, conditioned anxiety and normalize related biological mechanisms in the NAcSh which may guide therapeutic interventions for anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/39815058/

https://www.nature.com/articles/s41380-024-02881-2

An Unexpected Activity of a Minor Cannabinoid: Cannabicyclol (CBL) Is a Potent Positive Allosteric Modulator of Serotonin 5-HT1A Receptor

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“Cannabicyclol ((±)-CBL), a minor phytocannabinoid, is largely unexplored, with its biological activity previously undocumented. We studied its conversion from cannabichromene (CBC) using various acidic catalysts. Montmorillonite (K30) in chloroform at room temperature had the highest yield (60%) with minimal byproducts. Key reaction conditions, such as solvent, temperature, and time, significantly impacted the yield. The structure of (±)-CBL was confirmed via X-ray crystallography. Stability studies showed that (±)-CBL and its MCT oil dilution remain stable at 25-40 °C for three months. Radioligand binding assays revealed high affinity of CBL for the 5-HT1A receptor but weak interaction with CB1 and CB2 receptors. At 10 μM and 1 μM, (±)-CBL inhibited [3H]-8-hydroxy-DPAT binding to 5-HT1A by 75% and 20%, respectively. Functional assays showed that (±)-CBL acts as a weak agonist at high concentrations but a potent positive allosteric modulator of serotonin-induced activation at low concentrations. At 4 μM, (±)-CBL increased serotonin-induced β-arrestin recruitment from 20% to 80%. This unique modulatory profile highlights the potential of (±)-CBL in drug discovery targeting serotonin receptors.”

https://pubmed.ncbi.nlm.nih.gov/39811943/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.4c00977

“Positive allosteric modulators of the 5-HT1A receptor can help relieve anxiety and depression.”

CBD and the 5-HT1A receptor: A medicinal and pharmacological review

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“Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms.

It has the ability to bind multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD’s pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated.

This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling.

A comprehensive survey of the literature underscores CBD’s multifaceted neurotherapeutic effects, encompassing antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR.

Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.”

https://pubmed.ncbi.nlm.nih.gov/39778776/

“Cannabis was one of the first inhaled drugs utilized by humans, with evidence of use for gout, rheumatism, and malaria dating to 2737 BCE”

“The concurrent literature revealed that CBD produces several therapeutic effects through its complex pharmacodynamic interactions with 5-HT1AR. Therapeutic applications of CBD, including its anxiolytic, antidepressant, antipsychotic, anti-degenerative, neuroprotective, anti-epileptic, and anti-addictive properties were mediated, at least in part, by its binding to 5-HT1AR.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225000048?via%3Dihub

Cannabidiol for Scan-Related Anxiety in Women With Advanced Breast Cancer: A Randomized Clinical Trial

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“Importance: Early evidence from studies outside of oncology has suggested that cannabidiol (CBD) may have anxiolytic effects without neuropsychiatric risks. An understanding of oral CBD in patients with cancer-related anxiety is urgently needed.

Objective: To determine whether a single 400-mg oral dose of a US Food and Drug Administration-approved CBD improves clinical anxiety in an oncologic population.

Design, setting, and participants: This phase II, double-masked, placebo-controlled, randomized clinical trial was performed at the Dana-Farber Cancer Institute’s Breast Oncology Center from November 2, 2021, through March 1, 2023. Women aged 18 years or older with advanced breast cancer and baseline clinical anxiety were included.

Interventions: Patients were randomized 1:1 to receive oral CBD, 400 mg, vs placebo within 48 hours before a scan assessing tumor burden.

Main outcomes and measures: The primary end point was a between-arm comparison of change scores on the afraid subscale of the Visual Analog Mood Scale (VAMS) before and 2 to 4 hours after study drug ingestion. The VAMS scores were converted to T-scores to facilitate interpretation of mood change (>20 indicates a reliable change, >30 indicates both a reliable and clinically significant change). Exploratory outcomes included between-arm comparisons of anxiety levels 2 to 4 hours after study drug ingestion, between-arm comparisons of change scores on other VAMS subscales, and safety.

Results: Among the 50 participants, 25 were randomized to the placebo arm (mean [range] age, 57 [37-81] years) and 25 were randomized to the CBD arm (mean [range] age, 60 [30-79] years). The primary end point of VAMS afraid subscale change score, although numerically greater in the CBD arm, was not significantly different between arms (mean [SD]: CBD, -19.1 [15.4]; placebo, -15.0 [10.9]; P = .37). The secondary outcome directly comparing anxiety levels between arms 2 to 4 hours after study drug ingestion demonstrated significantly lower VAMS afraid T-scores for participants who received CBD compared with those receiving placebo (mean [SD]: CBD, 51.5 [12.8]; placebo, 58.0 [11.6]; P = .02). No grade 3 or 4 toxic effects were reported.

Conclusions and relevance: The findings of this randomized clinical trial show that CBD can be used safely in women with advanced breast cancer and clinical anxiety. Although the study did not meet its primary end point comparing preingestion vs postingestion anxiety change scores between study arms, anxiety levels in the CBD arm were significantly lower 2 to 4 hours after ingestion, suggesting a possible anxiolytic effect and warranting further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39680411/

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2828077

Therapeutic potential of minor cannabinoids in psychiatric disorders: A systematic review

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“Interest in cannabinoids’ therapeutic potential in mental health is growing, supported by evidence of the involvement of the endocannabinoid system in psychiatric disorders such as anxiety, depression, and addiction.

While the major cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have been more extensively researched, approximately 120 minor cannabinoids from the cannabis plant have been identified. Although some displayed promising pharmacological profiles, research on their application for psychiatric disorders is fragmented.

This systematic review evaluates, for the first time, both preclinical and clinical studies exploring minor cannabinoids’ therapeutic potential in psychiatric disorders. 22 preclinical studies and one clinical study were included, investigating various minor cannabinoids in substance use disorders, anxiety disorders, depressive disorders, trauma and stressor-related disorders, psychotic disorders, neurodevelopmental disorders, and eating disorders. Despite the heterogeneous results and the moderate to high risk of bias in several articles, certain compounds demonstrate promise for further investigation.

Δ8-tetrahydrocannabidivarin (Δ8-THCV) exhibited potential for nicotine addiction; Δ9-tetrahydrocannabidivarin (Δ9-THCV) for psychotic-like symptoms; cannabidiolic acid methyl ester (CBDA-ME) alleviated anxiety and depression-like symptoms, and cannabidivarin (CBDV) autism spectrum disorder-like symptoms.”

https://pubmed.ncbi.nlm.nih.gov/39541799/

https://www.sciencedirect.com/science/article/pii/S0924977X24007508?via%3Dihub

Cannabis-Based Phytocannabinoids: Overview, Mechanism of Action, Therapeutic Application, Production, and Affecting Environmental Factors

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“This review provides an overview of cannabis-based phytocannabinoids, focusing on their mechanisms of action, therapeutic applications, and production processes, along with the environmental factors that affect their quality and efficacy.

Phytocannabinoids such as THC (∆9-tetrahydrocannabinol), CBD (cannabidiol), CBG (cannabigerol), CBN (cannabinol), and CBC (cannabichromene) exhibit significant therapeutic potential in treating various physical and mental health conditions, including chronic pain, epilepsy, neurodegenerative diseases, skin disorders, and anxiety.

The cultivation of cannabis plays a crucial role in determining cannabinoid profiles, with indoor cultivation offering more control and consistency than outdoor methods. Environmental factors such as light, water, temperature, humidity, nutrient management, CO2, and the drying method used are key to optimizing cannabinoid content in inflorescences.

This review outlines the need for broader data transfer between the health industry and technological production, especially in terms of what concentration and cannabinoid ratios are effective in treatment. Such data transfer would provide cultivators with information on what environmental parameters should be manipulated to obtain the required final product.”

https://pubmed.ncbi.nlm.nih.gov/39457041/

“Phytocannabinoids, including THC, CBD, CBG, CBN, and CBC, present broad therapeutic potential in a wide range of physical and mental conditions. They have shown efficacy in treating chronic pain, reducing seizure activity, slowing neurodegenerative processes, psoriasis, acne, loss of appetite, sleep disorders, and psychosis. Dose dependence was notable in most cases, and thus, this requires careful management.”

https://www.mdpi.com/1422-0067/25/20/11258

Effects of Cannabidiol (CBD) on Doxorubicin-Induced Anxiety and Depression-like Behaviors and mRNA Expression of Inflammatory Markers in Rats

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“Background: Post-treatment side effects of chemotherapy can include cognitive deficits commonly known as Chemo-brain. The treatment of patients with Doxorubicin (DOX), one of the most widely used chemotherapeutic drugs in the treatment of cancer, can induce depression, anxiety, and impaired cognitive function. Cannabidiol (CBD) is a non-psychoactive component of Cannabis sativa that has been identified as a possible therapeutic agent against many neurodegenerative disorders, including traumatic brain injury, spinal cord injury, Tau-protein-induced neurodegeneration, and neuropathic pain. Therefore, this study aimed to assess whether oral CBD administration could reduce DOX-induced anxiety and depression-like behaviors and alter the expression of mRNA associated with neuroinflammation. 

Methods: Female Long Evans Hooded rats received intraperitoneal injections of DOX (6 mg/kg) or the vehicle (0.9% saline) once a week for four weeks, followed by oral administration of CBD (10 mg/kg) three times a week for the same period. 

Results: CBD was significantly protective against DOX-induced anxiety and depression-like behaviors, as measured by several behavioral tests. Furthermore, CBD improved DOX-induced alterations in the gene expression of biomarkers of neuroinflammation in the hippocampus and prefrontal cortex. 

Conclusions: This provides insights into future studies on possible mechanisms by which DOX-induced cognitive dysfunction could be alleviated by CBD.”

https://pubmed.ncbi.nlm.nih.gov/39452013/

“In conclusion, this study demonstrated that the chronic, systemic administration of DOX impairs cognitive abilities in rats, increases anxiety and depression-like behaviors, and regulates the expression of genes involved in neuroinflammation. We found that CBD-treated rats had fewer anxiety and depression-like behaviors than rats treated with DOX alone.”

https://www.mdpi.com/2076-3425/14/10/999

Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring

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“Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited.

We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams.

Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma.

CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females.

These findings underscore the persistent influence of maternal obesity on the offspring’s health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.”

https://pubmed.ncbi.nlm.nih.gov/39447736/

“Treatment with cannabidiol rescues anxiety and social disturbances in the offspring.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390824003654?via%3Dihub


Phytocannabinoids restore seizure-induced alterations in emotional behaviour in male rats

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“Epilepsy often presents with severe emotional comorbidities including anxiety and abnormal fear responses which impose a significant burden on, and reduce, quality of life in people living with the disease. Our lab has recently shown that kindled seizures lead to changes in emotional processing resulting from the downregulation of anandamide signalling within the amygdala.

Phytocannabinoids derived from the Cannabis sativa plant have attracted a lot of interest as a new class of drugs with potential anticonvulsant effects.

Among the wide number of compounds occurring in Cannabis sativa, Δ9- tetrahydrocannabinol (THC), the one responsible for its main psychoactive effects, and the nonpsychoactive cannabidiol (CBD) have been extensively examined under pre-clinical and clinical contexts to control seizures, however, neither have been assessed in the context of the management of emotional comorbidities associated with seizure activity.

We used two behavioural procedures to assess anxiety- and fear-like responding in adult male Long-Evans rats: elevated plus maze and auditory fear conditioning.

In agreement with previous reports, we found seizure-induced increases in anxiety- and fear-like responding. These effects were reversed by either CBD (vaporized) or THC (oral). We also found that antagonism of serotonin 1 A receptors prior to CBD exposure prevented its protective effects.

Phytocannabinoids offer a novel and reliable opportunity to treat seizure induced comorbid emotional alterations.”

https://pubmed.ncbi.nlm.nih.gov/39433952/

https://www.nature.com/articles/s41386-024-02005-y

Psychiatric comorbidities before and after cannabidiol treatment in adult patients with drug resistant focal epilepsy

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“Cannabidiol oil (CBD) has been approved as an antiseizure medication for the treatment of drug -resistant epilepsy in pediatric patients in 2018 for some special types of epilepsy.

Since this time its use was extended to other forms of epilepsy. However, to date, there are few publications on the use of CBD in adult patients with drug-resistant focal epilepsy and psychiatric comorbidities. We conducted a prospective, observational, open cohort study, with a before-after design, in adult patients, we assessed the effectiveness, dosage, and tolerance of adjunctive CBD treatment.

Our study concluded that CBD was effective and safe.

Our study in line with others examining CBD use in adult patients with drug-resistant epilepsy, omits consideration of psychiatric aspects. The aim of this study was to evaluate, in the same patient population that was part of a previous observational study, depression, quality of life, anxious symptoms and daytime sleepiness before and after CBD treatment.

RESULTS: Forty-four patients were enrolled in the study. Prior to CBD treatment, 50 % of participants exhibited symptoms of depression. Following CBD treatment, 95.4 % of these individuals demonstrated a marked improvement (p = 0.001). Among this cohort, 71.5 % of patients reported minimal or no depressive symptoms post-treatment. Moreover, 68 % of patients experienced an enhancement in their overall quality of life. Comparative analysis of BDI-II and QOLIE-10 scores before and after CBD treatment revealed a statistically significant positive correlation (p < 0.036 and < 0.001, respectively). Improvements in depressive symptoms were found to correspond with enhancements in quality of life. In terms of anxiety symptoms, 54.5 % of patients exhibited such symptoms prior to CBD treatment, with 71 % showing improvement post-treatment.

Adjunctive CBD treatment in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated and associated with significant improvement in depressive symptoms, anxiety and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/39433001/

https://www.epilepsybehavior.com/article/S1525-5050(24)00414-1/abstract