Category Archives: Anxiety

Maternal obesity induces sex-specific changes in the endocannabinoid system of the hypothalamus and dorsal hippocampus of offspring associated with anxiety-like behavior in adolescent female rats

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“Maternal obesity during perinatal period increases the risk of metabolic and behavioral deleterious outcomes in the offspring, since it is critical for brain development, maturation, and reorganization. These processes are highly modulated by the endocannabinoid system (ECS), which comprises the main lipid ligands anandamide and 2-arachidonoylglycerol, cannabinoid receptors 1 and 2 (CB1R and CB2R), and several metabolizing enzymes.

The ECS is overactivated in obesity and it contributes to the physiological activity of the hypothalamus-pituitary-adrenal (HPA) axis, promoting stress relief. We have previously demonstrated that maternal high-fat diet during gestation and lactation programmed the food preference for fat in adolescent male offspring and adult male and female offspring.

In the present study, we hypothesized that maternal diet-induced obesity would induce sex-specific changes of the ECS in the hypothalamus and dorsal hippocampus of rat offspring associated with dysregulation of the HPA axis and stress-related behavior in adolescence. Rat dams were fed a control (C) or an obesogenic high-fat high-sugar diet (OD) for nine weeks prior to mating and throughout gestation and lactation. Maternal obesity differentially altered the CB1R in the hypothalamus of neonate offspring, with significant increase in male but not in female pups, associated with decreased CB2R prior to obesity development. In adolescence, maternal obesity induced anxiety-like behavior only in adolescent females which was associated with increased content of CB1R in the dorsal hippocampus.

Our findings suggest that the early origins of anxiety disorders induced by maternal exposome is associated with dysregulation of the brain ECS, with females being more susceptible.”

https://pubmed.ncbi.nlm.nih.gov/39362071/

“The prevalence of obesity has reached pandemic proportions worldwide, and it is important to better understand the impact of maternal obesity on offspring metabolic health and susceptibility to neurodevelopmental and neuropsychiatric disorders such as anxiety and depression. In the present study, we used a rat model of maternal diet-induced obesity to explore these interactions. The main findings of this study were that maternal obesogenic diet elicited sex-specific molecular changes on the ECS.”

https://www.sciencedirect.com/science/article/abs/pii/S0018506X24001739?via%3Dihub

Cannabidiol Modulation of Nicotine-Induced Toxicity: Assessing Effects on Behavior, Brain-Derived Neurotrophic Factor, and Oxidative Stress in C57BL/6 Male Mice

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“High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds’ potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward.

Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice.

In this context, the open-field behavioral test was specially conducted to assess CBD’s effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood’s metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function.

Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue’s systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).”

https://pubmed.ncbi.nlm.nih.gov/39297526/

https://onlinelibrary.wiley.com/doi/10.1002/jnr.25384

Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts

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“Interest in medical cannabis and cannabis-based medicinal products (CBMPs) has increased greatly in recent years. Two cannabinoids are of principal importance; delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive component, and also cannabidiol (CBD), considered non-intoxicating. Each has distinct mechanisms of action and different therapeutic potentials. CBMPs differ in their ∆9-THC and CBD components; predominantly ∆9-THC, balanced formulations with equivalent ∆9-THC and CBD elements, and CBD-predominant products.

In this narrative review, we evaluate the published evidence for the clinical benefits of CBMPs and overall benefits in well-being. We also review the overall safety profile and discuss the potential for dependence with CBMPs. Evidence can be drawn from a wide range of randomized and other controlled studies and from observational real-world studies.

Most data from observational registry studies are supportive of ∆9-THC-based products (∆9-THC-predominant or balanced CBMPs) in the management of chronic neuropathic pain. Balanced products are also effective in reducing spasticity in multiple sclerosis. Most CBMPs show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, but the place of specific products is more subtle, and choice guided by specific circumstances. Symptomatic improvements are accompanied by improved quality of life and well-being. Safety data indicate that CBMPs are generally well tolerated in most patients without specific contraindications. The majority of adverse effects are non-serious, and transient; most are principally associated with ∆9-THC and are dose-dependent. In contrast to recreational cannabis use, there is little evidence from clinical studies that CBMPs have any potential for dependence.”

https://pubmed.ncbi.nlm.nih.gov/39096481/

https://link.springer.com/article/10.1007/s40122-024-00643-0

In the weeds: A comprehensive review of cannabis; its chemical complexity, biosynthesis, and healing abilities

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“For millennia, various cultures have utilized cannabis for food, textile fiber, ethno-medicines, and pharmacotherapy, owing to its medicinal potential and psychotropic effects. An in-depth exploration of its historical, chemical, and therapeutic dimensions provides context for its contemporary understanding. The criminalization of cannabis in many countries was influenced by the presence of psychoactive cannabinoids; however, scientific advances and growing public awareness have renewed interest in cannabis-related products, especially for medical use.

Described as a ‘treasure trove,’ cannabis produces a diverse array of cannabinoids and non-cannabinoid compounds. Recent research focuses on cannabinoids for treating conditions such as anxiety, depression, chronic pain, Alzheimer’s, Parkinson’s, and epilepsy. Additionally, secondary metabolites like phenolic compounds, terpenes, and terpenoids are increasingly recognized for their therapeutic effects and their synergistic role with cannabinoids. These compounds show potential in treating neuro and non-neuro disorders, and studies suggest their promise as antitumoral agents. This comprehensive review integrates historical, chemical, and therapeutic perspectives on cannabis, highlighting contemporary research and its vast potential in medicine.”

https://pubmed.ncbi.nlm.nih.gov/39056093/

https://www.sciencedirect.com/science/article/pii/S2214750024000684?via%3Dihub

Effects of Medical Cannabis Treatment for Autistic Children on Anxiety and Restricted and Repetitive Behaviors and Interests: An Open-Label Study

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“Background: The literature supports the benefits of medical cannabis for core and comorbid symptoms in autistic individuals and anxiety-related symptoms in individuals without autism. However, no study has specifically investigated how cannabidiol (CBD)-rich cannabis affects anxiety subtypes in autistic children or its relationship with restricted and repetitive behaviors and interests (RRBI). Understanding the effects of CBD-rich cannabis treatment on anxiety subtypes and RRBI could offer more precise treatment approaches to managing anxiety symptoms and reducing RRBI frequency in autistic children. 

Objectives: To examine (1) the impact of CBD-rich cannabis treatment on autistic children’s (1a) anxiety levels and subtypes and (1 b) RRBI and subtypes and (2) whether changes in anxiety explain changes in RRBI following cannabis treatment. 

Method: In this open-label study, we analyzed data from 65 autistic children (5-12 years) who had participated in research on the effects of CBD-rich cannabis on children with autism. Their parents completed the Repetitive Behavior Scale-revised to assess the frequency and severity of six subgroups of their children’s recurrent behaviors and the Screen for Child Anxiety-Related Emotional Disorders for symptoms related to five types of anxiety disorders. They completed these assessments at three time points: (T1) before treatment, (T2) after 3 months, and (T3) after 6 months of treatment. 

Results: The results indicated reduced RRBI and symptoms related to various anxiety subtypes in autistic children following 6 months of CBD-rich cannabis treatment. Specifically, we observed significant differences in the autistic children’s overall anxiety and in some anxiety subtypes (i.e., general, social, panic, and separation anxieties). Significant improvements were observed in RRBI, including the total score, and specifically in compulsive, ritualistic, and sameness behaviors. Our findings revealed that reduced anxiety, particularly within the panic- and separation-related subtypes, predicted a subsequent decrease in RRBI, specifically sameness behaviors, following cannabis treatment. 

Conclusions: The findings of the cannabis treatment’s potential benefits for alleviating anxiety symptoms, leading to reduced RRBI, may provide evidence for the meaningful relationship between these variables and for the potential benefits of cannabis treatment for autistic children. We strongly recommend further double-blind, placebo-controlled studies using standardized assessments to validate these findings.”

https://pubmed.ncbi.nlm.nih.gov/39047052/

https://www.liebertpub.com/doi/10.1089/can.2024.0001

The anxiolytic effects of cannabinoids: A comprehensive review

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“Cannabinoids, notably cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), have emerged as promising candidates for anxiety disorder treatment, supported by both preclinical and clinical evidence.

CBD exhibits notable anxiolytic effects with a favourable safety profile, though concerns regarding mild side effects and drug interactions remain. Conversely, THC, the primary psychoactive compound, presents a range of side effects, underscoring the importance of careful dosage management and individualized treatment strategies. So far there are no FDA approved cannabinoid medications for anxiety. The review highlights challenges in cannabinoid research, including dosage variability, variable preclinical data, and limited long-term data.

Despite these limitations, cannabinoids represent a promising avenue for anxiety management, with the potential for further optimization in formulation, dosing protocols, and consideration of interactions with conventional therapies. Addressing these challenges could pave the way for novel and personalized approaches to treating anxiety disorders using cannabinoid-based therapies.”

https://pubmed.ncbi.nlm.nih.gov/39032530/

“Cannabinoids have promising anxiolytic effects and favourable safety profile compared to contemporary anxiolytics.”

https://www.sciencedirect.com/science/article/abs/pii/S0091305724001229?via%3Dihub

Cannabidiol in anxiety disorders: Current and future perspectives

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“Anxiety disorders are highly prevalent psychiatric disorders, characterized by a chronic course and often accompanied by comorbid symptoms that impair functionality and decrease quality of life. Despite advances in basic and clinical research in our understanding of these disorders, currently available pharmacological options are associated with limited clinical benefits and side effects that frequently lead to treatment discontinuation. Importantly, a significant number of patients do not achieve remission and live with lifelong residual symptoms that limit daily functioning.

Since the 1970s, basic and clinical research on cannabidiol (CBD), a non-psychotomimetic compound found in the Cannabis sativa plant, has indicated relevant anxiolytic effects, garnering attention for its therapeutic potential as an option in anxiety disorder treatment. This chapter aims to review the history of these studies on the anxiolytic effects of CBD within the current understanding of anxiety disorders. It highlights the most compelling current evidence supporting its anxiolytic effects and explores future perspectives for its clinical use in anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/39029985/

“In conclusion, the experimental and clinical use of CBD revealed significant anxiolytic effects. Since initial research in the 1970s, its potential as an anxiolytic agent has been explored by a growing number of studies using different models for anxiety disorders in pre-clinical, clinical and neuroimaging paradigms. This body of research has introduced CBD as a potential option for the treatment of anxiety disorders,”

https://www.sciencedirect.com/science/article/abs/pii/S0074774224000710?via%3Dihub

Cannabidiol effects on fear processing and implications for PTSD: Evidence from rodent and human studies

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“Cannabidiol (CBD) modulates aversive memory and its extinction, with potential implications for treating anxiety- and stress-related disorders. Here, we summarize and discuss scientific evidence showing that CBD administered after the acquisition (consolidation) and retrieval (reconsolidation) of fear memory attenuates it persistently in rats and mice. CBD also reduces fear expression and enhances fear extinction. These effects involve the activation of cannabinoid type-1 (CB1) receptors in the dorsal hippocampus, bed nucleus of stria terminalis, and medial prefrontal cortex, comprising the anterior cingulate, prelimbic, and infralimbic subregions. Serotonin type-1A (5-HT1A) receptors also mediate some CBD effects on fear memory. CBD effects on fear memory acquisition vary, depending on the aversiveness of the conditioning procedure. While rodent findings are relatively consistent and encouraging, human studies investigating CBD’s efficacy in modulating aversive/traumatic memories are still limited. More studies are needed to investigate CBD’s effects on maladaptive, traumatic memories, particularly in post-traumatic stress disorder patients.”

https://pubmed.ncbi.nlm.nih.gov/39029986/

“Rodent studies show that CBD can attenuate fear memories at several stages through its interaction with the endocannabinoid system (CB1 receptors). CBD can also reduce the intensity of fear responses through its interaction with 5-HT1A receptors and enhance the extinction of fear. However, the findings regarding CBD effects on fear memory acquisition are mixed. More research is needed to clarify these discrepancies.”

https://www.sciencedirect.com/science/article/abs/pii/S0074774224000503?via%3Dihub

Acute effects of cannabigerol on anxiety, stress, and mood: a double-blind, placebo-controlled, crossover, field trial

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“Cannabigerol (CBG) is a phytocannabinoid increasing in popularity, with preclinical research indicating it has anxiolytic and antidepressant effects. However, there are no published clinical trials to corroborate these findings in humans.

The primary objective of this study was to examine acute effects of CBG on anxiety, stress, and mood. Secondary objectives were to examine whether CBG produces subjective drug effects or motor and cognitive impairments. A double-blind, placebo-controlled cross-over field trial was conducted with 34 healthy adult participants. Participants completed two sessions (with a one-week washout period) via Zoom. In each, they provided ratings of anxiety, stress, mood, and subjective drug effects prior to double-blind administration of 20 mg hemp-derived CBG or placebo tincture (T0). These ratings were collected again after participants ingested the product and completed an online survey (T1), the Trier Social Stress Test (T2), a verbal memory test and the DRUID impairment app (T3).

Relative to placebo, there was a significant main effect of CBG on overall reductions in anxiety as well as reductions in stress at T1. CBG also enhanced verbal memory relative to placebo. There was no evidence of subjective drug effects or impairment. CBG may represent a novel option to reduce stress and anxiety in healthy adults.”

https://pubmed.ncbi.nlm.nih.gov/39003387/

“In conclusion, results of this double-blind, placebo-controlled, cross-over field trial indicate that 20 mg of hemp-derived CBG reduces subjective ratings of anxiety and stress in healthy cannabis-using adults in the absence of motor or cognitive impairment, intoxication, or other subjective drug effects (e.g., heart palpitations, dry mouth).”

https://www.nature.com/articles/s41598-024-66879-0

Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial

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“Background: Anxiety disorders, an increasingly prevalent global mental health illness, affected approximately 301 million individuals worldwide in 2019. There is an unmet need for the treatment of anxiety disorders, as current therapies are associated with limited response rates, residual symptoms, and adverse effects.

Objectives: To evaluate the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol (CBD) oral solution versus placebo for the treatment of mild to moderate anxiety disorders.

Methods: This phase 3 prospective, randomized, double blind, parallel group, placebo-controlled, 15-week cohort study took place at multiple sites across India. Eligible participants were randomly assigned to one of the two treatment arms (CBD or placebo) in a 1:1 ratio.

Results: 178 participants were randomized to receive CBD (n=89) or placebo (n=89). The study met both primary (GAD-7 and HAM-A scores) and secondary outcomes (CGI-I, CGI-S, PHQ-9 and PSQI scores). The GAD-7 score difference between the end of treatment and baseline for the CBD versus the placebo was -7.02 (S.E: 0.25, 95% CI -7.52; -6.52), p<0.0001. Similarly, the HAM-A score difference at the end of treatment compared to baseline for the CBD versus the placebo was -11.9 (S.E: 0.33, 95% CI -12.6; -11.3), p<0.0001.

Conclusions: Nanodispersible CBD was therapeutically safe with no serious adverse events, well tolerated, and effective for the treatment of mild to moderate anxiety disorders, as well as associated depression and sleep quality disturbances. These results pave way for probable prospective use of nanodispersible CBD formulation for various psychiatry disorders alone or in conjunction with other drugs.”

https://pubmed.ncbi.nlm.nih.gov/38797087/

“Nanodispersible CBD oral solution was effective treating mild to moderate anxiety.”

https://www.sciencedirect.com/science/article/pii/S1876201824001667?via%3Dihub