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Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: A preliminary report
Abstract and Figures
Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.
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... For example, anxiety is at least twice as prevalent in those with chronic neck or back pain [34]. Both CBD and THC are both thought to have anxiolytic effects, however clinical studies to date have been limited and of low quality [32,[35][36][37]. The relationship between anxiety and CP is complex and bidirectional, as described by the biopsychosocial model of pain, in which anxiety is both a cause and consequence of CP [38,39]. ...
... However, anxiety marginally increased in the no anxiety cohort. The reduction in anxiety in the anxiety cohort is consistent with the clinical studies also showing reductions in anxiety following CBMP treatment, however these limited studies focused on only social anxiety and used different PROMs compared to this study, so direct comparison is difficult [35,37]. Moreover, it may be expected for anxiety to have decreased for over 50% of the participants who were illicit cannabis users through accessing legal CBMP treatment, due to a reduction in the potential stress and stigma analogous with illicit drug use [21,97,98]. ...
Introduction
There is growing evidence on the efficacy of cannabis-based medicinal products (CBMPs) for chronic pain(CP). Due to the complex interaction between chronic pain and anxiety, and the potential impact of CBMPs on both anxiety and chronic pain, this article aimed to compare the outcomes of CP patients with and without co-morbid anxiety following CBMP treatment.
Methods
Participants were prospectively enrolled in this cohort study and categorized by baseline General Anxiety Disorder-7(GAD-7) scores, into ‘no anxiety’(GAD-7<5) and ‘anxiety’(GAD-7≥5) cohorts. Primary outcomes were changes in Brief Pain Inventory Short-Form, Short-form McGill Pain Questionnaire-2, Pain Visual Analogue Scale, Sleep Quality Scale (SQS), GAD-7 and EQ-5D-5L index values at 1, 3 and 6 months compared to baseline.
Results
1254 patients (anxiety=711; no anxiety=543) met inclusion criteria. Significant improvements in all primary outcomes were observed in both cohorts at all timepoints (p<0.050), except GAD-7 in the no anxiety group(p>0.050). The anxiety cohort reported greater improvements in EQ-5D-5L index values, SQS and GAD-7(p<0.050), but there were no consistent differences in pain outcomes.
Conclusion
A potential association between CBMPs and improvements in pain and health-related quality of life (HRQoL) in CP patients was identified. CP patients with co-morbid anxiety achieved greater improvements in general HRQoL, but not pain-specific outcomes.
... Clinical studies (i.e., placebo-controlled, case-control studies) have shown that CBD is able to decrease social anxiety symptoms and sedation [176] and anxiety and cognitive impairment during speech performance [177], as well as symptoms (i.e., anxiety and cognitive impairments) in post-traumatic stress disorder (PTSD) patients [178][179][180][181]. A recent clinical trial reported significant improvements in anxiety, mood, sleep, and executive functions in patients with moderate-severe anxiety treated with high-CBD/low-THC sublingual solutions (CBD: 9.97 mg/mL, THC: 0.23 mg/mL, 4 weeks). ...
Cannabis is the most used drug of abuse worldwide. It is well established that the most abundant phytocannabinoids in this plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These two compounds have remarkably similar chemical structures yet vastly different effects in the brain. By binding to the same receptors, THC is psychoactive, while CBD has anxiolytic and antipsychotic properties. Lately, a variety of hemp-based products, including CBD and THC, have become widely available in the food and health industry, and medical and recreational use of cannabis has been legalized in many states/countries. As a result, people, including youths, are consuming CBD because it is considered “safe”. An extensive literature exists evaluating the harmful effects of THC in both adults and adolescents, but little is known about the long-term effects of CBD exposure, especially in adolescence. The aim of this review is to collect preclinical and clinical evidence about the effects of cannabidiol.
... The copyright holder for this preprint this version posted March 5, 2023. ; https://doi.org/10.1101/2023.03.02.23286709 doi: medRxiv preprint anxiogenic effects 28-32 of delta-9-tetrahydrocannabinol, the main intoxicating cannabinoid in cannabis, CBD is non-intoxicating and has anxiolytic 33,34 and antipsychotic properties. [35][36][37] CBD modulates brain activation in response to cognitive and emotional fMRI tasks, particularly in medial temporal cortex and striatal regions, in both healthy and established psychosis cohorts. ...
Background
Preclinical and human data suggest that the onset of psychosis involves hippocampal glutamatergic dysfunction, driving hyperactivity/hyperperfusion in a hippocampal-midbrain-striatal circuit. Whether glutamatergic dysfunction is related to cerebral perfusion in patients at Clinical High Risk (CHR) for psychosis, and whether cannabidiol (CBD) has ameliorative effects on glutamate or its relationship with blood flow remains unknown.
Methods
Using a double-blind, parallel-group design, 33 CHR patients were randomised to 600mg CBD or placebo; 19 healthy controls did not receive any drug. Proton magnetic resonance spectroscopy was used to measure glutamate concentrations in left hippocampus. We examined differences relating to CHR status (controls vs placebo), effects of CBD (placebo vs CBD) and linear between-group effects, such that placebo>CBD>controls or controls>CBD>placebo. We also examined group x glutamate x cerebral perfusion (measured using arterial spin labelling) interactions.
Results
Compared to controls, CHR-placebo patients had significantly lower hippocampal glutamate (p=.015) and a significant linear relationship was observed across groups, such that glutamate was highest in controls, lowest in CHR-placebo and intermediate in patients under CBD (p=.031). There was also a significant interaction between group (controls vs CHR-placebo), hippocampal glutamate and perfusion in the putamen and insula (p FWE =.012), driven by a strong positive correlation in the CHR-placebo group vs a negative correlation in controls.
Conclusions
Our findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalised by CBD treatment. Furthermore, we provide the first in vivo evidence of an abnormal relationship between hippocampal glutamate and resting perfusion in the striatum and insula in these patients.
... One trial [61] reported a greater improvement in anxiety, assessed by VAS for mood with 600 mg cannabidiol compared with placebo in 24 patients. In another small double-blinded crossover study, CBD resulted in significantly lower anxiety in 10 patients with SAD [62]. However, these studies were limited by small sample sizes. ...
Purpose
During the treatment of cancer, 18% of patients use cannabis for symptom management. Anxiety, depression, and sleep disturbances are common symptoms in cancer. A systematic review of the evidence for cannabis use for psychological symptoms in cancer patients was undertaken to develop a guideline.
Methods
A literature search of randomized trials and systematic reviews was undertaken up to November 12, 2021. Studies were independently assessed for evidence by two authors and then evaluated by all authors for approval. The literature search involved MEDLINE, CCTR, EMBASE, and PsychINFO databases. Inclusion criteria included randomized control trials and systematic reviews on cannabis versus placebo or active comparator in patients with cancer and psychological symptom management (anxiety, depression, and insomnia).
Results
The search yielded 829 articles; 145 from Medline, 419 from Embase, 62 from PsychINFO, and 203 from CCTR. Two systematic reviews and 15 randomized trials (4 on sleep, 5 on mood, 6 on both) met eligibility criteria. However, no studies specifically assessed the efficacy of cannabis on psychological symptoms as primary outcomes in cancer patients. The studies varied widely in terms of interventions, control, duration, and outcome measures. Six of 15 RCTs suggested benefits (five for sleep, one for mood).
Conclusion
There is no high-quality evidence to recommend the use of cannabis as an intervention for psychological symptoms in patients with cancer until more high-quality research demonstrates benefit.
... Regarding the therapeutic purpose of CBD, its use extends to multiple psychiatric and neurological pathologies. Perhaps the most frequently mentioned therapeutic purpose of CBD is anxiety, its anxiolytic effect being demonstrated in various clinical studies [57][58][59][60][61]. As presented throughout this review, the endocannabinoid system acts as an inhibitor through retrograde signaling at synaptic levels of GABAergic and glutamatergic systems and thus can have both anxiolytic and anxiogenic effects [62,63]. ...
The literature provides scientific evidence for the beneficial effects of cannabidiol (CBD), and these effects extend beyond epilepsy treatment (e.g., Lennox–Gastaut and Dravet syndromes), notably the influence on oxidative status, neurodegeneration, cellular protection, cognitive function, and physical performance. However, products containing CBD are not allowed to be marketed everywhere in the world, which may ultimately have a negative effect on health as a result of the uncontrolled CBD market. After the isolation of CBD follows the discovery of CB1 and CB2 receptors and the main enzymatic components (diacylglycerol lipase (DAG lipase), monoacyl glycerol lipase (MAGL), fatty acid amino hydrolase (FAAH)). At the same time, the antioxidant potential of CBD is due not only to the molecular structure but also to the fact that this compound increases the expression of the main endogenous antioxidant systems, superoxide dismutase (SOD), and glutathione peroxidase (GPx), through the nuclear complex erythroid 2-related factor (Nrf2)/Keep1. Regarding the role in the control of inflammation, this function is exercised by inhibiting (nuclear factor kappa B) NF-κB, and also the genes that encode the expression of molecules with a pro-inflammatory role (cytokines and metalloproteinases). The other effects of CBD on cognitive function and physical performance should not be excluded. In conclusion, the CBD market needs to be regulated more thoroughly, given the previously listed properties, with the mention that the safety profile is a very good one.
... In Parkinson's patients, CBD ameliorated the motor symptoms and also improved the quality of life of these patients [205]. CBD also decreases anxiety in socially anxious individuals [206,207]. In sum, based on the accumulated data so far, CBD seems to have great therapeutic potential without the significant adverse psychoactive effects associated with THC and this is likely due to its multiple mechanisms of action. ...
Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components—tetrahydrocannabinol (THC) and cannabidiol (CBD)—or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.
... Cannabinoids' increased prevalence in consumer products makes them ideal analytes to facilitate student engagement. 29 From their benefit as medical treatments 30,31 to their legalization for recreational use, public interest in cannabis spans diverse student backgrounds and majors. 32 Both cannabidiol (CBD) and tetrahydrocannabinoid (THC) are linked to various topics in pharmacology, toxicology, and forensics. ...
Medicinal and aromatic plants have been one of the most important sources of medicine since the dawn of human civilization. Indigenous communities have used products from these plants in different conditions throughout history. Cannabis sativa L. is one of the most widely employed herbaceous medicinal plants for textiles, and fibers, in medicine, as a source of food, animal food, animal bedding, and agriculture for seeds. This paper highlights the traditional applications, botany, phytochemistry, and pharmacological properties of C. sativa. Extensive database retrieval, such as Google Scholar, Semantic Scholar, ResearchGate, Academia.edu, PubMed, SciFinder, ChemSpider, CNKI, PubFacts was performed using the keywords "Hemp" and "Cannabis," as well as the scientific name of this plant species (Cannabis sativa). Besides, reviews of relevant textbooks, documents, and patents were also employed to collect sufficient information. This study revealed numerous pharmacological activities of C. sativa that could help with several health issues. Additionally, more than 565 bioactive constituents have been isolated and identified from diverse parts of C. sativa. This could help discover potential therapeutic effects and develop new medications to benefit human health. Abstract Cancer is the second leading cause of death worldwide, and due to the emergence of resistance to synthetic drugs in different cancers, developing new green drugs have become crucial. In this study, chitosan nanoparticles containing Cinnamomum verum J.Presl essential oil and cinnamaldehyde (major ingredient) were first prepared. The obtained nanoparticles were then characterized using Dynamic Light Scattering (DLS), Transmission electron microscopy (TEM), and Attenuated Total Reflection-Fourier Transform In-fraRed (ATR-FTIR). After that, anticancer effects of the as-prepared nanoparticles were investigated. IC 50 values of chitosan nanoparticles containing the essential oil were observed at 79 and 112 µg/mL against A-375 and MDA-MB-468 cells, respectively. These values for chitosan nanoparticles containing cinnamaldehyde were obtained at 135 and 166 µg/mL. The results of the current study indicated that chitosan nanoparticles containing C. verum essential oil can inhibit the growth of human melanoma (A-375) and breast cancer (MDA-MB-468) cells.
Cannabidiol (CBD) is a non-psychotropic phytocannabinoid of the plant Cannabis sativa L. CBD is increasingly being explored as an alternative to conventional therapies to treat health disorders in dogs and cats. Mechanisms of action of CBD have been investigated mostly in rodents and in vitro and include modulation of CB1, CB2, 5-HT, GPR, and opioid receptors. In companion animals, CBD appears to have good bioavailability and safety profile with few side effects at physiological doses. Some dog studies have found CBD to improve clinical signs associated with osteoarthritis, pruritus, and epilepsy. However, further studies are needed to conclude a therapeutic action of CBD for each of these conditions, as well as for decreasing anxiety and aggression in dogs and cats. Herein, we summarize the available scientific evidence associated with the mechanisms of action of CBD, including pharmacokinetics, safety, regulation, and efficacy in ameliorating various health conditions in dogs and cats.
Cannabidiol (CBD) is an easily accessible and affordable Marijuana (Cannabis sativa L.) plant derivative with an extensive history of medical use spanning thousands of years. Interest in the therapeutic potential of CBD has increased in recent years, including its anti-tumour properties in various cancer models. In addition to the direct anticancer effects of CBD, preclinical research on numerous cannabinoids, including CBD, has highlighted their potential use in: (i) attenuating chemotherapy-induced adverse effects and (ii) enhancing the efficacy of some anticancer drugs. Therefore, CBD is gaining popularity as a supportive therapy during cancer treatment, often in combination with standard-of-care cancer chemotherapeutics. However, CBD is a biologically active substance that modulates various cellular targets, thereby possibly resulting in unpredictable outcomes, especially in combinations with other medications and therapeutic modalities. In this review, we summarize the current knowledge of CBD interactions with selected anticancer chemotherapeutics, discuss the emerging mechanistic basis for the observed biological effects, and highlight both the potential benefits and risks of such combined treatments. Apart from the experimental and preclinical results, we also indicate the planned or ongoing clinical trials aiming to evaluate the impact of CBD combinations in oncology. The results of these and future trials are essential to provide better guidance for oncologists to judge the benefit-versus-risk ratio of these exciting treatment strategies. We hope that our present overview of this rapidly advancing field of biomedicine will inspire more preclinical and clinical studies to further our understanding of the underlying biology and optimize the benefits for cancer patients.
In-vivo neuroimaging allows the investigation of brain circuits involved in the experience of anxiety and of receptor changes associated with anxiety disorders. This review focuses on studies by research groups who have compared brain activation maps in different forms of anxiety and on binding studies of the benzodiazepine-GABA(A) receptor. Activation studies have revealed the involvement of many brain areas depending on the condition and the paradigm. However, the orbitofrontal cortex/anterior insula and the anterior cingulate are implicated in all the studies and may represent the nodal point between somatic and. cognitive symptoms of any form of anxiety. Most studies of binding at the benzodiazepine-GABA(A) receptor are not interpretable because of substantial methodological problems, however, regional and/or global reductions are the most consistent finding in panic disorder.
1. Despite increased understanding of the prevalence and pharmacotherapy of social phobia (or social anxiety disorder), the neurobiology of the disorder is little understood. 2. Little data exists on the effect of pharmacotherapeutic intervention on regional cerebral blood flow (rCBF) in this disorder. Patients (n=15) who met DSM-IV diagnostic criteria for social phobia were subjected to single photon emission computed tomography (SPECT) with technetium-99m hexamethylpropylene amine oxime (Tc-99m HMPAO) before and after an eight-week trial of pharmacotherapy with the selective serotonin reuptake inhibitor (SSRI) citalopram. 3. Pharmacotherapy led to significantly reduced activity in the anterior and lateral part of the left temporal cortex; the anterior, lateral and posterior part of the left mid frontal cortex; and the left cingulum. 4. Despite the small sample size, medication non-responders (n=6) had higher activity at baseline in the anterior and lateral part of the left temporal cortex and the lateral part of the left mid frontal regions compared with responders (n=9). These data from this exploratory study are consistent with work suggesting that the anxiety disorders share certain mediating neurocircuitry, although activity in other brain regions may differ. 5. Further research is necessary to determine the neurobiological underpinnings of social phobia.
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.