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Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats

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... Recent work in animal models has focused on the effect of CBD on sleep quality and the sleep-wake cycle [32,33]. Chagas and colleagues found an increase in total percentage of sleep in rats after administration of mid-range and highdose CBD injections as compared to placebo. ...
... The effects on REM varied by dosage such that high-dose CBD increased REM sleep latency on the day of administration and midrange dose CBD decreased REM sleep latency the day after administration [33]. Meanwhile, Hsiao and colleagues found that CBD blocked anxiety-induced REM sleep suppression but had no effect on NREM sleep [32]. This work is further supported by a recent case report in which administration of CBD oil reduced insomnia symptoms and PTSD-related sleep disturbances [54•]. ...
... In comparison, medium-and high-dose CBD is sedating [28,30] and has been examined in the context of a number of sleep disorders including insomnia. Here, initial basic research has suggested that medium-/high-dose CBD is associated with an increase in the percentage of total sleep [32,33]. This is supported by a pilot study in humans showing that high-dose CBD was associated with improved sleep [28]; however, when combined with THC may result in a decrease in slow wave sleep [28]. ...
Article
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Purpose of review: The current review aims to summarize the state of research on cannabis and sleep up to 2014 and to review in detail the literature on cannabis and specific sleep disorders from 2014 to the time of publication. Recent findings: Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. Research on cannabis and sleep is in its infancy and has yielded mixed results. Additional controlled and longitudinal research is critical to advance our understanding of research and clinical implications.
... Hsiao et al. [69] employed repeated combination tests (RCT) as a model for progressive anxiety. RCT induced an anxiogenic effect in the elevated plus maze and the open field tests. ...
... Taken together, these preclinical results strongly suggest that exogenous cannabinoids administered in proximity to trauma exposure could prevent the development of PTSD-like symptoms [4,60,66,67,69]. ...
... It has been suggested that using indirect pathways to enhance the endocannabinoid system (e.g. by blocking its enzymatic hydrolysis) will produce a more circumscribed and beneficial spectrum of biological effects than those caused by direct CB1 receptor activation (using THC for example) [6]. In support, clinical and preclinical studies indicate that cannabidiol has anxiolytic properties [69,[88][89][90] and studies blocking FAAH by the specific inhibitor URB597 demonstrate anxiolytic behaviors in a variety of species using different anxiety paradigms [91][92][93][94]. ...
Background According to GLOBOCAN 2018, oral cancer was reported as the second highest cancer prevalent in India. Despite the several therapies available for oral cancer treatment, tumor recurrence and distant metastasis persist. This study investigates the anticancer potential of Persicaria odorata , commonly known as Vietnamese coriander, used widely in traditional systems of medicine for the treatment of inflammation, stomach ailments, tumors, etc. Methods The crude methanolic extract of P. odorata (MPo) was prepared. The anticancer properties of MPo on SAS cells and other human oral squamous cell carcinoma cell line were evaluated using in vitro experimental conditions. The phytochemical constituents present in the MPo were also determined. Results Persicaria odorata possesses antiproliferative, antisurvival, antimetastatic activities, and induced cell cycle arrest in the G2 phase. It inhibited Akt-mammalian target of rapamycin (mTOR) signaling pathway and also downregulated the expression of essential proteins that are involved in tumorigenesis such as cyclin D1, cyclooxygenase 2 (COX2), survivin, matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor-A (VEGF-A). Moreover, the presence of flavonoids and quinones also revealed the anticancer activity of the plant. Conclusion Overall, our study concludes that P. odorata exhibits its anticancer properties through the downregulation of Akt/mTOR signaling pathway in a dose-dependent manner.
... The majority of previous clinical studies have focused on investigating either a high THC, high CBD or balanced THC: CBD product, rather than exploring all three options and identifying which is most effective per medical condition. For example, the scientific evidence for anxiety treatment is primarily derived from the use of investigating high CBD products (26)(27)(28)(29)(30)(31), whereas for pain, the majority of data has been generated from either high THC products [synthetic THC (32)(33)(34) or high THC herbal cannabis (35)(36)(37)] or nabiximols (a balanced THC:CBD product) (15,(38)(39)(40)(41). There is also a disparity between the cannabinoid ratios used in pre-clinical and clinical research that requires further data to address. ...
... There is also a disparity between the cannabinoid ratios used in pre-clinical and clinical research that requires further data to address. For example, PTSD pre-clinical studies have focused on the effects of CBD on PTSD symptoms (42)(43)(44)(45)(46)(47)(48) while clinical studies have reported the efficacy of high THC products or simply "cannabis" in treating PTSD (35,(49)(50)(51). ...
... Of our patients who self-identified as having PTSD, 40% reported that high THC products were most helpful for treating their PTSD. While the research is limited, our findings of a preference for high THC products agree with previously selfreported data (35,81). To date, primarily synthetic THC (manmade chemical compounds rather than THC from cannabis plants) has been investigated as a possible therapy for PTSD. ...
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With the medical use of cannabis permitted in Canada since 2001, patients seek to use this botanical drug to treat a range of medical conditions. However, many healthcare practitioners express the need for further scientific evidence around the use of medical cannabis. This real-world evidence study aimed to address the paucity of scientific data by surveying newly registered medical cannabis patients, before beginning medical cannabis treatment, and at one follow up 6 weeks after beginning medical cannabis treatment. The goal was to collect data on efficacy, safety and cannabis product type information to capture the potential impact medical cannabis had on patient-reported quality of life (QOL) and several medical conditions over a 6-week period using validated questionnaires. The 214 participants were mainly male (58%) and 57% of the population was older than 50. The most frequently reported medical conditions were recurrent pain, post-traumatic stress disorder (PTSD), anxiety, sleep disorders [including restless leg syndrome (RLS)], and arthritis and other rheumatic disorders. Here we report that over 60% of our medical cannabis cohort self-reported improvements in their medical conditions. With the use of validated surveys, we found significant improvements in recurrent pain, PTSD, and sleep disorders after 6 weeks of medical cannabis treatment. Our findings from patients who reported arthritis and other rheumatic disorders are complex, showing improvements in pain and global activity sub-scores, but not overall changes in validated survey scores. We also report that patients who stated anxiety as their main medical condition did not experience significant changes in their anxiety after 6 weeks of cannabis treatment, though there were QOL improvements. While these results show that patients find cannabis treatment effective for a broad range of medical conditions, cannabis was not a remedy for all the conditions investigated. Thus, there is a need for future clinical research to support the findings we have reported. Additionally, while real-world evidence has not historically been utilized by regulatory bodies, we suggest changes in public policy surrounding cannabis should occur to reflect patient reported efficacy of cannabis from real-world studies due to the uniqueness of medical cannabis's path to legalization.
... CBD efficiently stops anxiety-induced REM sleep suppression, but has little effect on the alteration of NREM sleep, possibly due to its anxiolytic effect, rather than through a direct regulation of sleep mechanisms. This is an important result for patients with post-traumatic stress disorder that often complain of having sleep disturbances, such as REM sleep abnormality and insomnia (Hsiao et al., 2012). ...
... Depression Anti-depressant effect in genetic rodent model of depression. El-alfy et al., 2010;Hsiao et al., 2012;Shoval et al., 2016 Cancer Antiproliferative and anti-invasive actions in a large range of cancer types; induction of autophagy-mediated cancer cell death; chemopreventive effects. Ligresti et al., 2006;McAllister et al., 2011;Pisanti et al., 2013;Rocha et al., 2014;Ramer et al., 2014;Scott et al., 2014 Nausea Suppression of nausea and conditioned gaping in rats Parker et al., 2002;Rock et al., 2009 Inflammatory diseases Antinflammatory properties in several in vitro and in vivo models; inhibition of inflammatory cytokines and pathways. ...
Article
Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ(9)-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ(9)-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.
... Anxiety and PTSD are very common psychiatric disorders in the US and are associated with substance use. While cannabis with its THC content has shown to be anxiogenic during intoxication as well as withdrawal, CBD has been discussed to have some anxiolytic potential [42,43]. ...
... In animal models, studies have been performed to show the effect of CBD on the sleep quality as well as the sleep cycle [43]. In rats, studies have shown that high doses of CBD lead to increased total percentage of sleep. ...
Article
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Cannabidiol (CBD) is a substance chemically derived from Cannabis sativa and discussed to be non-psychoactive. According to the FDA, marijuana is classified as a schedule I substance; however, hemp which is defined as extracts from marijuana including cannabinoids containing less than 0.3% tetrahydrocannabinol (THC), is excluded from that controlled substance act and available at local convenience stores in the US as it is seen as an herbal supplement. CBD is purported to be used for various medical and psychiatric conditions: depression, anxiety, post-traumatic stress disorder, Alzheimer's or other cognitive illnesses as well as pain. There is also a new trend to use CBD for the treatment of opioid use disorder. The one CBD product on the market that is FDA approved for the treatment of childhood epilepsy forms Dravet and Lennox-Gastaut syndromes is available under the name Epidiolex. There is a significant difference between this medication and the over-the-counter CBD products that contain very inconsistent strengths of CBD, if they contain it at all, and vary in percentage even from sample to sample. Frequently the so-called CBD products are not containing any CBD at all, but mostly containing THC. This article is a systematic review of literature reviewing the available clinical data on CBD, for use in various medical and psychiatric conditions with focus on a review of the pharmacology and toxicity. Resources used were ORVID, PubMed, MEDLINE, PsychINFO, EMBASE with keywords CBD, cannabidiol, hemp and cannabinoids.
... On the other hand, CBD-induced sedation has been shown both in animal and human studies, supposedly because of a corticotropin releasing hormone (CRH)-related gene downregulation (Lafaye et al., 2018;Russo et al., 2007). In a study using a PTSD-mice model, CBD microinjected in amygdala both reduced anxiety and reversed REM blockage associated with anxiety (Hsiao et al., 2012). However, acute administration of CBD 300 mg in healthy volunteers did not interfere with volunteers' sleep-wake cycle (Linares et al., 2016). ...
Article
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the most represented phytocannabinoids in Cannabis sativa plants. However, CBD may present with a different activity compared with the psychotomimetic THC. Most typically, CBD is reported to be used in some medical conditions, including chronic pain. Conversely, the main aim of this systematic review is to assess and summarise the available body of evidence relating to both efficacy and safety of CBD as a treatment for psychiatric disorders, alone and/or in combination with other treatments. Eligible studies included randomized controlled trials (RCT) assessing the effect of CBD in a range of psychopathological conditions, such as substance use; psychosis, anxiety, mood disturbances, and other psychiatric (e.g., cognitive impairment; sleep; personality; eating; obsessive-compulsive; post-traumatic stress/PTSD; dissociative; and somatic) disorders. For data gathering purposes, the PRISMA guidelines were followed. The initial search strategy identified some n = 1301 papers; n = 190 studies were included after the abstract's screening and n = 27 articles met the inclusion criteria. There is currently limited evidence regarding the safety and efficacy of CBD for the treatment of psychiatric disorders. However, available trials reported potential therapeutic effects for specific psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety. Further large-scale RCTs are required to better evaluate the efficacy of CBD in both acute and chronic illnesses, special categories, as well as to exclude any possible abuse liability.
... Critically, our null findings for the effect of CBD on experimentally induced stress are in contrast to previous findings reporting that CBD attenuated task-induced anxiety (Bergamaschi et al. 2011;Zuardi et al. 1993Zuardi et al. , 2017, and these discrepant findings may be due to the potentially dosedependent nature of CBD's effects. Recent work suggests that CBD may have an inverted U-shaped dose-response curve (Campos and Guimaraes 2008;Freeman et al. 2020;Hsiao et al. 2012;Linares et al. 2019;Zuardi et al. 2017) with best efficacy for human anxiety at 300 mg (Linares et al. 2019;Zuardi et al. 1993Zuardi et al. , 2017 compared to our dose of 600 mg. However, the finding that CBD was able to reduce drug cue-induced craving and anxiety at single doses of 400 mg and 800 mg (Hurd et al. 2019) suggests that our dose of 600 mg still falls within the effective range. ...
Article
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Rationale There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. Objectives We sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. Methods We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during functional magnetic resonance imaging) and cognitive (emotional appraisal) measures as well as subjective response to experimentally induced anxiety. Results CBD did not produce effects on brain responses to emotional faces and cognitive measures of emotional processing, or modulate experimentally induced anxiety, relative to placebo. Conclusions Given the rising popularity of CBD for its putative medical benefits, these findings question whether further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.
... Their results suggest that inactivation of the right or both hippocampi disrupts retrieval in a spatial water maze task. Unilateral microinjections of endocannabinoid-related drugs into the central nucleus of the amygdala (right side) (Hsiao et al., 2012) and ventral hippocampus (right side) (Roohbakhsh et al., 2009) showed effects in behavioral tests. It would also be interesting to test whether activation of the CB1 receptors in the right CA1 impairs memory retrieval. ...
Article
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The endocannabinoid system modulates many brain functions, including episodic memories, which contain memories of time and places. Most studies have focused on the involvement of the endocannabinoid system in spatial memory; however, its role in temporal memory is not well understood. Few studies have tested whether the unilateral endocannabinoid system is sufficient to modulate memory retrieval. Here, we tested whether type 1 cannabinoid receptors in the right hippocampal cornu ammonis area 1 region are enough to modulate the retrieval of episodic memories, specifically their spatial and temporal components. Because rats have innate preferences for displaced or old familiar objects, we changed the locations of "old familiar" and "recent familiar" objects in an open field and measured the rats' exploration times to evaluate spatial and temporal memory. To address the influence of the type 1 cannabinoid receptors on the retrieval of episodic-like memories, two doses of arachidonylcyclopropylamide, a selective type 1 cannabinoid receptor agonist, were infused into the cornu ammonis area 1 of rats ten minutes before the discrimination trials. We observed that rats injected with a low dose of arachidonylcyclopropylamide spent less time investigating displaced objects, suggesting spatial memory impairment, whereas those receiving a high dose explored old familiar objects less frequently, suggesting temporal memory impairment. This indicates that unilateral activation of type 1 cannabinoid receptors in the cornu ammonis area 1 impairs the spatial and temporal aspects of episodic memories. This research mimics the influence of marijuana intoxication effects in humans, such as spatial and temporal disintegration.
... Additionally, cannabidiol has been shown to induce anxiolytic-like effects in rodents (see revision in de Mello Schier et al. 2014), among multiple examples from the literature, following sleep disruption (Hsiao et al. 2012), a prior foot shock (Rock et al. 2017) or the induction of neuropathic pain (de Gregorio et al. 2019). Therefore, the lack of cannabidiol significant effects on modulating anxiety-like behavior, as measured by different features in the open-field test, in adolescent or adult rats, could be explained by the fact that cannabidiol might require the presence of a specific stressor to induce anxiolytic-like effects or that other behavioral tests more specific to measure changes in anxiety-like behavior (i.e., elevated plus maze, novelty-suppressed feeding) are needed to capture cannabidiol anxiolytic-like effects. ...
Article
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RationaleCannabidiol is a non-psychoactive phytocannabinoid with great therapeutic potential in diverse psychiatric disorders; however, its antidepressant potential has been mainly ascertained in adult rats.Objectives To compare the antidepressant-like response induced by cannabidiol in adolescent and adult rats and the possible parallel modulation of hippocampal neurogenesis.Methods Male Sprague-Dawley rats were repeatedly treated with cannabidiol (3, 10, and 30 mg/kg) or vehicle (1 mL/kg) during adolescence (postnatal days, PND 27-33) or adulthood (PND 141-147) and exposed to 3 consecutive tests (forced swim, open field, two-bottle choice) that quantified behavioral despair, anxiety, and sucrose intake respectively.ResultsCannabidiol induced differential effects depending on the age and dose administered, with a decreased sensitivity observed in adolescent rats: (1) cannabidiol (30 mg/kg) decreased body weight only in adult rats; (2) cannabidiol ameliorated behavioral despair in adolescent and adult rats, but with a different dose sensitivity (10 vs. 30 mg/kg), and with a different extent (2 vs. 21 days post-treatment); (3) cannabidiol did not modulate anxiety-like behavior at any dose tested in adolescent or adult rats; and (4) cannabidiol increased sucrose intake in adult rats.Conclusions Our findings support the notion that cannabidiol exerts antidepressant- and anorexigenic-like effects in adult rats and demonstrate a decreased potential when administered in adolescent rats. Moreover, since cannabidiol did not modulate hippocampal neurogenesis (cell proliferation and early neuronal survival) in adolescent or adult rats, the results revealed potential antidepressant-like effects induced by cannabidiol without the need of regulating hippocampal neurogenesis.
... CBD has been reported to show an anxiolytic effect by reducing physiological rapid eye movement (REM) sleep and non-REM (NREM) sleep in normal rats. It has been suggested that this is an important outcome for patients with posttraumatic stress disorder, where sleep disorders such as REM sleep disorder and insomnia are common (42). According to the results obtained from preclinical and clinical studies, CBD also will be a promising treatment option in panic disorder (43). ...
Article
Cannabidiol (CBD) is the second-most common phytocannabinoid found in cannabis plants after tetrahydrocannabinol (THC). Unlike THC, no psychoactive effect has been demonstrated for CBD. Due to its effect on various neurotransmitter systems, it has been tried for the treatment of many physical and psychiatric diseases, considering its neuroprotective and anti-inflammatory properties. In this Editorial, the characteristics of CBD and its place in various psychiatric disorders will be briefly discussed. © 2019 Yerkure Tanitim ve Yayincilik Hizmetleri A.S. All rights reserved.
... In addition to the possibility of CBD affecting different processes involved in aversive memory, animal studies also show favorable effects of this compound in the control of other frequent manifestations of PTSD symptomatology, such as sleep disorders. Studies in rats indicate that CBD may contribute to an increase in sleep duration and depth, and a decrease in anxiety responses induced by sleep disturbance (Monti, 1977;Hsiao et al., 2012;Chagas et al., 2013). In the case of anxiety, another frequent manifestation of PTSD symptomatology, therapeutic potential of CBD has also been reported. ...
Article
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Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects. Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD. Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system. These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well. Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD. The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.
... CBD users exhibited varying levels of sleep quality (Figure 3), however, respondents who consume CBD statistically significantly rated their sleep as 'good' compared to non-CBD users. This is consistent with previous research whereby a clinical study conducted on rats found that CBD in the amygdala reverses REM sleep reduction (Hsiao et al. 2012). Additionally, a case study on a PTSD victim who used CBD oil, found that CBD improved her quality of sleep (Shannon and Opila-Lehman 2016). ...
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Insomnia is becoming a public health concern and costs the country £13.9 billion annually. Stress may induce feelings of anxiety and insomnia. Cannabis contains cannabidiol (CBD) which is thought to have some health benefits, as it can reduce levels of anxiety. However, the use of CBD for therapeutic purposes remains controversial amidst the scientific community. This study aims to investigate attitudes concerning the therapeutic use of CBD for insomnia and stress relief, alongside the relationship between gender and CBD use. A paper-based questionnaire was distributed to 60 Biomedical Science students from Coventry University. The results were analysed through quantitative and qualitative analysis. Of the 60 respondents, there was an equal proportion of both genders. There were 18 CBD users in the respondent pool, more males were found to use CBD products as opposed to females. Respondents stress levels varied, however, more CBD users felt 'very relaxed' compared to non-CBD users. Individuals who consumed CBD were statistically significantly more likely to have a 'good' sleep quality (p=0.049 <0.05) as opposed to non-CBD users. Females were more likely to orally administer CBD as opposed to males, but vaping was the most common administration method for both genders. Females predominantly use CBD for 'stress/anxiety' relief, whereas males primarily expressed 'other' motivations. This study has revealed interesting insights regarding gender differences in use and attitudes towards CBD. These findings may be explained by changes in socio-cultural perception, and gender based neurological or gonadal hormone differences in cannabinoid effects. The results provide cautious optimism that CBD is beneficial for health purposes, particularly as findings regarding sleep quality and CBD usage were consistent with previous research. Whilst CBD business markets continue to thrive, future work is required on a larger pool of human respondents to confirm the health benefits of CBD, and to generalise current findings.
... 65 In pre-clinical studies, CBD has been shown to block anxiety-related rapid eye movement sleep alterations. 66 Observational uncontrolled clinical studies investigating the effects on sleep found CBD (25-300 mg/day) to have positive effects on sleep quality and to decrease sleep disturbances in patients with autism spectrum disorder, 67,68 Parkinson's disease, 69 chronic pain, 70 and in patients with insomnia. 44,71 Again, although the evidence base is of low quality, there is sufficient data to support the hypothesis that CBD would be beneficial in sleep disorders associated with anxiety, which merits testing. ...
Article
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Coronavirus disease-19 (COVID-19)-related anxiety and post-traumatic stress symptoms (PTSS) or post-traumatic stress disorder (PTSD) are likely to be a significant long-term issue emerging from the current pandemic. We hypothesize that cannabidiol (CBD), a chemical isolated from Cannabis sativa with reported anxiolytic properties, could be a therapeutic option for the treatment of COVID-19-related anxiety disorders. In the global over-the counter CBD market, anxiety, stress, depression, and sleep disorders are consistently the top reasons people use CBD. In small randomized controlled clinical trials, CBD (300–800 mg) reduces anxiety in healthy volunteers, patients with social anxiety disorder, those at clinical high risk of psychosis, in patients with Parkinson’s disease, and in individuals with heroin use disorder. Observational studies and case reports support these findings, extending to patients with anxiety and sleep disorders, Crohn’s disease, depression, and in PTSD. Larger ongoing trials in this area continue to add to this evidence base with relevant patient cohorts, sample sizes, and clinical end-points. Pre-clinical studies reveal the molecular targets of CBD in these indications as the cannabinoid receptor type 1 and cannabinoid receptor type 2 (mainly in fear memory processing), serotonin 1A receptor (mainly in anxiolysis) and peroxisome proliferator-activated receptor gamma (mainly in the underpinning antiinflammatory/antioxidant effects). Observational and pre-clinical data also support CBD’s therapeutic value in improving sleep (increased sleep duration/quality and reduction in nightmares) and depression, which are often comorbid with anxiety. Together these features of CBD make it an attractive novel therapeutic option in COVID-related PTSS that merits investigation and testing through appropriately designed randomized controlled trials.
... Similar findings were observed when CBD was injected into the lateral hypothalamus of rats during the lights-on period (Murillo-Rodríguez et al. 2008, 2011a. Recently, Hsiao et al. (2012) reported that CBD blocked anxiety-induced REMS suppression. Lastly, the wake-promoting effects of CBD might engage neurochemicals related to control of waking such as adenosine (Mijangos-Moreno et al. 2014). ...
Chapter
Marijuana is a colloquial name given to Cannabis sativa, which has been used for diverse purposes, including as a therapeutical element for multiple health issues. The neurobiological effects of C. sativa involve a complex biological machinery including receptors, named CB1 and CB2 cannabinoid receptors. These receptors recognize endogenous cannabinoid-like compounds, such as anandamide and 2-arachinonolglycerol which seems to display sleep-inducing properties. Along decades, the study of the putative role of exogenous and endogenous cannabinoids in sleep modulation has brought critical data. Since endocannabinoids have been described in sleep-related brain areas, intriguing issues regarding whether hypothalamic substrates, such as MHC, may be interacting with the endocannabinoids have been raised.
... The relationship of cannabidiol with sleep has had different noted outcomes; low-dose CBD has been found to create a stimulating effect, while high dose CBD has shown to have a sedating effect [17]. Other studies of CBD have been mixed; one study demonstrated that cannabidiol blocked anxiety-induced REM sleep suppression without an effect on NREM sleep [29], while other research found that CBD injections caused an increase in the total percentage of sleep in rats [30]. Meanwhile, administration of THC may promote sleep onset and decrease total REM sleep time. ...
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This review summarizes the available literature on the intersection of adolescent cannabis use and sleep disturbances, along with interventions for adolescent cannabis users who suffer sleep impairments. Adolescents are susceptible to various sleep disorders, which are often exacerbated by the use of substances such as cannabis. The relationship between cannabis and sleep is bidirectional. Interventions to improve sleep impairments among adolescent cannabis users to date have demonstrated limited efficacy, although few studies indicating the benefits of behavioral interventions-such as Cognitive Behavior Therapy for Insomnia or Mindfulness Based Stress Reduction-appear promising in the treatment of sleep disorders, which are present for users of cannabis. Further research is necessary to elucidate the precise mechanisms by which cannabis use coexists with sleep impairments, along with effective interventions for those users who suffer sleep difficulties.
... Cannabis sedativa wird in verschiedenen Kulturen sein Jahrhunderten gegen Schlafstörungen und Schmerzen angewendet [23] und Studien an Nagern zeigen eine CBD-assoziierte Verbesserung des Schlafes durch Blockierung von REM-Schlaf-Alterationen [24] und sowie eine CB1-Rezeptor vermittelte Stabilisierung des Non-REM Schlafes [25]. Bis dahin könnte sich der Arzt auf die unzureichende Datenlage bei Parkinson berufen und eine Verordnung ablehnen. ...
Article
Zusammenfassung In Deutschland können seit März 2017 Patienten mit einer schwerwiegenden Erkrankung Cannabisblüten und -extrakte sowie synthetische Cannabinoide zu Lasten der Krankenkassen verordnet werden. Die Zulassung von medizinischem Cannabis beinhaltet keine Festlegung auf eine Indikation und ist somit auch für Parkinson-Patienten relevant. Laut Gesetz haben schwerbetroffene Patienten sogar einen Anspruch auf Versorgung mit medizinischem Cannabis, wenn übliche Maßnahmen nicht erfolgreich waren oder nicht vertragen wurden oder „eine nicht ganz entfernte Aussicht auf eine spürbare positive Einwirkung auf schwerwiegenden Symptome besteht“. Vor diesem Hintergrund und verstärkt durch Medienberichte fragen zunehmend Parkinson Patienten nach Verordnung von Cannabis. Dies stellt die behandelnden Neurologen vor eine neue Herausforderung. Dieser Artikel gibt einen Überblick über die verschreibungsfähigen Cannabisprodukte und Applikationsformen sowie die Datenlage für Cannabis bei motorischen- und nicht-motorischen Parkinson Symptomen. Ferner werden aus Sicht der Autoren Indikationen definiert, für welche im Einzelfall Cannabis bei Parkinson-Patienten hilfreich sein könnte und ggf. dem Wunsch des Patienten nach Verordnung stattgegeben werden sollte. Es werden praxisrelevante Empfehlungen für die Verordnung von Cannabinoiden sowie die Beratung des Patienten, einschließlich hinsichtlich der Fahrfähigkeit ausgesprochen.
... Besides cannabinoid receptors, CBD also interacts with many other, non-endocannabinoid signaling systems, including theequilibrative nucleoside transporter, the orphan G-protein-coupled receptor GPR55, the transient receptor potential of melastatin type 8 channels, the 5-HT1a receptor, the α3 and α1 glycine receptors, and the transient receptor potential of ankyrin type 1 channel [14]. The multiple mechanistic-targets of CBD make it a unique candidate for treating complex symptoms associated with a tests-induced rapid eye movement sleep suppression, probably through its anxiolytic effect [35]. A case study reported CBD decreased anxiety and improved the quality and quantity of sleep of a ten-year-old girl diagnosed with post-traumatic stress disorder (PTSD) [36]. ...
... 12,13 CBD administered directly into key brain regions reduces anxiety-like behavior in rodents. [14][15][16] CBD may also reduce anxiety and alleviate other neurological disorders by enhancing anandamide through fatty acid amide hydrolase inhibition 17,18 or by altering serotonergic (5-HT) neurotransmission, including actions as an indirect 5-HT1A agonist. 1,[18][19][20][21] In this study, we examined the effects of CBD on responses to negative emotional stimuli in healthy human volunteers. ...
Article
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Introduction: Cannabidiol (CBD) is a nonpsychoactive constituent of whole plant cannabis that has been reported to reduce anxiety-like behaviors in both pre-clinical and human laboratory studies. Yet, no controlled clinical studies have demonstrated its ability to reduce negative mood or dampen responses to negative emotional stimuli in humans. The objective of this study was to investigate the effects of CBD on responses to negative emotional stimuli, as a model for its potential anxiety-reducing effects. Materials and Methods: The study used a double-blind, placebo (PLB)-controlled, within-subjects design in which 38 healthy, drug-free participants consumed oral CBD (300, 600, and 900 mg) or PLB before completing several behavioral tasks selected to assess reactivity to negative stimuli. Dependent measures included emotional arousal to negative and positive visual stimuli, perceptual sensitivity to emotional facial expressions, attentional bias toward emotional facial expressions, and feelings of social rejection. In addition, subjective drug effects and physiological data were also gathered during each experimental session to assess drug effects. Discussion: CBD did not dampen responses to negative emotional stimuli and did not affect feelings of social rejection. The high dose of CBD (900 mg) marginally reduced attentional bias toward happy and sad facial expressions, and produced a slight increase in late-session heart rate. CBD did not produce detectable subjective effects or alterations in mood or anxiety. Conclusion: These findings indicate that CBD has minimal behavioral and subjective effects in healthy volunteers, even when they are presented with emotional stimuli. Further research into the behavioral and neural mechanisms of CBD and other phytocannabinoids is needed to ascertain the clinical function of this drug.
... Systemic administration of CBD in rats exerts anxiolyticlike effects in the elevated plus-maze (Campos and Guimaraes, 2008;Campos et al., 2013b;Gomes et al., 2012;Guimaraes et al., 1990;Onaivi et al., 1990;Schiavon et al., 2016), Vogel conflict test (Campos and Guimaraes, 2008;Gomes et al., 2012;Moreira et al., 2006) and marble-burying test (in mice) (Casarotto et al., 2010), and reduces conditioned contextual fear (Resstel et al., 2006). Similar effects can be produced by microinjections of CBD into brain regions including the central nucleus of the amygdala (Hsiao et al., 2012), bed nucleus of the stria terminalis (BNST) (Gomes et al., 2011;Gomes et al., 2012), and dorsal periaqueductal gray (dPAG) (Campos and Guimaraes 2008). The anti-anxiety properties of CBD do, however, appear to be dose-dependent, with efficacy inversely correlated with dose (Guimaraes et al., 1990). ...
Article
The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.
... CBD efficiently stops anxiety-induced REM sleep suppression, but has little effect on the alteration of NREM sleep, possibly due to its anxiolytic effect, rather than through a direct regulation of sleep mechanisms. This is an important result for patients with post-traumatic stress disorder that often complain of having sleep disturbances, such as REM sleep abnormality and insomnia (Hsiao, Yi, Li, & Chang, 2012). ...
... The majority of recent studies have focused on understanding the individual contributions of either THC or CBD. Indeed, several recent studies have used cannabis extracts (Mondino et al., 2019), purified THC (Kimura et al., 2019), or CBD (Murillo-Rodriguez et al., 2006b, 2008b, 2011a to study how acute administration of these compounds affects sleep and sleep-pathologies including sleep apnea (Carley et al., 2002;Calik et al., 2014) and depression increased PS (Hsiao et al., 2012). This increased productivity in animal model studies of phytocannabinoid actions is likely to accelerate and will provide much-needed neurobiological information about the mechanisms involved in the actions of these substances. ...
Article
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Sleep is a vital function of the nervous system that contributes to brain and bodily homeostasis, energy levels, cognitive ability, and other key functions of a variety of organisms. Dysfunctional sleep induces neural problems and is a key part of almost all human psychiatric disorders including substance abuse disorders. The hypnotic effects of cannabis have long been known and there is increasing use of phytocannabinoids and other formulations as sleep aids. Thus, it is crucial to gain a better understanding of the neurobiological basis of cannabis drug effects on sleep, as well as the role of the endogenous cannabinoid system in sleep physiology. In this review article, we summarize the current state of knowledge concerning sleep-related endogenous cannabinoid function derived from research on humans and rodent models. We also review information on acute and chronic cannabinoid drug effects on sleep in these organisms, and molecular mechanisms that may contribute to these effects. We point out the potential benefits of acute cannabinoids for sleep improvement, but also the potential sleep-disruptive effects of withdrawal following chronic cannabinoid drug use. Prescriptions for future research in this burgeoning field are also provided.
... Le niveau d'anxiété des animaux au cours du protocole a été évalué en utilisant l'analyse de leurs déplacements dans l'Open field lors de l'étude de l'activité locomotrice (session de 10min/rat). En effet, le temps passé au centre du dispositif est susceptible d'être un indice de l'anxiété de l'animal puisqu'un rat anxieux traversera difficilement toute l'enceinte en passant par les diagonales du dispositif et passera ainsi moins de temps au centre du dispositif qu'un rat non anxieux (Ghafouri et al., 2016;Hsiao et al., 2012). ...
Thesis
La radiothérapie (RT) est une thérapie majeure des tumeurs cérébrales primitives ou métastatiques avec un gain de survie indéniable. Toutefois, les patients survivants au cancer éprouvent des séquelles après RT, dont de la fatigue et des déficits cognitifs qui deviennent irréversibles et altèrent la qualité de vie des patients. Il est donc nécessaire de mener des recherches qui vise à identifier la chronologie d’apparition des dommages cérébraux, leurs implications dans les troubles cognitifs et proposer de nouvelles thérapies. De même, il est primordial de proposer des outils capables de détecter et de prédire les toxicités neurologiques induites par la RT pour améliorer la prise en charge des patients. Dans ce contexte, l’objectif de la thèse est double : 1/ développer et caractériser un modèle préclinique de radiotoxicité cérébrale chez le rat adulte et identifier de potentiels biomarqueurs d’imagerie et sanguins et 2/ évaluer la pratique d’une activité physique (AP) comme thérapie pour atténuer les lésions cérébrales et les déficits cognitifs radio-induits. Ainsi, nous avons réalisé des évaluations temporelles (jusqu’à 6 mois post-irradiation cérébrale, 30 Gy) de l’état général et comportemental de l’animal (fatigue, locomotion, mémoire) et les modifications de différents paramètres IRM (anatomique, vasculaire et de diffusion) associées à une étude sur les espèces réactives quantifiées dans le cerveau et le plasma. Les rats ont été soumis ou non à une AP forcée réalisée régulièrement et à long terme avec un tapis de course. Nous avons alors montré que l’irradiation cérébrale engendre une fatigue radio-induite associée à des déficits de la locomotion et de la mémoire à court et à long terme. Les paramètres mesurés par IRM de diffusion et IRM vasculaire semblent pertinents pour détecter précocement et tardivement, respectivement, les dommages cérébraux radio-induits, tout comme le stress oxydatif mesurable au niveau plasmatique. Des bienfaits de l’AP sont observés sur les atteintes neuropathologies induites par l’irradiation. A terme, ce modèle animal qui a été démontré pertinent vis-à-vis des symptômes décrits en clinique sera utilisé pour tester de nouvelles thérapies.
... Critically, our null findings for the effect of CBD on experimentally-induced stress are in contrast to previous findings reporting that CBD attenuated task-induced anxiety (Bergamaschi et al., 2011;Zuardi et al., 1993;Zuardi et al., 2017), and these discrepant findings may be due to the potentially dose-dependent nature of CBD's effects. Recent work suggests that CBD may have an inverted-U shape dose-response curve (Campos & Guimaraes, 2008;Freeman et al., 2020;Hsiao, Yi, Li, & Chang, 2012;Linares et al., 2019;Zuardi et al., 2017) with best efficacy for human anxiety at 300 mg (Linares et al., 2019;Zuardi et al., 1993;Zuardi et al., 2017) compared to our dose of 600 mg. However, the finding that CBD was able to reduce drug-cue-induced craving and anxiety at single doses of 400 mg and 800 mg (Hurd et al., 2019), suggests that our dose of 600 mg still falls within the effective range, and so our negative finding remains important as evidence against the anxiolytic hypothesis of CBD. ...
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Background There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally-induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. We therefore sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. Methods We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during fMRI) and cognitive (emotional appraisal) measures as well as subjective response to experimentally-induced anxiety. Results CBD did not produce effects on BOLD responses to emotional faces, cognitive measures of emotional processing, or modulate experimentally-induced anxiety, relative to placebo. Conclusions Given the rising popularity of CBD for its putative medical benefits, further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.
... This result may be of clinical relevance since nightmares are not typically targeted by medications that appear to be efficient in treating other PTSD symptoms [66]. The efficacy of Cannabis derivates in ameliorating sleep disorders was already elucidated by animal studies, with specific effects on sleep duration and depth varying based on means and site of administration (e.g., intraperitoneal, amygdala, brain ventriculus, etc.) [67,68]. Diverse effects of CBD were over time detected depending on medication doses, with higher doses up to 160 mg/day increasing sedative-hypnotic effects [69,70]. ...
Article
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Post-Traumatic Stress Disorder (PTSD) is a complex disorder involving dysregulation of stress-related hormones and neurotransmitter systems. Research focused on the endocannabinoid system (eCBS) for anxiety and stress regulation, cognitive and emotional responses modulation and aversive memories extinction, leading to the hypothesis that it could represent a possible alternative treatment target for PTSD. In this systematic review, we summarize evidence about the efficacy and safety of medicinal cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), and nabilone in PTSD treatment. The PRISMA statement guidelines were followed. A systematic literature search was conducted in MEDLINE/PubMed, Scopus and Web of Science by two independent researchers, who also performed data extraction and quality assessment. Among the initial 495 papers, 234 were screened for eligibility and 10 were included. Studies suggested that different medicinal cannabinoids at distinct doses and formulations could represent promising treatment strategies for the improvement of overall PTSD symptomatology as well as specific symptom domains (e.g., sleep disorders, arousal disturbances, suicidal thoughts), also influencing quality of life, pain and social impact. Although there is a robust rationale for treatment with drugs that target the eCBS and the results are promising, further studies are needed to investigate the safety and efficacy profile of their prolonged use.
... Preclinical literature regarding CBD in rodent models of generalized anxiety suggest CBD's efficacy in minimizing anxiety associated behaviors relevant in GAD, SAD, PTSD, and OCD. Studies utilizing CBD in elevated plus and elevated T mazes with rodents have observed anxiolytic effects following both acute systemic administration (Campos et al., 2012;Campos et al., 2013a;Campos et al., 2013b) and acute local administrations in areas such as the amygdala central nucleus (Hsiao et al., 2012), bed nucleus of the stria terminalis (Gomes et al., 2011), and the intra-dorsal periaqueductal gray (Soares et al., 2010). Anxiolytic effects of CBD in these models are presented as a bell-shaped dose-response curve, with anxiolytic effects generally observed at moderate doses; 2.5-10.0 ...
Article
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Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.
... The EOLO at doses used did not interfere in the psychomotor activity, suggesting that it is not able to produce changes on the CNS in the animals, which reinforces the safety of this compound in non-clinical trials [51,52]. Throughout the treatment, and it is possible to suggest that EOLO does not interfere in emotional adaptation to a tense situation, however it should still be better investigated through other methodologies, such as the high cross maze or light / dark box. ...
Preprint
Alzheimer's disease is characterized by a progressive decline of cognitive functions. The class of drugs used for the treatment are acetylcholinesterase inhibitors. Essential oils have contributed to folk medicine and discovery of new drugs for a long time. The purpose of the study was to investigate the in vitro and in silico the anti-acetylcholinesterase activity, as well as acute toxicity of the essential oil of Lippia origanoides. EOLO was obtained by hydrostelting and analyzed by gas chromatography-mass spectrometry. The inhibition assay of acetylcholinesterase enzyme activity was evaluated in vitro, as well as in silico by docking. The effects of EOLO on hematological, biochemical and behavioral parameters were analyzed in mices. We expose that EOLO shows good anti-acetylcholinesterase activity and low toxicity, possibly resulting from the action of the majority compounds thymol, carvacrol and p-cymene. The anti-acetylcholinesterase potential in vitro demonstrating a 70% inhibition. The docking results elucidated the participation of the major phenolics in AChE inhibition by interacting with the catalytic cavity of AchE. The acute oral toxicity test classified as low toxicity. These results contribute to expand the knowledge about essential oil of Lippia origanoides. Therefore, appears to be promising for herbal medicine production with anti-acetylcholinesterase and antioxidant activity.
... Also, administration of CBD into the lateral hypothalamus increases waking, reduces REM sleep period, and reduces SWS [92]. Injection of CBD into the amygdala of rats exposed to anxiety-induced sleep disruption prevents REM sleep suppression with no effect on the non-REM phase [93]. It has been reported that both CBD and Δ9-THC regulate sleep-wake cycle and circadian rhythm, and are involved in promoting sleep [94]. ...
Article
Cannabis sativa (Marijuana) has a long history as a medicinal plant and Δ9-tetrahydrocannabinol (Δ9-THC) is the most active component in this plant. Cannabinoids are interesting compounds with various modulatory effects on physiological processes and cognitive functions. The use of cannabinoids is a double-edged sword, because they induce both adverse and therapeutic properties. One of the most important roles of cannabinoids is modulating sleep-wake cycle. Sleep, its cycle, and its mechanism are highly unknown. Also, the effects of cannabinoids on sleep-wake cycle are so inconsistent. Thus, understanding the role of cannabinoids in modulating sleep-wake cycle is a critical scientific goal. Cannabinoids interact with many neurotransmitter systems. In this review article, we chose serotonin due to its important role in regulating sleep-wake cycle. We found that the interaction between cannabinoids and serotonergic signaling especially in the dorsal raphe is extensive, unknown, and controversial.
... After the repeating combination tests, the decrease in non-rapid eye movement (NREM) sleep during the first hour and suppression of REM sleep during 4-10 hours shared similar clinical data in PTSD patients. It was concluded that CBD effectively reduced anxiety-induced REM sleep suppression while having minimal effect on NREM sleep disruption[46]. ...
Article
Over the past years, the use of medical cannabis is becoming of interest in the medical world. It has been recognized as an alternative treatment and has been legalized in many countries for medical purposes. Although there have been numerous claims of what cannabis can do, conclusive findings regarding its properties remain elusive. While access to cannabis is high, information accessible to consumers is still limited. Countless past studies have been done on cannabis’ effect on health issues. Hence, the purpose of this literature review was to conclude and summarize the past findings on the therapeutic effect of cannabis, focusing on the Delta-9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD), on the following medical conditions; chronic pain, opioid use disorder (OUD), obesity, sleep disorders, cancer, post-traumatic stress disorder (PTSD), psychosis, epilepsy, traumatic brain injury (TBI), Parkinson’s disease (PD), and Alzheimer’s disease. The risks of cannabis consumption for these issues were also identified. The results suggested that cannabis has the ability to assist in chronic pain, OUD, sleeping disorders, and Alzheimer’s disease. Regarding PTSD, psychosis, and TBI, there have been findings only about CBD which showed a beneficial effect on the diseases. It could not be concluded that cannabis can be used to treat obesity, cancer, epilepsy, and Parkinson’s disease due to limited evidence. The majority of the studies also demonstrated that high doses of CBD and low doses of THC should be used to maximize benefits. More clinical trials and research need to be conducted as there are research gaps and insufficient information in various subjects.
... Moreover, intra-dPAG administration of CBD (30 and 60 nmol/µL) also impaired inhibitory avoidance acquisition and inhibited the escape response in two proposed animal models of panic: the elevated T-maze (ETM) and the electric stimulation of the periaqueductal gray matter [23]. Additional results from studies carried out using the EPM and VCT tests in rats showed anxiolytic effects when CBD was microinjected into the central nucleus of the amygdala (1 µg/µL) [24], as well as into the bed nucleus of the stria terminalis (BNST) (30 nmol/µL) [25]. Microinjections of CBD (30 and 60 nmol/µL) into the BNST of rats also attenuated the expression of contextual fear conditioning (CFC) [26]. ...
Article
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Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.
Chapter
Anxiety is a common condition for which people have been found to self-medicate with cannabis. Anxiety is often comorbid with other conditions, including depression, sleep disorders and chronic pain. The pathomechanisms underpinning anxiety are complex. Animal and human research indicates that the endocannabinoid system is involved in our stress response and in anxiety. Evidence from preclinical studies has elucidated some of the potential mechanisms by which cannabidiol (CBD) is anxiolytic. Clinical research also supports the notion that CBD is anxiolytic, though the majority of studies have been studies of acute use rather than chronic use. There is evidence that tetrahydrocannabinol (THC) may have a bimodal effect, being anxiolytic in lower doses and anxiogenic in higher doses. The majority of studies of CBD and THC, in particular in animal studies, have utilised purified CBD or THC. Whole plant medicines that contain multiple phytocannabinoids, terpenes, polyphenols, flavonoids and other plant nutrients appear to act more potently, with different pharmacophysiologic relationships and reduced adverse effect profiles than purified isolates.
Article
Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour but the inappropriate expression of conditioned responding to fear- and drug-related stimuli can develop into anxiety-related and substance abuse disorders, respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via serotonin1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. Accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing also indicates that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely, and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in the lasting reduction of learned fear. Recent studies have also begun to determine the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. Emerging evidence suggests that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use in treating anxiety-related and substance abuse disorders.
Chapter
The cannabinoids are a family of chemical compounds that can be either synthesized or naturally derived. These compounds have been shown to modulate a wide variety of biological processes. In this chapter, the studies detailing the effects of cannabinoids on sleep in laboratory animals are reviewed. Both exogenous and endogenous cannabinoids generally appear to decrease wakefulness and alter rapid eye movement (REM) and non-REM sleep in animal models. In addition, cannabinoids potentiate the effects of sedative-hypnotic drugs. However, the individual contributions of each cannabinoid on sleep processes is more nuanced and may depend on the site of action in the central nervous system. Many studies investigating the mechanism of cannabinoid effects on sleep suggest that the effects of cannabinoids on sleep are mediated via cannabinoid receptors; however, some evidence suggests that some sleep effects may be elicited via non-cannabinoid receptor-dependent mechanisms. More research is necessary to fully elucidate the role of each compound in modulating sleep processes.
Chapter
Cannabis or marijuana is comprised of over 100 known sub-chemicals or cannabinoids. Two of these, delta-9-Tehtrahydrocannabinol (THC) and cannabidiol (CBD), have received increasing scrutiny regarding their effects on sleep-wake physiology and their potential for treating a wide variety of sleep disorders. The limited data available suggest there may be initial improvement in several sleep parameters but also a tendency toward tolerance with long-term use. Withdrawal effects following chronic use can be significant. There is presently little high-quality evidence currently available on the remedial properties of cannabinoids for primary sleep disorders. Large-scale, randomized, controlled studies in humans are needed.
Article
Objectives: Rehmanniae Radix Preparata (RRP) has been used as a traditional remedy to treat gynecology and endocrine diseases. Recently, studies on antioxidant and anti-inflammatory effects of RRP have been reported, so it was judged that RRP extracts would have an anti-depressive effect.Methods: We investigated the anti-neuroinflammatory and anti-depressive effect of RRP on lipopolysaccharide (LPS)-induced depression and LPS-stimulated BV2 microglia. RRP inhibited the LPS-stimulated excessive release of nitrite in the BV2 cells. RRP also significantly inhibited the inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in LPS-stimulated BV2 microglial cells.Results: RRP significantly suppressed the LPS-induced mitogen-activated protein kinase (MAPKs) and nuclear factor (NF)-κB activation. In addition, administration of RRP not only inhibited the immobility time in the forced swimming test (FST) but also increased the total travel distance in the open field test (OFT). Also, RRP inhibited the elevation of TNF-alpha, IL-1beta, and IL-6 in brain of LPS-injected mice.Conclusions: Considering the overall results, our study showed that RRP exhibited the anti-neuroinflammatory and anti-depressive activities via deactivation of MAPKs and NF-κB.
Article
Cannabidiol (CBD) is an abundant non-psychoactive phytocannabinoid in Cannabis extracts which has high affinity on a series of receptors, including type 1 cannabinoid receptor (CB1), type 2 cannabinoid receptor (CB2), GPR55, transient receptor potential vanilloid (TRPV), and peroxisome proliferator-activated receptor gamma (PPARγ). By modulating the activities of these receptors, CBD exhibits multiple therapeutic effects, including neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, analgesic and anti-cancer properties. CBD could also be applied to treat or prevent COVID-19 and its complications. Here, we provide a narrative review of CBD's applications in human diseases: from mechanism of action to clinical trials.
Article
Introduction Cannabis products, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are increasingly easy to procure and use across the United States. The 2018 National Survey on Drug Use and Health (NSDUH) reported a past-month cannabis use rate of 8.6% among adults 26 years of age or older in the U.S. general population. Cannabis use is commonly reported by U.S. Military Veterans with histories of mild traumatic brain injury (mTBI) receiving services at the Marcus Institute for Brain Health (MIBH), a specialty interdisciplinary clinic serving this population. The aims of this study are to describe the frequency and characteristics of cannabis product use among Veterans evaluated at MIBH and to compare the rate of cannabis use in this group to that in the general and Veteran populations reported in the 2018 NSDUH. Materials and Methods Study data were collected as part of MIBH clinical assessments between January 2018 and December 2019, which included the evaluation of the current use of cannabis products. Affirmative cannabis use responses were clarified with inquiries about the frequency of use, method of administration, product ingredients (i.e., THC and/or CBD), and reason(s) for use. Results Among 163 MIBH patients (92.6% male), 72 (44.2%) endorsed cannabis product use during the month preceding the clinical assessment. Cannabis users were significantly younger than nonusers. The frequency of past-month cannabis use was significantly greater than that reported in the comparably aged NSDUH survey general and Veteran populations (44.2% vs. 8.6% and 44.2% vs. 7.7%, respectively, both P < .00001). Among the 72 MIBH patients reporting cannabis use, 62 (86.1%) reported THC or combination product use, and 10 (13.9%) reported CBD product use. Concurrent medication use, including psychotropic medications use, did not differ significantly between cannabis users and nonusers. Conclusions Self-reported cannabis use is significantly higher in the MIBH population than in similarly aged individuals in the general population and significantly more frequent among younger than older members of this cohort. Self-reported reasons for cannabis use in this cohort included mTBI-associated neuropsychiatric symptoms, sleep disturbances, and pain for which standard treatments (both pharmacologic and nonpharmacologic) provided insufficient relief and/or produced treatment-limiting adverse events. However, cannabis use did not provide sufficient improvement in those symptoms to obviate the need for further evaluation and treatment of those problems at MIBH or to replace, in part or in whole, standard medications and other treatments for those problems. Further study of cannabis use, including standardized individual cannabinoid (i.e., THC and CBD) and whole-plant cannabis preparations, in this and similar cohorts is needed to more fully understand the drivers, benefits, risks, and safety of cannabis use in this and in similar Veteran populations, as well as the potential pharmacological and/or nonpharmacological therapeutic alternatives to cannabis use.
Chapter
Post-traumatic stress disorder (PTSD) is a debilitating mental illness that can result from exposure to a life-threatening or traumatic event. It has been described as an anxiety disorder, a disorder of dysregulation of fear and processing of stimuli associated with trauma, and a paradoxical disorder of memory. There is evidence that the endocannabinoid system is involved in the pathophysiology of PTSD, including findings that levels of endocannabinoids may be lower, and indications of changes in cannabinoid receptor levels in specific regions of the brain. Observational studies indicate that many people self-medicate with cannabis to help alleviate the symptoms associated with PTSD. Animal research indicates several mechanisms of actions by which cannabis and two of its key constituents, CBD and THC, may help address the pathophysiology of PTSD and reduce symptoms. Animal models of PTSD have demonstrated that CBD can disrupt acquisition of fear learning and formation of fear memories, attenuate fear memory reconsolidation, enhance extinction learning and retention, as well as reduce anxiety. THC appears to work in several ways including reducing anxiety, reducing acquisition of fear learning and decreasing fearful behaviors, and disrupting reconsolidation of fear memory. There is less clinical research available, with more focused on the efficacy of medicinal cannabis and less on CBD products. Systematic review evidence suggests that cannabis and synthetic cannabinoids may have the potential to improve PTSD symptoms including anxiety, sleep disorders, and memory processes.
Chapter
Good sleep is vital for good health, and poor sleep, in particular insomnia, is associated with a range of poor health outcomes. Sleep disorders are common and a key reason why people self-medicate with cannabis. We have two key biological mechanisms which work together to regulate our sleep-wake cycle, the processes of sleep-wake homeostasis and our circadian rhythms. The endocannabinoid system is involved in the circadian sleep-wake cycle, including maintenance and promotion of sleep, and may provide the link between the circadian regulation systems and the physiological process of sleep. Cannabis has been used for centuries to treat sleep disorders. Preclinical and clinical evidence indicate that cannabidiol and tetrahydrocannabinol may have a role to play in the treatment of sleep disorders.
Chapter
The main noradrenergic and serotonergic nuclei in the central nervous system (CNS) are the locus coeruleus (LC) and the dorsal raphe nucleus (DRN). These brain areas, located in the brainstem, play a pivotal role in the control of various functions and behaviors that are altered by cannabinoids (i.e., pain, arousal, mood, anxiety, or sleep-wake cycle). Anatomical, neurochemical, and functional data suggest that cannabinoids regulate both central noradrenergic and serotonergic neurotransmission. Thus, strong evidence has shown that the firing activity of LC and DRN monoamine neurons or the synthesis/release of noradrenaline (NA) and serotonin (5-HT) in the projection areas are all affected by cannabinoid administration. Herein, we propose that interaction between the endocannabinoid system and the noradrenergic-serotonergic systems could account for some of the anxiolytic, antidepressant, and antinociceptive effects of cannabinoids or the disruption of attention/sleep induced by these drugs.
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Cannabinoids, including the two main phytocannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being increasingly utilised as pharmacological interventions for sleep disorders. THC and CBD are known to interact with the endocannabinoid and other neurochemical systems to influence anxiety, mood, autonomic function, and circadian sleep/wake cycle. However, their therapeutic efficacy and safety as treatments for sleep disorders are unclear. The current systematic review assessed the available evidence base using PubMed, Scopus, Web of Science, Embase, CINAHL and PsycInfo databases. A total of 14 preclinical studies and 12 clinical studies met inclusion criteria. Results indicated that there is insufficient evidence to support routine clinical use of cannabinoid therapies for the treatment of any sleep disorder given the lack of published research and the moderate-to-high risk of bias identified within the majority of preclinical and clinical studies completed to-date. Promising preliminary evidence provide the rationale for future randomised controlled trials of cannabinoid therapies in individuals with sleep apnea, insomnia, post-traumatic stress disorder-related nightmares, restless legs syndrome, rapid eye movement sleep behaviour disorder, and narcolepsy. There is a clear need for further investigations on the safety and efficacy of cannabinoid therapies for treating sleep disorders using larger, rigorously controlled, longer-term trials.
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Background.—Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/ cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described. Most of the existing literature reports on the cannabinoids Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain. Objective.—Review the medical literature for the use of cannabis/cannabinoids in the treatment of migraine, headache, facial pain, and other chronic pain syndromes, and for supporting evidence of a potential role in combatting the opioid epidemic. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis. Summarize the individual medicinal benefits of these substances, including analgesic and anti-inflammatory properties. Conclusion.—There is accumulating evidence for various therapeutic benefits of cannabis/cannabinoids, especially in the treatment of pain, which may also apply to the treatment of migraine and headache. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards. Further research is anticipated to optimize breeding of strain-specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and diseasetargeted therapies.
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Introduction: Insomnia is among the most reported sleep disturbances in patients with post-traumatic stress disorder (PTSD). The pervasiveness of this disorder among trauma-inflicted civilians and military personnel has been associated with reduced quality of life, impaired psychosocial functioning including cognitive impairments, negative mood swings, cardiovascular complications, and increased utilization of medical services. Areas covered: This review describes the current state of science with respect to the impact of the most dispensed pharmacological interventions for posttraumatic insomnia. At the present, there are no established treatment algorithms for PTSD-related insomnia. Pharmacotherapy offers an alternative treatment modality for patients with PTSD who fail or decline cognitive behavioral therapy (CBT). Selection of a hypnotic/sedative agent should be based on the patient’s history, precipitating and perpetuating factors of insomnia, side effect profile, and potential medication-related interactions. Antipsychotics and benzodiazepines appear ineffective or are associated with significant harm in treating PTSD-related insomnia. Expert opinion: In the absence of randomized controlled trials, prescription patterns have been guided by anecdotal reports and expert opinion. Due to the complexity and multifactorial etiology of insomnia in PTSD, clinical investigations should examine available pharmacologic agents in comparative trials or in combination with CBT or complementary therapies to assess both short-term and long-term sleep outcomes in this population.
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Study objectives: Determine relationship between cannabis use with 1) expectations of cannabis being a sleep aid, 2) subjective sleep outcomes, and 3) the influence of age on these relationships. Methods: In 152 moderate cannabis users with a wide age range (67% female, mean age = 31.45, SD = 12.96, age range = 21-70; mean days of cannabis use in prior two weeks = 5.54, SD = 5.25) we examined the influence of cannabis use history and behaviors on expectations of cannabis being a sleep aid and sleep outcomes via the Pittsburgh Sleep Quality Index (PSQI). Moderation analysis examined the role of age in the relationship between cannabis use and sleep outcomes. Results: Endorsing current cannabis use and more days of cannabis use were associated with increased expectations that cannabis use improves sleep (all β > 0.03, p < 0.04). Frequency of recent use and reported average THC or CBD concentration were largely not associated with sleep outcomes. However, endorsing current cannabis use was associated with worse subjective sleep quality (β = 1.34, p = 0.02) and increased frequency of consuming edibles was associated with worse subjective sleep efficiency (β = 0.03, p = 0.04), lower sleep duration (β = 0.03, p = 0.01), and higher global PSQI scores (worse overall sleep) (β = 0.10, p = 0.01). Additionally, age had a moderating influence on the relationship between increased self-reported concentration of CBD and both better sleep duration and sleep quality (both p < 0.03). While the main effects of cannabis use on sleep outcomes did not survive multiple comparisons correction test (all p adj > 0.34), the adjusted p values for the main effects of cannabis behaviors/history on expectations of cannabis as a sleep aid (p adj = 0.07-0.09) and the main effects of CBD concentration on sleep duration (p adj = 0.08), as well as the interaction terms of CBD and age for that model (p adj = 0.07), were trending. Conclusion: Cannabis users have increased expectations of cannabis being a sleep aid, but few associations existed between cannabis use and sleep outcomes. The two exceptions were endorsing any cannabis use and frequency of edible use. Additionally, age may be an important moderator of the potential positive influence CBD concentration can have on sleep.
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Introduction: Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice. Areas covered: Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD. Expert opinion: Sleep disturbances in MDD should be recognized as at least one of the following: 1) a domain of depressive psychopathology; 2) a consequence of rhythm disruptions; 3) a manifestation of comorbidities of sleep disturbances; 4) a manifestation of the influence of sex hormones in the brain in MDD; 5) a general medical comorbidity; and 6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non- structured interviews. Other methods, such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy, and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long-lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretin and the endocannabinoid system.
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Abstract Stress is one of major factors that cause sleep problems. Hypocretin represents a stress-related neuropeptide and is well known in maintaining physiological wakefulness. The hypocretinergic neurons originate in the lateral hypothalamic area (LHA) and transmit to several brain regions, including the median raphe nuclei (MRNs). The MRNs modulate both fear responses and sleep-wake activity; however, it remains unclear whether stress alters the levels of hypocretin to regulate MRNs and consequently disrupt sleep. In this paper, we employed the inescapable footshock stimuli (IFS) as a stressor and hypothesized that the IFS-induced sleep disruption is mediated by increased hypocretins in the MRNs. Our results demonstrate that the concentrations of hypocretin in the hypothalamus increased after IFS. Rapid eye movement (REM) sleep was reduced after footshock, and microinjection of non-selective hypocretin receptor antagonist TCS-1102 into the MRNs blocked the IFS-induced decrease of REM sleep. Furthermore, administration of hypocretins into the MRNs mimicked the IFS-induced REM sleep reduction. These results conclude that the increased levels of hypocretins in the MRNs mediate the IFS-induced REM sleep reduction.
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The recent trend for legalization of medicinal cannabis and cannabinoid-containing products, together with their soporific effects, has led to a surge of interest of their potential therapeutic role in the management of some common sleep disorders, such as insomnia, sleep disordered breathing, and restless legs syndrome, and less common disorders such as narcolepsy and parasomnias. Although much of the pre-clinical and clinical data were derived from studies with relatively small sample sizes and limited by biases in assessment, and in clinical trials lack of allocation concealment, as a whole, the results indicate a potential therapeutic role for cannabinoids in the management of some sleep disorders. Clinical trials are underway for insomnia and obstructive sleep apnea management, but there remains a substantial need for rigorous large multi-center studies to assess the dose, efficacy, and safety of the various types of cannabinoids on sleep disorders. This review aims to summarize the modulatory effects of cannabinoids on sleep physiology and provide a critical evaluation of the research on their potential therapeutic benefit in various sleep disorders.
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Diazepam has been broadly accepted as an anxiolytic drug and is often used as a positive control in behavioral experiments with mice. However, as opposed to this general assumption, the effect of diazepam on mouse behavior can be considered rather controversial from an evidence point of view. Here we revisit this issue by studying the effect of diazepam on a benchmark task in the preclinical anxiety literature: the elevated plus maze. We evaluated the minute-by-minute time-course of the diazepam effect along the 10 min of the task at three different doses (0.5, 1 and 2 mg/kg i.p. 30 min before the task) in female and male C57BL/6J mice. Furthermore, we contrasted the effects of diazepam with those of a selective serotoninergic reuptake inhibitor (paroxetine, 10 mg/kg i.p. 1 h before the task). Diazepam had no anxiolytic effect at any of the tested doses, and, at the highest dose, it impaired locomotor activity, likely due to sedation. Noteworthy, our results held true when examining male and female mice separately, when only examining the first 5 min of the task, and when animals were subjected to one hour of restrain-induced stress prior to diazepam treatment. In contrast, paroxetine significantly reduced anxiety-like behavior without inducing sedative effects. Our results therefore suggest that preclinical studies for screening new anxiolytic drugs should be cautious with diazepam use as a potential positive control.
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This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines (CBM) for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are: 1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; 2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and 3) to identify important directions for future research. In service of these goals, this review a) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; b) describes pharmacokinetics of cannabinoids in rodents and humans; and c) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
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Palliative care is a specialized medical care that focuses on quality of life for patients with serious illnesses. In the realm of palliative care and symptom management, there is growing interest in the role for cannabis-based medicine. There is some evidence to support the use of cannabinoids for the palliation of some symptoms and quality of life issues. Most notably, research supports the efficacy of cannabinoids for the treatment of chemotherapy-induced nausea and vomiting, though the evidence for phytocannabinoids is lacking. Moreover, cannabis use in the treatment of neuropathic pain is supported by several small high-quality studies. There is great interest in cannabis-based medicine to aid in the management of other symptoms such as anorexia, cachexia, insomnia, fatigue, anxiety, and delirium, among others that are prevalent in palliative care patients. Though there are limited studies for these various applications of cannabis, the data is not conclusive, and patients’ treatment goals must be carefully considered prior to the administration of medical cannabis. Further research is needed to better understand the possible benefits of medical cannabis as well as the safety, side effects, and drug interactions.
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Dreams following trauma have been suggested to aid emotional adaptation, yet trauma-related nightmares are a diagnostic symptom of Posttraumatic Stress Disorder (PTSD). There is little published data relating dreams to PTSD soon after trauma. We assessed dreams and PTSD in 60 injured patients after life-threatening events and obtained follow-up assessments in 39 of these participants 6 weeks later. Ten of 21 dream reports from morning diaries were rated and described as similar to the recent traumatic event. The participants reporting these distressing “trauma dreams” had more severe concurrent PTSD symptoms than those reporting other categories of dreams and had more severe initial and follow-up PTSD than those without dream recall. These findings along with our preliminary longitudinal observations relating changes in dream patterns to outcome, suggest a relationship of dream characteristics and early adaptive versus maladaptive patterns of processing traumatic memory.
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Cannabidiol (CBD) is one of the psycho-inactive constituents of marijuana, the Cannabis sativa. The pharma-cological property of CBD, especially the anxiolytic effect, is significant in the therapeutic purposes. The central nucleus of amygdala (CeA) plays a key role in the anxiety and its related behavioral responses (e.g. sleep-wake activity), and sero-tonin is one of the major mediators. However, the sleep-wake effect of CBD remains unclear. This study was designed to elucidate the effects of CBD on sleep-wake alteration and the involvement of serotonin in the CeA. Administrations of 5-hydroxytryptamine (5-HT), 5-HT 1A receptor partial agonist (buspirone), 5-HT 2 antagonist (ritanserin), cannabinoid CB 1 receptor agonist (ACEA), or CB 1 antagonist (AM-251) were employed to elucidate the action of CBD on CeA presynaptic CB 1 receptors, serotonergic activity and the subsequent sleep alteration. We found that microinjection of CBD into the CeA prior to the beginning of the light period dose-dependently decreased slow wave sleep (SWS) with limited effect on rapid eye movement sleep (REMS). CBD-induced SWS suppression during the light period could be mimicked by admin-istering serotonin into the CeA. Buspirone and ritanserin dose-dependently blocked CBD-induced SWS decrease. Fur-thermore, administration of AM-251 exhibits similar effect as that of CBD on sleep-wake activity, and the CBD-induced SWS decrease was partially blocked by ACEA. These observations suggest that CBD acting on the CeA neurons de-creases SWS during the light phase, which is at least partially mediated by the consequence of antagonizing presynaptic CB 1 receptors, enhancing serotonin release from the presynaptic terminals and subsequently acting on the postsynaptic 5-HT 2 receptors.
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Sleep parameters in individuals with chronic PTSD were investigated. PTSD subjects were not found to differ from age-matched controls in total number of arousals, but there was a differential distribution of arousals across the sleep period. Control subjects showed a normal arousal pattern, with decreased arousals during the first half of the sleep period reflecting the delta sleep prominent during this period, whereas PTSD subjects demonstrated an abnormal arousal pattern characterized by a relatively consistent frequency of arousals across the sleep period. Overall, PTSD subjects had a decreased percentage of slow-wave sleep relative to controls, which may explain their increased arousals during the first half of the night. In addition, electrodermal recordings indicated that PTSD subjects showed significantly less storming than controls throughout the recording period.
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The effects of ipsapirone and cannabidiol (CBD) on healthy volunteers submitted to a simulated public speaking (SPS) test were compared with those of the anxiolytic benzodiazepine diazepam and placebo. Four independent groups of 10 subjects received, under a double-blind design, placebo or one of the following drugs: CBD (300 mg), diazepam (10 mg) or ipsapirone (5 mg). Subjective anxiety was evaluated through the Visual Analogue Mood Scale (VAMS) and the State-trait Anxiety Inventory (STAI). The VAMS anxiety factor showed that ipsapirone attenuated SPS-induced anxiety while CBD decreased anxiety after the SPS test. Diazepam, on the other hand, was anxiolytic before and after the SPS test, but had no effect on the increase in anxiety induced by the speech test. Only ipsapirone attenuated the increase in systolic blood pressure induced by the test. Significant sedative effects were only observed with diazepam. The results suggest that ipsapirone and CBD have anxiolytic properties in human volunteers submitted to a stressful situation.
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In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.
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To examine correlations among chronic Posttraumatic Stress Disorder (PTSD), control-related beliefs, and sleep difficulties 7 PTSD casualities and 7 non-PTSD matched subjects were compared in their laboratory sleep patterns as well as in their beliefs about personal control over external and internal events in general and over sleep-related events in particular. Analyses indicated that PTSD casualties had poorer sleep and reported more doubts regarding their ability to control external and internal events than control subjects. Further, we found a significant association between perceived control and sleep difficulties. Results were discussed in terms of Horowitz's conception of intrapsychic processes related to PTSD.
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Sleep data were obtained on 11 patients who had survived traumatic events and who complained of sleep disturbances. Each was awakened from REM and non-REM sleep for dream recall. The patients had lower sleep efficiency indices (because of prolonged sleep latency and larger amounts of "awake" plus "movement" time within sleep periods), shorter REM time, and longer REM latencies than did control subjects. Four of the 11 patients had REM- and non-REM-related nightmares, which, in two sea disaster patients, were associated with REM-related motor activity. The rest of the patients had unusually low dream recall in spite of high eye movement density.
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The role of 5-HT mechanisms in the amygdala in the modulation of sleep and arousal states and PGO waves was examined. Studies of the amygdala suggest that it provides a neural mechanism by which emotionally-relevant or significant stimuli may influence behavioral state and alerting mechanisms. The amygdala projects massively (via the central nucleus) into brainstem regions involved in alerting and in the generation of REM and PGO waves. Serotonergic innervation of the amygdala comes from DRN and to a lesser degree MRN. Microinjections of 5-HT into the amygdala produced short-latency changes of state from NREM and REM with the effect being relatively greater in REM. Microinjections of the 5-HT antagonist, methysergide, increased sleep efficiency and increased PGO wave frequency in waking and NREM. These results demonstrate an important role for the amygdala in the control of behavioral state and alerting mechanisms and suggest that 5-HT exerts some of its regulatory effects via an influence on forebrain regions.
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This study analyzed questionnaire items that address complaints about sleep from the National Vietnam Veterans Readjustment Study, a nationally representative sample of the 3.1 million men and women who served in Vietnam. This study compared the frequency of nightmares and difficulties with sleep onset and sleep maintenance in male Vietnam theater veterans with male Vietnam era veteran and male civilian comparison subjects. It focused on the role of combat exposure, nonsleep posttraumatic stress disorder (PTSD) symptoms, comorbid psychiatric and medical disorder, and substance abuse in accounting for different domains of sleep disturbance. The authors undertook an archival analysis of the National Vietnam Veterans Readjustment Study database using correlations and linear statistical models. Frequent nightmares were found exclusively in subjects diagnosed with current PTSD at the time of the survey (15.0%). In the sample of veterans who served in Vietnam (N = 1,167), combat exposure was strongly correlated with frequency of nightmares, moderately correlated with sleep onset insomnia, and weakly correlated with disrupted sleep maintenance. A hierarchical multiple regression analysis showed that in Vietnam theater veterans, 57% of the variance in the frequency of nightmares was accounted for by war zone exposure and non-sleep-related PTSD symptoms. Alcohol abuse, chronic medical illnesses, panic disorder, major depression, and mania did not predict the frequency of nightmares after control for nonsleep PTSD symptoms. Frequent nightmares appear to be virtually specific for PTSD. The nightmare is the domain of sleep disturbance most related to exposure to war zone traumatic stress.
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We have previously hypothesized that corticotropin-releasing hormone (CRH) is involved in the regulation of physiological waking. To further elucidate this role for CRH, we administered intracerebroventricularly into rats two specific CRH-receptor antagonists, alpha-helical CRH-(9-41) (alpha-hCRH) or astressin, and determined changes in electroencephalogram-defined waking and sleep. Our results indicate that both of these receptor antagonists reduce the amount of time spent awake in a dose-related manner when administered before the dark period of the light-dark cycle. However, the time courses for these effects differ between antagonists; effective doses of alpha-hCRH reduce waking during the first 2 h postinjection, whereas effective doses of astressin reduce waking during postinjection hours 7-12. In contrast to dark-onset administrations, the amount of waking is not altered by either CRH-receptor antagonist when administered before the light period. These results support our hypothesis that CRH contributes to the regulation of physiological waking, since interfering with the binding of CRH to its receptor reduces spontaneous waking.
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Disturbed sleep is a common complaint among patients with posttraumatic stress disorder (PTSD) that appears in the reexperiencing and hyperarousal symptom clusters in DSM-IV. The causal relationship between sleep complaints and PTSD is unclear. Self-reported insomnia and excessive daytime sleepiness were assessed in 102 victims of motor vehicle accidents and 19 comparison subjects 1 week and 1, 3, 6, and 12 months after the trauma. At 12 months the Structured Clinical Interview for DSM-III-R was administered to determine diagnoses of PTSD. Twenty-six of the accident victims but none of the comparison subjects met the criteria for PTSD. Logistic regression models indicated that sleep complaints from 1 month on were significant in predicting PTSD at 1 year. These results suggest that on the basis of sleep complaints as early as 1 month after the trauma, it is possible to detect subjects who will later develop chronic PTSD.
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The potential for chronicity and treatment resistance once posttraumatic stress disorder (PTSD) has become established has stimulated interest in understanding the early pathogenesis of the disorder. Arousal regulation and memory consolidation appear to be important in determining the development of PTSD; both are functions of sleep. Sleep findings from patients with chronic PTSD are complex and somewhat contradictory, and data from the acute phase are quite limited. The aim of the present study was to obtain polysomnographic recordings during an acute period after life-threatening experiences and injury and to relate measures of sleep duration and maintenance and the timing, intensity, and continuity of REM sleep to the early development of PTSD. Twenty-one injured subjects meeting study criteria received at least one polysomnographic recording close to the time of medical/surgical stabilization and within a month of injury. PTSD symptoms were assessed concurrently and 6 weeks later. Sleep measures were compared among injured subjects with and without significant PTSD symptoms at follow-up and 10 noninjured comparison subjects and were also correlated with PTSD severity. There was more wake time after the onset of sleep in injured, trauma-exposed patients than in noninjured comparison subjects. Development of PTSD symptoms was associated with shorter average duration of REM sleep before a stage change and more periods of REM sleep. The development of PTSD symptoms after traumatic injury is associated with a more fragmented pattern of REM sleep.
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Animal and human studies have suggested that cannabidiol (CBD) may possess anxiolytic properties, but how these effects are mediated centrally is unknown. The aim of the present study was to investigate this using functional neuroimaging. Regional cerebral blood flow (rCBF) was measured at rest using (99m)Tc-ECD SPECT in 10 healthy male volunteers, randomly divided into two groups of five subjects. Each subject was studied on two occasions, 1 week apart. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. SPECT images were acquired 90 min after drug ingestion. The Visual Analogue Mood Scale was applied to assess subjective states. 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 (SPM). CBD significantly decreased subjective anxiety and increased mental sedation, while placebo did not induce significant changes. Assessment of brain regions where anxiolytic effects of CBD were predicted a priori revealed two voxel clusters of significantly decreased ECD uptake in the CBD relative to the placebo condition (p<0.001, uncorrected for multiple comparisons). These included a medial temporal cluster encompassing the left amygdala-hippocampal complex, extending into the hypothalamus, and a second cluster in the left posterior cingulate gyrus. There was also a cluster of greater activity with CBD than placebo in the left parahippocampal gyrus (p<0.001). These results suggest that CBD has anxiolytic properties, and that these effects are mediated by an action on limbic and paralimbic brain areas.
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The high rate of co-occurrence of substance use disorders and other psychiatric disorders is well established. The population of people with co-occurring disorders is heterogeneous, and the prevalence of comorbidity differs by diagnostic group. One of the overarching issues in the area of comorbidity is the nature of the connection between psychiatric disorders and substance use disorders. The rapid development of technical advances in the neurosciences has led to a better understanding of the molecular biology, neurotransmitter systems, and neural circuitry involved in mental illness and substance use disorders. The authors discuss the neurobiological interface between substance use disorders and other psychiatric disorders with an emphasis on emerging data concerning four psychiatric disorders that commonly co-occur with substance use disorders: depression/mood disorders, posttraumatic stress disorder, attention deficit hyperactivity disorder, and schizophrenia. Better understanding of the connection between substance use disorders and psychiatric disorders could have a profound effect on prevention and treatment.
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To determine the effects of temporary functional inactivation of the central nucleus of the amygdala on sleep and on activity in an arousing environment, an open field. Rats were implanted with electrodes for recording the electroencephalogram (EEG) and electromyogram (EMG), and with guide cannulae aimed into CNA. Sleep was recorded for 22 h (10 h light, 12 h dark) following microinjections of tetrodotoxin (TTX: 5.0 ng/0.2 microl given unilaterally [TTXUH] or bilaterally [TTXBH], and 2.5 ng/0.1 microl given bilaterally [TTXBL]) or saline (SAL) alone on separate days. Activity during 1 h in an OF was recorded after microinjections of TTXBH and SAL. NA. Three-month-old Wistar rats (n=12). Functional inactivation of the central nucleus of the amygdala with TTX. Compared to SAL, all TTX microinjections significantly shortened NREM latency, but did not alter total NREM during either light or dark periods. During the light period, TTXBH significantly reduced total REM and REM episode number, and TTXBL decreased REM episode number. All TTX microinjections increased EEG slow wave activity (0.5-4 Hz, SWA) during wakefulness, NREM and REM. Activity in OF was decreased after TTXBH compared to SAL. Functional lesions of the amygdala, including the central nucleus of the amygdala, decreased REM sleep and reduced arousal, as indicated by shortened NREM latency and decreased activity in an arousing environment. These findings suggest that the amygdala plays a broad role in modulating spontaneous sleep and wakefulness and in modulating responsiveness in arousing situations.
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This study sought to determine whether electrical stimulation of the amygdaloid central nucleus (ACe) produces cholinergically mediated neocortical arousal manifested in the suppression of frontal cortex delta wave (1-4 Hz) activity. Stimulation in both anesthetized and conscious rabbits produced a suppression of delta activity that was accompanied by bradycardia and blocked by cholinergic antagonists. Stimulation of the adjacent putamen did not produce delta suppression, whereas stimulation of the adjacent ventral globus pallidus produced a suppression of shorter duration than that produced by ACe stimulation. The results suggest that the ACe influences neocortical arousal, which may be mediated by its influence on the activity of cholinergic neurons of the nucleus basalis.
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Seven open-field measures (defecation, ambulation, urination, washing, rearing, latency and inner circle activity) were obtained using a number of different scoring methods for albino and hooded rats. The validity of these measures was examined using (a) day by day decrease of open-field behaviour, (b) effects of retesting over a period of time, (c) variation of stimulus intensity (light and noise). It was found that methods a and b did not provide satisfactory validity estimates. Method c indicated that defecation and latency can be accepted as valid indices of emotionality in rats.
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Observed behavior of inbred mouse strains BALB, C3H, DBA, and C57BL in an open field for 10 min by a multi-event time sampling method. Data from 10 male mice of each strain were coded into 9 behavioral items, the occurrence or absence of which in consecutive 5-sec time bins was called a behavioral state. 14 states described the behavior of all strains. Sniffing was the most common behavioral item. Immediately after introduction into the open field, mice showed a more or less strong stretching tendency, which was replaced by behaviors like locomotion, rearing, and leaning against a wall. The change occurred quite soon in C57BL as well as in DBA strains, later in the C3H strain, and rarely in the BALB strain. It is suggested that the observed stretching tendency is the behavioral expression of emotional arousal evoked on introduction into a novel situation. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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The purpose of the writer was to determine the possible relationship between emotional behavior (defecation) and the speed of ambulatory activity (distance travelled per unit time). Each of 50 rats was observed individually in a round enclosure two minutes a day for 28 days. The results demonstrate a negative correlation between individual differences in defecating (emotional) behavior and individual differences in defecating (emotional) behavior and individual differences in ambulatory activity. Emotional rats were less active than non-emotional. "This relationship suggests that whenever activity is of utility to the animal, emotionality will hinder adjustment; whenever activity is of disservice to the animal, emotionality will facilitate adjustment." (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
Article
Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans. Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown. In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta 9-tetrahydrocannabinol (Delta 9-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety. In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces. This is the first study to show that the disruption of prefrontal-subocritical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties.
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Eleven patients who had combat neuroses resulting from the 1973 Yom Kippur War and complained of sleep disturbances were studied in a sleep laboratory. Sleep-onset insomniacs, dream-interruption insomniacs, and pseudoinsomniacs were differentiated on the basis of electrophysiologic recordings. Compared with normal controls who actively participated in the Yom Kippur War, patients showed significantly longer sleep latencies, lower sleep efficiency indices, lower percentage of REM sleep, and longer REM latencies.
Article
The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats. During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.
Article
An immobilisation stress (IS) of 2 h applied to rats at the beginning of the dark period (12 h), i.e. when the animals are more active, induces during the 10 consecutive h a significant rebound (+92%) of paradoxical sleep (PS) while slow-wave sleep state (SWS) is poorly affected. Two h of sleep deprivation, also applied at the beginning of the dark period and realized either by the platform technique or by maintaining the animals awake with gentle handling, do not affect significantly subsequent SWS and PS. Finally, when repetitive IS are inflicted to the animals (one IS of 2 h every 3 days) an attenuation of the PS rebound is observed. These data suggest that a qualitative aspect of the waking state as in an intense stressful situation might be the source of a hormonal process inducing a PS excess.
Article
Combat veterans (N = 25) with posttraumatic stress disorder had flashbacks related to their combat stressors, which included major losses and exposure to danger. Certain affects, loud noises, fatigue, and personal stress tended to precipitate flashback episodes. Flashbacks began a year or more after exposure to combat in 50% of patients; 56% of patients experienced daily flashbacks. Flashback phenomenology met DSM-III criteria for panic attacks. The similarity of flashbacks to panic attacks suggests treatment trials with monoamine oxidase inhibitors or imipramine for these selected symptoms.
Article
1. The oral sedative potencies of cannabis herb, crude ethanolic and petroleum-ether fractions, were assayed against delta'-trans-tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h. 2. The THC contents of the extracts were determined chemically by gas-liquid chromatography analysis and the B/C ratio (biological activity divided by chemical activity) calculated for each. The B/C values for cannabis herb, which contained THC but no CBD, was 4.47 and for ethanolic and petroleum-ether extracts, 5.26 and 4.39, respectively. 3. The sedative potency expressed as SDA50, the dose required to give 50% effect over 6 h, was 1.06 (0.98 to 1.15) mg/kg for THC; 4.72 (4.22 to 5.27) mg/kg for cannabidiol and 1.26 (1.22 to 1.80) mg/kg for chlorpromazine. 4. An infusion of cannabis herb made with boiling water was shown to have sedative activity of very low potency. 5. When the cannabinoids were completely extracted from a sample of herb with petroleum-ether the aqueous and ethanolic extracts of the marc had some sedative activity; but the 70% ethanolic fraction had none. 6. The sedative activity of THC, cannabis herb and a water soluble fraction is blocked by aspirin, a cyclo-oxygenase inhibitor, and restored by prostaglandin E2 (PGE2). 7. The sedative effect of chlorpromazine is not blocked by aspirin.
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Subjects from a family study who had panic disorder and generalized anxiety disorder were compared on the pattern of their symptoms, age and type of onset, personality characteristics, course of illness, and outcome. Subjects with generalized anxiety disorder were shown to have fewer autonomic symptoms and an earlier, more gradual onset. Their illness was also observed to have a more chronic course and a more favorable outcome, although these differences were not statistically significant. The validity of generalized anxiety disorder and panic disorder as discrete diagnostic entities is supported.
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The new diagnostic nomenclature of the American Psychiatric Association (DSM-III) provides well-described categories of stress response syndromes that were not included in the previous nosology. The signs and symptoms of these syndromes used in the descriptive statements have been understood largely in terms of field studies of nonpatient populations and clinical descriptive and impressionistic studies of patient populations. We report quantitative data from the study of a population with post-traumatic stress disorder. The results confirm clinical impressions of the importance and wide prevalence of episodes of intrusive ideas and feelings in states of distress precipitated by serious life events.
Article
The subjective sleep disturbance in posttraumatic stress disorder (PTSD), including the repetitive, stereotypical anxiety dream, suggests dysfunctional rapid eye movement (REM) sleep mechanisms. The polysomnograms of a group of physically healthy combat veterans with current PTSD were compared with those of an age-appropriate normal control group. Tonic and phasic REM sleep measures in the PTSD subjects were elevated on the second night of recorded sleep. Increased phasic REM sleep activity persisted in the PTSD group on the subsequent night. During the study, an anxiety dream occurred in a PTSD subject in REM sleep. The results are consistent with the view that a dysregulation of the REM sleep control system, particularly phasic event generation, may be involved in the pathogenesis of PTSD. The finding of a specific disturbance of sleep unique to PTSD may have significant implications for the design of effective treatments for PTSD.
Article
This study sought to determine whether electrical stimulation of the amygdaloid central nucleus (ACe) produces cholinergically mediated neocortical arousal manifested in the suppression of frontal cortex delta wave (1-4 Hz) activity. Stimulation in both anesthetized and conscious rabbits produced a suppression of delta activity that was accompanied by bradycardia and blocked by cholinergic antagonists. Stimulation of the adjacent putamen did not produce delta suppression, whereas stimulation of the adjacent ventral globus pallidus produced a suppression of shorter duration than that produced by ACe stimulation. The results suggest that the ACe influences neocortical arousal, which may be mediated by its influence on the activity of cholinergic neurons of the nucleus basalis.
Article
Untreated rats normally avoid the open arms of the "elevated plus-maze," preferring instead the closed arms, whereas rats treated with antianxiety drugs (e.g., diazepam) show far less open-arm avoidance. Although it has often been assumed that rats avoid the open arms because of novelty, height, or open space, the anxiogenic role of these stimuli in the plus-maze has not been systematically examined. In Experiment 1, rats were repeatedly exposed to the elevated plus-maze with the expectation that their "fear" of the open arms would habituate over trials. Instead, open-arm avoidance actually increased on the second trial and showed no evidence of habituating after 18 trials. In Experiment 2, three 30-min sessions of confinement to the open arms ("flooding") failed to decrease rats' open-arm avoidance. Instead, rats that had received flooding avoided the open arms significantly more than control rats during the first test. Experiment 3 showed that although diazepam-treated rats avoided the open arms less than vehicle-controls on the first test this difference dissipated across test trials. Further, diazepam had no carryover effect on rats' subsequent avoidance of the open arms in a nondrugged state. In Experiment 4, plus-maze height was varied from 50 to 6 cm, but rats did not display more open-arm activity as maze height decreased. In Experiment 5, height cues were manipulated by placing a "floor" 8 cm beneath one open arm while leaving the floor of the other open arm at 50 cm. Rats did not avoid the "low" open arm less than the "high" open arm.(ABSTRACT TRUNCATED AT 250 WORDS)