Article

The Nonpsychoactive Cannabis Constituent Cannabidiol Is a Wake-Inducing Agent

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  • Universidad Anáhuac Mayab. Mérida, Yucatán. México
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Abstract

Cannabidiol (CBD) is a constituent of Cannabis sativa that induces nonpsychotropic effects, and some of its biological actions in sleep have been described by the authors' group. Here, the authors report that when administered 10 or 20 microg/1 microl during the lights-on period directly into either lateral hypothalamus (LH) or dorsal raphe nuclei (DRN), which are wake-inducing brain areas, CBD enhanced wakefulness and decreased slow wave sleep and REM sleep. Furthermore, CBD increased alpha and theta power spectra but diminished delta power spectra. Additionally, CBD increased c-Fos expression in LH or DRN. These findings suggest that this cannabinoid is a wake-inducing compound that presumably activates neurons in LH and DRN.

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... CBC is nearly 2.5-times more toxic than D 9-THC and, like D 9-THC, it may cause hypothermia, sedation and hypoactivity in mice [3]. CBC exerts anti-inflammatory, antimicrobial and modest analgesic activity [3,32,39,75]. It is a potent TRPA1 agonist and weak anandamide reuptake inhibitor [11,14]. ...
... Notably, the effect of CBD in humans is biphasic, exhibiting alerting properties at low doses and sedative actions at high doses [7]. Early studies showed that CBC, like D 9THC, prolonged hexobarbital hypnosis in mice [3,39]. ...
... Inflammation, pain and the immune response Early reports suggested that CBC exerted anti-inflammatory effects [39] and modest analgesic activity [32] in rodents. CBC was superior to the non-steroidal antiinflammatory drug phenylbutazone in carrageenaninduced rat paw edema and in the erythrocyte membrane stabilization method [39]. ...
Article
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
... Thus, we investigated the effects of AA-5-HT (5, 10, 20 mg/Kg, i.p.) on sleep as well as extracellular contents of neurotransmitters linked to the sleep-wake cycle such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD). Moreover, to provide further evidence regarding the putative sleep-inducing properties of AA-5-HT, we tested whether this drug would block the alertness caused by the phytocannabinoid cannabidiol (CBD, 30 mg/Kg, ip;MurilloRodríguez et al., 2006, 2008b, 2011bKim, 2012) or the stimulant drug modafinil (MOD, 30 mg/Kg, i.p.;Sukhal et al., 2015;Wang et al., 2015;Barateau et al., 2016). In addition, the role of AA-5-HT in sleep homeostasis was addressed in CBD-or MOD-treated animals that were sleep deprived. ...
... At last, REMS was characterized by regular theta activity across the EEG coupled with low EMG accompanied with myoclonic features. The sleep-recordings procedures were followed as previously reported (MurilloRodríguez et al., 2006, 2007b, 2008bMijangos-Moreno et al., 2016). ...
... However, administration of CBD (30 mg/Kg, i.p.) enhanced alertness and decreased SWS as well as REMS. This effects confirmed previous reports (Murillo-Rodríguez et al., 2006, 2008b). Interestingly, AA-5-HT administered 15min before the injection of CBD was able to block the increase in W (). The Scheffé's post hoc test showed inter-group differences for among sham/vehicle and AA-5-HT as well as CBD and AA-5-HT + CBD for waking, SWS and REMS (P < 0.01). ...
Article
The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB 1 and CB 2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep–wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol Frontiers in Molecular Neuroscience | www.frontiersin.org 1 May 2017 | Volume 10 | Article 152 Murillo-Rodríguez et al. Injections of N-Arachidonoyl-Serotonin (AA-5-HT) Increase Sleep (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The injection of CBD or MOD increased alertness during sleep rebound period after TSD. However, AA-5-HT blocked this effect by allowing animals to display an enhancement in sleep across sleep rebound period. Overall, our findings provide evidence that AA-5-HT is an important modulator of sleep, sleep homeostasis and neurotransmitter contents.
... In rats, intracerebroventricular (ICV) injection of CBD increased wakefulness and decreased REM compared to sham or vehicle-injected groups (Murillo-Rodríguez et al. 2006). CBD also increased wakefulness and decreased SWS and REM when injected into the lateral hypothalamus (Murillo-Rodríguez et al. 2008a, 2011 or dorsal raphe (Murillo-Rodríguez et al. 2008a) of rats. These findings are supported by sleep quality studies that demonstrate that injection of CBD into the lateral hypothalamus or dorsal raphe nuclei increased alpha power, yet decreased delta and theta power (Murillo-Rodríguez et al. 2008a). ...
... In rats, intracerebroventricular (ICV) injection of CBD increased wakefulness and decreased REM compared to sham or vehicle-injected groups (Murillo-Rodríguez et al. 2006). CBD also increased wakefulness and decreased SWS and REM when injected into the lateral hypothalamus (Murillo-Rodríguez et al. 2008a, 2011 or dorsal raphe (Murillo-Rodríguez et al. 2008a) of rats. These findings are supported by sleep quality studies that demonstrate that injection of CBD into the lateral hypothalamus or dorsal raphe nuclei increased alpha power, yet decreased delta and theta power (Murillo-Rodríguez et al. 2008a). ...
... CBD also increased wakefulness and decreased SWS and REM when injected into the lateral hypothalamus (Murillo-Rodríguez et al. 2008a, 2011 or dorsal raphe (Murillo-Rodríguez et al. 2008a) of rats. These findings are supported by sleep quality studies that demonstrate that injection of CBD into the lateral hypothalamus or dorsal raphe nuclei increased alpha power, yet decreased delta and theta power (Murillo-Rodríguez et al. 2008a). In addition, CBD dose-dependently prevented sleep rebound in sleep-deprived rats (Murillo-Rodríguez et al. 2011). ...
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.
... Whatever its exact mechanisms of action, several reports have shown that CBD exerts actions in neurobiological functions such as learning and memory [16,17], pain perception [18,19], and sleep [20][21][22][23]. In this regard, our laboratory reported that administrations of CBD in rats during the lights-on period increased wakefulness, but decreased sleep [20][21][22]. ...
... Whatever its exact mechanisms of action, several reports have shown that CBD exerts actions in neurobiological functions such as learning and memory [16,17], pain perception [18,19], and sleep [20][21][22][23]. In this regard, our laboratory reported that administrations of CBD in rats during the lights-on period increased wakefulness, but decreased sleep [20][21][22]. Remarkably, the effects of CBD on sleep has been found after systemic or central injections, as well as posterior to intracerebral perfusion [20][21][22]24]. Moreover, CBD also caused a significant enhancement of the extracellular levels of dopamine (DA) collected from nucleus accumbens [20][21][22]. ...
... In this regard, our laboratory reported that administrations of CBD in rats during the lights-on period increased wakefulness, but decreased sleep [20][21][22]. Remarkably, the effects of CBD on sleep has been found after systemic or central injections, as well as posterior to intracerebral perfusion [20][21][22]24]. Moreover, CBD also caused a significant enhancement of the extracellular levels of dopamine (DA) collected from nucleus accumbens [20][21][22]. ...
Article
Full-text available
Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion. Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh). Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD. Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.
... Surprisingly, in rats the endocannabinoid anandamide did not block the effects of CBD. [123,124] The mechanism of action of CBD on sleep modulation remains to be elicited [125] but it was speculated that CBD may modulate wakefulness by via an activation of neurons in the hypothalamus and the dorsal raphe nucleus. [124] Anandamide was observed to decrease wakefulness in addition to increases in slow wave sleep and REM sleep in rats. ...
... [124] When the action of anandamide was blocked by the CB 1 receptor antagonist SR 141716A, i.e. 15 min prior to anandamide administration, these anandamide-induced changes in sleep were not observed, hence providing indication that the CB 1 receptor was a major target for the sleep-inducing actions of anandamide. [125] According to the study of Cousens and DiMascio [126] there was a decrease in the number of sleep interruptions, especially in the first third of the night which suggested that the hypnotic actions of THC were relatively short-lived. Some subjects complained in the morning about a mild to moderate feeling of being hungover or being stoned, but subjects who received the 20 mg dose did not observe any interference with their daily work function. ...
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It is known from clinical studies that some patients attempt to cope with the symptoms of post-traumatic stress disorder (PTSD) by using recreational drugs. This review presents a case report of a 19-year-old male patient with a spectrum of severe PTSD symptoms, such as intense flashbacks, panic attacks, and self-mutilation, who discovered that some of his major symptoms were dramatically reduced by smoking cannabis resin. The major part of this review is concerned with the clinical and preclinical neurobiological evidence in order to offer a potential explanation of these effects on symptom reduction in PTSD. This review shows that recent studies provided supporting evidence that PTSD patients may be able to cope with their symptoms by using cannabis products. Cannabis may dampen the strength or emotional impact of traumatic memories through synergistic mechanisms that might make it easier for people with PTSD to rest or sleep and to feel less anxious and less involved with flashback memories. The presence of endocannabinoid signalling systems within stress-sensitive nuclei of the hypothalamus, as well as upstream limbic structures (amygdala), point to the significance of this system for the regulation of neuroendocrine and behavioural responses to stress. Evidence is increasingly accumulating that cannabinoids might play a role in fear extinction and antidepressive effects. It is concluded that further studies are warranted in order to evaluate the therapeutic potential of cannabinoids in PTSD.
... THC also significantly decreased duration of nighttime sleep, suggesting development of tolerance to the sedative effect [265]. CBD appeared to counteract the activity of THC by activating neurons in awaken-inducing brain zones including lateral hypothalamus and/or dorsal nuclei and increasing dopamine extracellular levels [264,[266][267][268]. The CBD awakening properties were not inhibited by the sleepinducing AEA [267,269]. ...
... The CBD awakening properties were not inhibited by the sleepinducing AEA [267,269]. CBD increased wakefulness during light-on period, increased sleep lights-off period and prevented sleep rebound after total sleep deficiency [265][266][267][268]270]. In a trial with 72 adults CBD upgraded sleep scores in 66.7% patients [243]. ...
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Autism spectrum disorder (ASD) is a group of disabilities with impairments in physical, verbal, and behavior areas. Regardless the growing frequency of autism, no medicine has been formed for the management of the ASD primary symptoms. The most frequently prescribed drugs are off-label. Therefore, there is necessity for an advance tactic for the treatment of autism. The endocannabinoid system has a central role in ruling emotion and social behaviors. Dysfunctions of the system donate to the behavioral deficits in autism. Therefore, the endocannabinoid system represents a potential target for the development of a novel autism therapy. Cannabis and associated compounds have produced substantial research attention as a capable therapy in neurobehavioral and neurological syndromes. In this review we examine the potential benefits of medical cannabis and related compounds in the treatment of ASD and concurrent disorders
... At the end of the implantation procedures, all rats received amoxicillin (100 mg/kg, sc) and they were placed individually in microdialysis bowls for recovery and habituation to the experimental conditions. The entire surgical procedure was followed according to previous reports (Murillo-Rodríguez et al., 2008. ...
... Under our experimental conditions, microinjections of CBD into LH promoted the enhancement of the extracellular levels of AD collected from AcbC. Although previous reports have shown that this cannabinoid modifies the activity of different neurochemical systems, including DA (Mechoulam et al., 2007;Murillo-Rodríguez et al., 2008, no evidence was available regarding the effects of CBD on the endogenous accumulation of AD. ...
Article
Cannabidiol (CBD) is a constituent of Cannabis sativa that promotes wakefulness as well as enhances endogenous levels of wake-related neurotransmitters, including dopamine. However, at this date, the effects of CBD on the sleep-inducing molecules, such as adenosine (AD), are unknown. Here, we report that intrahypothalamic injection of CBD (10μg/1μL) increases the extracellular levels of AD collected from nucleus accumbens. Furthermore, the pharmacodynamic of this drug shows that effects on the contents of AD last 2h post-injection. These preliminary findings suggest that CBD promotes the endogenous accumulation of AD.
... When administered intracranially into the DRN, WAY100635 was prepared in sterile SAL at 21 ng/0.5 μl (Herges and Taylor, 1999) and intracranially microinfused at 0.5 ul/min for 1 min. Intracranial CBD was prepared in 45% 2-hydroxypropyl-βcyclodextrin (2-HPβCD) at 10 μg/μl and intracranially microinfused into the DRN at 1 μl/min for 1 min (based on Murillo-Rodriguez et al., 2008). Paxinos and Watson, 1986) in the stereotaxic frame. ...
... 85,88 Administration of THC doses in the higher amount has been shown to have sleep-promoting effects over a short period of time; 89 however, long-term effects are not clearly known, particularly because of some evidence that long-term administration of THC actually reduces SWS. The non-psychoactive cannabinoid called cannabidiol is described as a wake promoting agent in contrast to THC. 90,91 This suggests that cannabinoids have a complex effect on the sleep-wake cycle and different preparations have varying effects ranging from sleep promotion to alertness and reduced somnolence. ...
Article
Pain and sleep share a bidirectional relationship, with each influencing the other. Several excellent reviews have explored this relationship. In this article, we revisit the evidence and explore existing research on this complex inter-relationship. The primary focus of the article is on the pharmacological treatment of chronic non-malignant pain and the main purpose is to review the effect of various pharmacological agents used in the management of chronic pain on sleep. This has not been comprehensively done before. We explore the clinical use of these agents, their impact on sleep architecture and sleep physiology, the mechanism of action on sleep parameters and sleep disorders associated with these agents. Pharmacological classes reviewed include antidepressants, opioid analgesics, anti-epileptics, cannabinoids and non-steroidal anti-inflammatory agents, drugs most commonly used to manage chronic pain. The objective is to help health professionals gain better insight into the complex effect that commonly used analgesics have on an individual’s sleep and how this could impact on the effectiveness of the drug as an analgesic. We conclude that antidepressants have both positive and negative effects on sleep, so do opioids, but in the latter case the evidence shifts towards the counterproductive side. Some anticonvulsants are sleep sparing and non-steroidal anti-inflammatory drugs (NSAIDs) are sleep neutral. Cannabinoids remain an underexplored and researched group.
... Furthermore, we have found that CBD enhanced the extracellular levels of dopamine collected from nucleus accumbens and induced an enhancement of c-Fos expression in wakingrelated brain areas, including hypothalamus and dorsal raphe nucleus (Murillo-Rodríguez et al. 2006). Similar results were obtained by injecting CBD into the lateral hypothalamus during the lights-on period at doses of 10 or 20 micrograms/1 microliter (Murillo-Rodríguez et al. 2008). Recently, Hsiao et al. (2012) showed that CBD efficiently blocked anxiety-induced REM sleep suppression. ...
Chapter
Sleep is a universal phenomenon that occurs in every species studied so far. A normal sleep period fluctuates in a regular cycle of two basic forms: slow wave sleep (SWS) and rapid eye movement (REM) sleep. The sleep–wake cycle is modulated by diverse brain circuits and neuromodulators as well as by several endogenous and exogenous molecules, including cannabinoids. Here, we describe the effects of certain cannabis-derived and synthetic cannabinoids on sleep. Additionally, we provide an overview of current knowledge about potential uses of natural or synthetic cannabinoids for the treatment of sleep disorders.
... However, the administration of CBD to rats resulted in an increase in total sleep time, although it also increased sleep latency (Chagas et al., 2013). This last observation may be concordant with the results of other preclinical studies that considered CBD as a wake-inducing agent (Murillo-Rodríguez et al., 2008b), a fact also found in humans (Nicholson et al., 2004). The mechanisms involved in these effects of CBD remains to be elucidated, but it has been proposed that its wake-inducing activity may be related to its in vitro properties as a CB 1 receptor antagonist (see details in Murillo-Rodríguez, 2008). ...
Chapter
After more than 50 years of research on plant-derived cannabinoids and more than 25 years after the identification of the first elements of the endocannabinoid signalling system in the brain, it is widely accepted that we have significantly progressed in the identification of the changes occurring in this system in numerous brain pathologies, as well as in the development of novel treatments for these disorders based on the elevation or the inhibition of the endocannabinoid activity. The present chapter has been designed with the idea of giving an overview of both aspects in those brain pathologies that have been more intensively studied in relation with cannabinoids; for example, motor disorders, pain, epilepsy, memory-related disorders, addiction and other psychiatric disorders, sleep disorders, nausea and vomiting, feeding disorders, neurodegeneration and brain cancer.
... Its systemic administration prolonged pentobarbitone sleep in mice [37] and reduced ambulation and operant behavior in rats [1,7,8]. However, when CBD was directly administered into specific wake-related areas, such as the lateral hypothalamus or dorsal raphe nuclei, an enhancement in rat alertness was observed [38]. Notably, the effect of CBD in humans is biphasic, exhibiting alerting properties at low doses and sedative actions at high doses [7]. ...
Article
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
... Regarding the parahippocampal gyrus, although its deactivation has been observed after panic attacks induced by lactate [31] or cholecystokinin-4 [32], spontaneous panic attacks have also been associated with the activation of this area [25]. Because the study of Crippa and colleagues [30] Clinical studies 400mg, p.o., single dose ↓ rCBF in posterior cingulated cortex; ↓ subjective anxiety and ↑ mental sedation [30] 600mg, p.o., single dose ↓ activation left temporal and insular cortex during motor inhibition task [36] 600mg, p.o., single dose ↓BOLD signal in fearful faces presentation [29] and ↓amygdala-anterior cingulated connectivity during fearful faces presentation [13] 400mg, p.o., single dose ↑ rCBF in posterior cingulated cortex and ↓ rCBF in temporal gyrus; ↓ generalized social anxiety disorder patients [39] Preclinical studies 30 10 and 20μg , intra-dorsal raphe nucleus, single dose ↓sleep [70] 5mg/Kg, i.p., single dose inhibited reward-facilitating effect of morphine via 5-HT1A receptor located in raphe nucleus [71] Raphe nuclei 5mg/Kg (s.c.) or 10μg (intra-dorsal raphe nucleus), single dose suppressed nausea via 5-HT1A [53] i.p. -intraperitoneal; i.c.v-intracerebroventricular; s.c-subcutaneal, BNST-bed nucleus striaterminalis, PAG-periaqueductal grey matter, CBF-cerebral blood flow; AEAanandamide. ...
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Full-text available
BACKGROUND Panic disorder (PD) is a disabling psychiatry condition that affects approximately 5% of the worldwide population. Currently, long-term selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PD; however, the common side-effect profiles and drug interactions may provoke patients to abandon the treatment, leading to PD symptoms relapse. Cannabidiol (CBD) is the major non-psychotomimetic constituent of the Cannabis sativa plant with anti-anxiety properties that has been suggested as an alternative for treating anxiety disorders. The aim of the present review was to discuss the effects and mechanisms involved in the putative anti-panic effects of CBD. METHODS electronic database was used as source of the studies selected selected based on the studies found by crossing the following keywords: cannabidiol and panic disorder; canabidiol and anxiety, cannabidiol and 5-HT1A receptor). RESULTS In the present review, we included both experimental laboratory animal and human studies that have investigated the putative anti-panic properties of CBD. Taken together, the studies assessed clearly suggest an anxiolytic-like effect of CBD in both animal models and healthy volunteers. CONCLUSION CBD seems to be a promising drug for the treatment of PD. However, novel clinical trials involving patients with the PD diagnosis are clearly needed to clarify the specific mechanism of action of CBD and the safe and ideal therapeutic doses of this compound.
... 42 CBD shows clearly a biphasic effect. In rats, very low doses of about 0.04 to 0.08 mg/kg, which would correspond roughly to a dose of about 3 to 6 mg CBD in humans, significantly enhanced the total time of waking in a dose-dependent fashion, 43 whereas higher doses of 160 to 600 mg increased sleep time and sedation in humans 44,45 as well as in animals. 46 CBD also positively affects REM sleep behavior disorder (RBD). ...
Article
Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC. Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive. Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further. Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today’s scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.
... Moreover, CBD seems to modulate diverse neurobiological functions, including the sleep-wake cycle. In this regard, it has been demonstrated that CBD enhances alertness as well as wake-related neurochemicals [35,[51][52][53][54]. Thus, we hypothesized that CBD might ameliorate the excessive sleepiness in narcoleptic-like animals. ...
Article
Full-text available
Background Excessive daytime sleepiness and cataplexy are among the symptoms of narcolepsy, a sleep disorder caused by the loss of hypocretin/orexin (HCRT/OX) neurons placed into the Hypothalamus (LH). Several treatments for managing narcolepsy include diverse drugs to induce alertness, such as antidepressants, amphetamine, or modafinil, etc. Recent evidence has shown that cannabidiol (CBD), a non-psychotropic derived from Cannabis sativa, shows positive therapeutic effects in neurodegenerative disorders, including Parkinson´s disease. Furthermore, CBD provokes alertness and enhances wake-related neurochemicals in laboratory animals. Thus, it is plausible to hypothesize that excessive somnolence observed in narcolepsy might be blocked by CBD. Objective Here, we determined whether the systemic injection of CBD (5mg/kg, i.p.) would block the excessive sleepiness in a narcoleptic model. Methods To test this idea, the neurotoxin hypocretin-2-saporin (HCRT2/SAP) was bilaterally injected into the LH of rats to eliminate HCRT leading to the establishment of narcoleptic-like behavior. Since excessive somnolence in HCRT2/SAP lesioned rats has been observed during the lights-off period, CBD was administered at the beginning of the dark phase. Results Hourly analysis of sleep data showed that CBD blocked the sleepiness during the lights-off period across 7h post-injection in lesioned rats. Conclusion Taking together, these preliminary findings suggest that CBD might prevent sleepiness in narcolepsy.
... In addition, it was found that CBD enhanced the extracellular levels of dopamine collected from nucleus accumbens, whereas an increase in c-Fos expression was detected in waking-related brain areas, such as hypothalamus and dorsal raphe nucleus (Murillo-Rodríguez et al. 2006a, b). 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. ...
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 alertness was observed after the first hour post-injection [14]. A similar effect on sleep was observed when CBD was injected into the lateral hypothalamus [15] suggesting that CBD behaves as a wakepromoting compound. Supporting this observation, it was also found that this cannabinoid increased c-Fos expression in wake-related brain areas, such as hypothalamic nuclei as well as dorsal raphe nuclei (DRN). ...
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Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased. Most attention has focused on ∆9-tetrahydrocannabinol (∆9-THC) as it is the psychoactive constituent of Cannabis sativa (C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropic properties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacological properties of CBD with significant findings; furthermore, this compound has raised promising pharmacological properties as a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role of CBD as a wake-inducing drug.
... 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. ...
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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.
... 11 CBD has a broad spectrum of pharmacological effects, including anxiolytic, antipsychotic, neuroprotective, anti-inflammatory and anti-emetic actions. 12,13 In addition to the effect of maintaining the stimulation of CB1 receptors by anandamide, CBD's anxiolytic effects in men 14-17 and animals, 18,19 its antidepressant properties 20 and biphasic effects on sleep [21][22][23] can be useful in the treatment of cannabis abstinence. CBD has proven to be a safe drug with no significant adverse effects in humans, even with chronic use 24 and in high doses. ...
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What is known and objective: Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB1 receptors by THC. Case summary: This report describes the case of a 19-year-old woman with cannabis withdrawal syndrome treated with cannabidiol (CBD) for 10 days. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment. What is new and conclusion: CBD can be effective for the treatment of cannabis withdrawal syndrome.
... When administered intracranially into the DRN, WAY100635 was prepared in sterile saline at a concentration of 21 ng in 0.5 mL (Herges and Taylor, 1999) and intracranially microinfused at 0.5 mL·min -1 for 1 min. Intracranial CBD was prepared in 45% 2-hydroxypropyl-b-cyclodextrin at 10 mg·mL -1 and intracranially microinfused into the DRN at 1 mL·min -1 for 1 min (based on Murillo-Rodriguez et al., 2008). In vitro experiments. ...
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Background and purpose: To evaluate the hypothesis that activation of somatodendritic 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis. Experimental approach: The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPγS binding in rat brainstem membranes. Key results: CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg·kg(-1) , but not 40 mg·kg(-1) )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. Conclusions and implications: These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT(1A) autoreceptors in the DRN. Linked articles: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
... Hz). The sleep and power spectra data were obtained during that period of time and were analyzed as previously reported [30,36]. For the microdialysis experiment, a different group of rats (n = 8) was implanted with a guide-cannula (IC guide. ...
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Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are amides of fatty acids and ethanolamine named N-acylethanolamines or acylethanolamides. The hydrolysis of OEA and PEA is catalyzed by the fatty acid amide hydrolase (FAAH). A number of FAAH inhibitors that increase the levels of OEA and PEA in the brain have been developed, including URB597. In the present report, we examined whether URB597, OEA or PEA injected into wake-related brain areas, such as lateral hypothalamus (LH) or dorsal raphe nuclei (DRN) would promote wakefulness (W) in rats. Male Wistar rats (250-300 g) were implanted for sleep studies with electrodes to record the electroencephalogram and electromyogram as well as a cannulae aimed either into LH or into DRN. Sleep stages were scored to determine W, slow wave sleep (SWS) and rapid eye movement sleep (REMS). Power spectra bands underly neurophysiological mechanisms of the sleep-wake cycle and provide information about quality rather than quantity of sleep, thus fast Fourier transformation analysis was collected after the pharmacological trials for alpha (for W; α = 8-12 Hz), delta (for SWS; δ = 0.5-4.0 Hz) and theta (for REMS; θ = 6.0-12.0 Hz). Finally, microdialysis samples were collected from a cannula placed into the nucleus accumbens (AcbC) and the levels of dopamine (DA) were determined by HPLC means after the injection of URB597, OEA or PEA. We found that microinjection of compounds (10, 20, 30 µg/1 µL; each) into LH or DRN during the lights-on period increased W and decreased SWS as well as REMS and enhanced DA extracellular levels. URB597, OEA or PEA promoted waking and enhanced DA if injected into LH or DRN. The wake-promoting effects of these compounds could be linked with the enhancement in levels of DA and indirectly mediated by anandamide.
... Although CBD has potential to treat a wide range of clinical conditions like disorders of generalized anxiety, social anxiety, panic, and PTSD (Blessing et al. 2015), and depressive disorders via serotonergic pathways (de Mello et al. 2014) and endocannabinoid system (Ashton and Moore 2011), more clinical research from well-designed clinical trials is needed to support its use in treating anxiety and depressive disorders and bipolar disorders (Ashton et al. 2005). CBD also may be effective in promoting wakefulness, via triggering increased dopamine levels in either lateral hypothalamus or dorsal raphe nuclei, the areas of brain responsible for wakefulness, suggesting that CBD could treat sleeping disorders such as narcolepsy (Murillo-Rodriguez et al. 2008). In fact, CBD did improve the quality and quantity of sleep of a 10-year-old young patient with PTSD, likely due to its anxiety-relieving benefits (Shannon and Opila-Lehman 2016). ...
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COVID-19 epidemic has resulted in devastating mortality and morbidity consisting of socioeconomic and health effects that have included respiratory/pulmonary, cardiovascular, mental health and neurological consequences such as anxiety, depression, and substance use. Several effective vaccines have been developed and extensive efforts are underway to develop therapeutics to treat COVID-19. Cannabis and/or its product-cannabidiol (CBD) are being advertised for the treatment of COVID-19 associated mental/neurological complications and substance use disorders. However, research reviewed shows that there is insufficient data from clinical studies to support the use of cannabis or CBD for the treatment of COVID-19 associated mental health and neurological complications. Additional basic and clinical research is suggested to develop cannabis or cannabidiol for the treatment of mental health problems associated with coronavirus infection and or substance use disorders. In the meantime, it is important that the addiction physician/psychiatrist must caution while prescribing or recommending cannabis or CBD for treating such clinical indications. Graphical abstract Research shows that currently there is no clinical evidence to support the use of cannabis or any of its compounds including CBD for treating any of the neuropsychiatric complications of COVID-19. Thus, it is important that the addiction physicians/psychiatrists caution their patients from using cannabis or cannabis products for treating any such complications.
... Additionally, it is worth noting that when administered intracerebroventricular (icv) in a dose of 10 μg/5 μL at the beginning of the lights-on period increased alertness, diminished sleep and increased dopamine (DA) levels (Murillo-Rodríguez et al. 2006). Furthermore, when administered into lateral hypothalamus (LH) during the lights-on period at doses of 10 or 20 μg/1 μL, enhanced wakefulness (W) and decreased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS; Murillo-Rodríguez et al. 2008). This result prompted us to question whether perfusion of CBD into a wake-inducing brain area such as LH would enhance alertness and induce an effect on DA levels collected from AcbC. ...
Article
The major non-psychoactive component of Cannabis sativa, cannabidiol (CBD), displays a plethora of actions including wakefulness. In the present study, we addressed whether perfusing CBD via microdialysis into lateral hypothalamus (LH) during the lights-on period would modify the sleep-wake cycle of rats as well as the contents of dopamine (DA) collected from nucleus accumbens (AcbC). Additionally, we tested whether perfusion of CBD into LH would block the sleep rebound after a sleep deprivation period. Electroencephalogram and electromyogram electrodes were implanted in rats as well as a guide-cannula aimed to LH or AcbC. CBD perfusion was carried out via cannulae placed into LH whereas contents of DA were collected from AcbC and analyzed using HPLC means. We found that microdialysis perfusion of CBD (30, 60, or 90 nM) into LH of rat enhances alertness and suppresses sleep. This effect was accompanied with an increase in DA extracellular levels collected from the AcbC. Furthermore, perfusion of CBD into LH after total sleep deprivation prevented the sleep rebound. These findings enhance the investigation about the neurobiological properties of CBD on sleep modulation.
... 9 A complementary study found reductions in slow-wave and REM sleep, accompanied by increased wakefulness after CBD infusion into the lateral hypothalamus and dorsal raphe nucleus. 10 CB 1 receptors are found in many brain areas, including those directly related to the regulation of the sleep-wake cycle. 11 In animal models, the activation of CB 1 receptors by anandamide, an endogenous cannabinoid, increased the duration of slow-wave and REM sleep and reduced wakefulness. ...
Article
What is known and objective: Cannabidiol (CBD) is the main non-psychotropic component of the Cannabis sativa plant. REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during REM sleep associated with nightmares and active behaviour during dreaming. We have described the effects of CBD in RBD symptoms in patients with Parkinson's disease. Cases summary: Four patients treated with CBD had prompt and substantial reduction in the frequency of RBD-related events without side effects. What is new and conclusion: This case series indicates that CBD is able to control the symptoms of RBD.
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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.
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Marijuana generally refers to the dried mixture of leaves and flowers of the cannabis plant, and the term cannabis is a commonly used to refer to products derived from the Cannabis sativa L. plant. There has been an increasing interest in the potential medicinal use of cannabis to treat a variety of diseases and conditions. This review will provide the latest evidence regarding the medical risks and potential therapeutic benefits of cannabis in managing patients with sleep disorders or those with other medical conditions who commonly suffer with sleep disturbance as an associated comorbidity. Published data regarding the effects of cannabis compounds on sleep in the general population, as well as in patients with insomnia, chronic pain, posttraumatic stress disorder, and other neurological conditions, will be presented. Current trends for marijuana use and its effects on the economy and the implications that those trends and effects have on future research into medical cannabis are also presented.
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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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The sleep-wake cycle is a complex composition of specific physiological and behavioral characteristics. In addition, neuroanatomical, neurochemical and molecular systems exerts influences in the modulation of the sleep-wake cycle. Moreover, homeostatic and circadian mechanisms interact to control the waking or sleeping states. As many other behaviors, sleep also develops pathological features that include several signs and symptoms corresponding to medical conditions known as sleep disorders.In addition to the neurobiological mechanisms modulating sleep, external elements also influence the sleep-wake cycle, including the use of Cannabis sativa (C. sativa). In this regard, and over the last decades, the interest of studying the pharmacology of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of C. sativa, has been addressed. Moreover, in recent years, the focus of scientific interest has moved on to studying the second plant constituent with non-psychotropic pharmacological properties: Cannabidiol (CBD).The pharmacological and pharmaceutical interest of CBD has been focus of attention due to the accumulating body of evidence regarding the positive outcomes of using CBD for the treatment of several health issues, such as psychiatric and neurodegenerative disorders, epilepsy, etc. Since the most prominent sleep disruptions include excessive daytime sleepiness (EDS), current treatments include the use of drugs such as stimulants of antidepressants. Notwithstanding, side effects are commonly reported among the patients under prescription of these compounds. Thus, the search of novelty therapeutical approaches aimed to treat ESD may consider the use of cannabinoid-derived compounds, such as CBD. In this chapter, we will show experimental evidence regarding the potential role of CBD as a wake-inducing compound aimed to manage EDS.
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The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology is rather puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.
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RationaleThe medical uses of cannabidiol (CBD), a constituent of the Cannabis sativa, have accelerated the legal and social acceptance for CBD-based medications but has also given the momentum for questioning whether the long-term use of CBD during the early years of life may induce adverse neurobiological effects in adulthood, including sleep disturbances. Given the critical window for neuroplasticity and neuro-functional changes that occur during stages of adolescence, we hypothesized that CBD might influence the sleep-wake cycle in adult rats after their exposure to CBD during the adolescence.Objectives Here, we investigated the effects upon behavior and neural activity in adulthood after long-term administrations of CBD in juvenile rats.Methods We pre-treated juvenile rats with CBD (5 or 30 mg/Kg, daily) from post-natal day (PND) 30 and during 2 weeks. Following the treatments, the sleep-wake cycle and NeuN expression was analyzed at PND 80.ResultsWe found that systemic injections of CBD (5 or 30 mg/Kg, i.p.) given to adolescent rats (post-natal day 30) for 14 days increased in adulthood the wakefulness and decreased rapid eye movement sleep during the lights-on period whereas across the lights-off period, wakefulness was diminished and slow wave sleep was enhanced. In addition, we found that adult animals that received CBD during the adolescence displayed disruptions in sleep rebound period after total sleep deprivation. Finally, we determined how the chronic administrations of CBD during the adolescence affected in the adulthood the NeuN expression in the suprachiasmatic nucleus, a sleep-related brain region.Conclusions Our findings are relevant for interpreting results of adult rats that were chronically exposed to CBD during the adolescence and provide new insights into how CBD may impact the sleep-wake cycle and neuronal activity during developmental stages.
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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.
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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ(9)-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.
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Marijuana extract, given in daily doses containing 70 to 210 mg delta-9-tetrahydrocannabinol (THC), induced effects on sleep that were virtually identical to those produced by the same doses of relatively pure (96%) THC. Both drugs reduced eye movements density with some tolerance developing to this effect. Stage 4 tendend to increase with drug administration. Abrupt withdrawal led to extremely high densities of eye movement, increased rapid eye movement (REM) durations, and a sharp but transient fall in stage 4 to baseline levels. These effects may be useful in the elucidation of the pharmacology of sleep. The effects on sleep of THC administration (but not withdrawal) closely resemble those induced by lithium. For this reason, we suggest further studies of THC in affective disorders. Evidence available thus far suggests that THC produces dysphoric symptoms in unipolar but not in bipolar depressed patients; these differences in response may prove of diagnostic value. An adequate therapeutic trial of THC in bipolar depressed patients has not yet been carried out.
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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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This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.
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Delta-9-tetrahydrocannabinol (Delta-9-THC) is the main psychoactive ingredient of cannabis (marijuana). The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC) and nabilone. The variability of THC in plant material (0.3% to 30%) leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152&mnplus;86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively). THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes) occurs via the feces and urine. Metabolites persist in the urine and feces for several weeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h). As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokinetic-pharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.
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Cannabidiol (CBD) is a major, biologically active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concentration-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concentration range. In signal transduction studies, CBD acts as an agonist at the human 5-HT1a receptor as demonstrated in two related approaches. First, CBD increases [35S]GTPgammaS binding in this G protein coupled receptor system, as does the known agonist serotonin. Second, in this GPCR system, that is negatively coupled to cAMP production, both CBD and 5-HT decrease cAMP concentration at similar apparent levels of receptor occupancy, based upon displacement data. Preliminary comparative data is also presented from the cloned rat 5-HT2a receptor suggesting that CBD is active, but less so, relative to the human 5-HT1a receptor, in binding analyses. Overall, these studies demonstrate that CBD is a modest affinity agonist at the human 5-HT1a receptor. Additional work is required to compare CBD's potential at other serotonin receptors and in other species. Finally, the results indicate that cannabidiol may have interesting and useful potential beyond the realm of cannabinoid receptors.
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Pharmacological inhibition of beta-amyloid (Abeta) induced reactive gliosis may represent a novel rationale to develop drugs able to blunt neuronal damage and slow the course of Alzheimer's disease (AD). Cannabidiol (CBD), the main non-psychotropic natural cannabinoid, exerts in vitro a combination of neuroprotective effects in different models of Abeta neurotoxicity. The present study, performed in a mouse model of AD-related neuroinflammation, was aimed at confirming in vivo the previously reported antiinflammatory properties of CBD. Mice were inoculated with human Abeta (1-42) peptide into the right dorsal hippocampus, and treated daily with vehicle or CBD (2.5 or 10 mg kg(-1), i.p.) for 7 days. mRNA for glial fibrillary acidic protein (GFAP) was assessed by in situ hybridization. Protein expression of GFAP, inducible nitric oxide synthase (iNOS) and IL-1beta was determined by immunofluorescence analysis. In addition, ELISA assay of IL-1beta level and the measurement of NO were performed in dissected and homogenized ipsilateral hippocampi, derived from vehicle and Abeta inoculated mice, in the absence or presence of CBD. In contrast to vehicle, CBD dose-dependently and significantly inhibited GFAP mRNA and protein expression in Abeta injected animals. Moreover, under the same experimental conditions, CBD impaired iNOS and IL-1beta protein expression, and the related NO and IL-1beta release. The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Abeta evoked neuroinflammatory responses.
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The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.
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Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.
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Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic effects of PrPres and affected PrPres-induced microglial cell migration in a concentration-dependent manner. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.
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In order to determine critical sites within the hypothalamus responsible for the induction and maintenance of wakefulness (W), we performed microinjections of muscimol, a potent F-aminobutyric acid (GABA) agonist, in various lateral hypothalamic regions of freely moving cats. We found that bilateral injections of a small amount of muscimol (0.1-1.0/ag/0.5 ~ul) in the preoptic and anterior hypothalamus and rostral mesencephalic tegmentum resulted in increased vigilance and insomnia. In contrast, microinjections of muscimol in the middle and anterior parts of the posterior hypothalamus induced long-lasting behavioral and electroencephalographic signs of sleep with short latency. The hypersomnia was characterized by a significant increase in both light and deep slow wave sleep (SWS), and a nearly complete suppression of paradoxical sleep (PS). Animals with muscimol microinjections in the ventrolateral part of the posterior hypothalamus, hovever, exhibited increased SWS followed by a significant increase in PS. When injected into the "msterior hypothalamus of insomniac cats pretreated with p-chiorophenylalanine (PCPA), muscimol induced not only SWS but also PS with short latency. The present data thus support the hypotheses that the posterior hypothalamus plays a critical role in the mechanisms of W and that sleep might result from functional blockade of the hypothalamic waking center.
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Anandamide (ANA) alters sleep by increasing the amount of time spent in slow wave sleep 2 (SWS2) and rapid eye movement sleep (REMS) at the expense of wakefulness (W) in rats. In this report, we describe a similar effect of ANA when injected itracerebroventricularly (i.c.v.) or into the peduriculopontine tegmental nucleus (PPTg) and the lack of an effect when ANA is administered into the medial preoptic area (MPOA). Furthermore, the i.c.v. or PPTg administration of SR141716A, a CB1 antagonist, or U73122, a PLC inhibitor, 15 min prior to ANA, readily prevents the ANA induced changes in sleep. The present results suggest that a cannabinoid system in the PPTg may be involved in sleep regulation and that the cannabinoid effect is mediated by the CB1 receptor coupled to a PLC second messenger system.
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Numerous lesion, stimulation and recording studies in experimental animals demonstrate the importance of neurons within the preoptic/anterior hypothalamic area (POA) in the regulation of sleep induction and sleep maintenance. Recently, a discrete cluster of cells in the ventrolateral POA (vlPOA) of rats was found to exhibit elevated c-fos gene expression during sleep, indicating that these neurons are strongly activated during nonREM and/or REM sleep stages. We examined neuronal discharge during wakefulness and sleep throughout the dorsal to ventral extent of the lateral POA in rats, using chronic microwire technique. We found that neurons with elevated discharge rates during sleep, compared to waking, were localized to the vlPOA. As a group, vlPOA neurons displayed elevated discharge rates during both nonREM and REM sleep. Discharge of vlPOA neurons reflected the depth of sleep, i.e., discharge rates increased significantly from light to deep nonREM sleep. During recovery sleep following 12–14 h of sleep deprivation, vlPOA neurons displayed increased sleep-related discharge, compared to baseline sleep. Neurons in the vlPOA displaying increased neuronal discharge during sleep were located in the same area where neurons exhibit increased c-fos gene expression during sleep. Such neurons are likely components of a rostral hypothalamic mechanism that regulates sleep onset and sleep maintenance.
Article
Electroencephalographic readings and eye movement were recorded in experienced marijuana users under placebo and tetrahydrocannabinol (THC). Four subjects were studied for 3 baseline nights, 3 nights under initial dosage of 70 mg/day, the last 3 nights of a 2-wk period of 210 mg/day, and the first 3 nights of withdrawal. Three other subjects were studied only during the latter 2 conditions. Administration of THC significantly reduced eye movement activity during sleep with rapid eye movements (REM) and, to a lesser extent, the duration of REM itself. Withdrawal led to increases above baseline in both measures but the "rebound" effect was greater for eye movement. Stage 4 sleep tended to increase on drug, but this effect was not statistically significant. On withdrawal, stage 4 sleep decreased significantly; this change was marked only on the first withdrawal night. The functional or biological significance of these changes is unclear. Nevertheless, these are the most marked effects of THC on brain electrical activity demonstrated thus far. Since its pattern of effects on sleep appears unique to THC, this drug may prove to be a valuable tool in the elucidation of the pharmacology of sleep. Possible relations between effects on sleep pattern and on behavior are discussed.
Article
Dorsal raphe unit activity in freely moving cats showed a slow, rhythmic discharge rate during quiet waking (X=2.82 +/- 0.17 spikes/sec), and displayed a strong positive correlation with level of behavioral arousal. Presentation of an auditory stimulus during quiet waking resulted in significant increases in unit activity of 112% and 39% during the first sec and first 10 sec after the stimulus, respectively. This effect rapidly habituated with repeated stimulus presentations. During active waking, unit activity was significantly increased by 22% as compared to quiet waking, but there was no correlation between unit activity and gross body movements. Raphe unit activity showed a significant decrease of 17% during drowsiness (first appearance of EEG synchronization) as compared to quiet waking, and then progressive decreases during the early (--34%), middle (--52%) and late (--68%) phases of slow wave sleep. During all phases of slow wave sleep, the occurrence of sleep spindles was frequently associated with a transitory decrease in unit activity. The discharge rate would typically decrease during the few seconds immediately preceding the spindle, remains at this low level during the occurrence of the spindle, and then increase immediately after the spindle. Raphe unit activity showed decreases of 81% during pre-REM (the 60 sec immediately before REM onset) and 98% during REM, as compared to quiet waking. Unit activity reappeared 3.2 sec before the end of REM, with significant increases in unit activity of 83% and 17% during the first sec and first 10 sec of unit activity, respectively, as compared to quiet waking. The results of these studies are discussed in relation to the hypothesis that serotonin may play a modulatory, rather than mediative, role in behavioral and physiological processes.
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
In order to determine critical sites within the hypothalamus responsible for the induction and maintenance of wakefulness (W), we performed microinjections of muscimol, a potent gamma-aminobutyric acid (GABA) agonist, in various lateral hypothalamic regions of freely moving cats. We found that bilateral injections of a small amount of muscimol (0.1-1.0 micrograms/0.5 microliters) in the preoptic and anterior hypothalamus and rostral mesencephalic tegmentum resulted in increased vigilance and insomnia. In contrast, microinjections of muscimol in the middle and anterior parts of the posterior hypothalamus induced long-lasting behavioral and electroencephalographic signs of sleep with short latency. The hypersomnia was characterized by a significant increase in both light and deep slow wave sleep (SWS), and a nearly complete suppression of paradoxical sleep (PS). Animals with muscimol microinjections in the ventrolateral part of the posterior hypothalamus, however, exhibited increased SWS followed by a significant increase in PS. When injected into the posterior hypothalamus of insomniac cats pretreated with p-chlorophenylalanine (PCPA), muscimol induced not only SWS but also PS with short latency. The present data thus support the hypotheses that the posterior hypothalamus plays a critical role in the mechanisms of W and that sleep might result from functional blockade of the hypothalamic waking center.
Article
A sample of hashish was extracted consecutively with petroleum ether, benzene, and methanol. When tested intravenously in monkeys only the petroleum-ether fraction was active. This material was further fractionated. The only active compound isolated was Δ1-tetrahydrocannabinol. Cannabinol, cannabidiol, cannabichromene, cannabigerol, and cannabicyclol when administered together with Δ1-tetrahydrocannabinol do not cause a change in the activity of the latter, under the experimental conditions used. These results provide evidence that, except for Δ1-tetrahydrocannabinol, no other major, psychotomimetically active compounds are present in hashish.
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.
Article
Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic patients conducted in the authors' laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.
Article
For direct measurement of the extracellular concentration of serotonin (5-HT) in the dorsal raphe nucleus (DRN) over the sleep-wake cycle we used the technique of in vivo microdialysis in six freely moving, naturally sleeping cats whose behavioral state was polygraphically determined. Perfusate samples from microdialysis probes histologically localized to the DRN showed the following significantly different levels of extracellular 5-HT, with the numbers in parentheses indicating successively the mean value in fmol/5 microliters perfusate sample, the % level relative to waking, and the sample n: waking (4.02, 100%, n = 38) > slow wave sleep (2.02, 50%, n = 30) > REM sleep (1.61, 38%, n = 17). These data, to our knowledge the first direct DRN 5-HT measurements during behavioral state changes, directly parallel the levels of serotonergic neuronal action potential activity and suggest that DRN extracellular 5-HT is determined by this action potential activity through synaptic release by recurrent axonal collaterals in the DRN.
Article
The effects of the central (CB1) cannabinoid receptor antagonist SR 141716A on the sleep-waking cycle were investigated in freely-moving rats using time scoring and power spectral analysis of the electroencephalogram (EEG). Over a 4-hour recording period, SR 141716A (0.1, 0.3, 1, 3, and 10 mg/kg I.P.) dose-dependently increased the time spent in wakefulness at the expense of slow-wave sleep (SWS) and rapid eye movement sleep (REMS), delayed the occurrence of REMS but did not change the mean duration of REMS episodes. Moreover, the compound induced no change in motor behavior. At the efficient dose of 3 mg/kg I.P., SR 141716A reduced the spectral power of the EEG signals typical of SWS but did not affect those of wakefulness. Taken together, these results demonstrate that the EEG effects of SR 141716A reflect arousal-enhancing properties. In addition, the present study suggests that an endogenous cannabinoid-like system is involved in the control of the sleep-waking cycle.
Article
Cannabis is one of the most widely used drugs throughout the world. The psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (delta 9-THC), produces a myriad of pharmacological effects in animals and humans. For many decades, the mechanism of action of cannabinoids, compounds which are structurally similar to delta 9-THC, was unknown. Tremendous progress has been made recently in characterizing cannabinoid receptors both centrally and peripherally and in studying the role of second messenger systems at the cellular level. Furthermore, an endogenous ligand, anandamide, for the cannabinoid receptor has been identified. Anandamide is a fatty-acid derived compound that possesses pharmacological properties similar to delta 9-THC. The production of complex behavioral events by cannabinoids is probably mediated by specific cannabinoid receptors and interactions with other neurochemical systems. Cannabis also has great therapeutic potential and has been used for centuries for medicinal purposes. However, cannabinoid-derived drugs on the market today lack specificity and produce many unpleasant side effects, thus limiting therapeutic usefulness. The advent of highly potent analogs and a specific antagonist may make possible the development of compounds that lack undesirable side effects. The advancements in the field of cannabinoid pharmacology should facilitate our understanding of the physiological role of endogenous cannabinoids.
Article
Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum. The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana. Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system.
Article
Over the past few years, considerable attention has focused on cannabidiol (CBD), a major nonpsychotropic constituent of cannabis. The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors, and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.
Article
Chronic experiments were performed on cats to study neuron spike activity in the lateral preoptic region of the hypothalamus in active and calm arousal and in the slow-wave and paradoxical phases of sleep. The dynamics of spike frequencies and the patterns of activity in the sleep-waking cycle allowed neurons to be divided into three populations. Cells showing increases in the frequency of single spikes as the level of consciousness decreased, on the transition to slow-wave sleep and then to the paradoxical phase of sleep were assigned to the "anti-waking" system, which, being a component of the somnogenic system of the brain, is involved in the mechanisms initiating and increasing the depth of sleep by inactivating the arousal-maintaining system. Cells with maximum spike frequencies in light, slow-wave sleep and demonstrating single and train discharges in association with "sleep" spindles, were regarded as elements of the system responsible for forming this state. The remaining neurons had activity characteristics which were similar in the active arousal state and paradoxical sleep and decreased their spike frequencies in calm arousal and the slow-wave phase of sleep in parallel with the transition from the continuous-arithmetic to the mixed type of activity. Changes in the activity of this type of cell during the sleep-waking cycle appear to reflect rearrangements in controlling influences from the somnogenic and arousal systems of the brain.
Article
Cataplexy, a symptom associated with narcolepsy, represents a unique dissociation of behavioural states. During cataplectic attacks, awareness of the environment is maintained, as in waking, but muscle tone is lost, as in REM sleep. We have previously reported that, in the narcoleptic dog, noradrenergic cells of the locus coeruleus cease discharge during cataplexy. In the current study, we report on the activity of serotonergic cells of the dorsal raphe nucleus. The discharge patterns of serotonergic dorsal raphe cells across sleep-waking states did not differ from those of dorsal raphe and locus coeruleus cells recorded in normal rats, cats and monkeys, with tonic discharge in waking, reduced activity in non-REM sleep and cessation of activity in REM sleep. However, in contrast with locus coeruleus cells, dorsal raphe REM sleep-off neurones did not cease discharge during cataplexy. Instead, discharge continued at a level significantly higher than that seen in REM sleep and comparable to that seen in non-REM sleep. We also identified several cells in the dorsal raphe whose pattern of activity was the opposite of that of the presumed serotonergic cells. These cells were maximally active in REM sleep and minimally active in waking and increased activity during cataplexy. The difference between noradrenergic and serotonergic cell discharge profiles in cataplexy suggests different roles for these cell groups in the normal regulation of environmental awareness and muscle tone and in the pathophysiology of narcolepsy.
Article
The principal component of marijuana, delta-9-tetrahydrocannabinol increases sleep in humans. Endogenous cannabinoids, such as N-arachidonoylethanolamine (anandamide), also increase sleep. However, the mechanism by which these molecules promote sleep is not known but might involve a sleep-inducing molecule such as adenosine. Microdialysis samples were collected from the basal forebrain in order to detect levels of adenosine before and after injection of anandamide. Rats were implanted for sleep studies, and a cannula was placed in the basal forebrain to collect microdialysis samples. Samples were analyzed using high-performance liquid chromatography. Basic neuroscience research laboratory. Three-month-old male F344 rats. At the start of the lights-on period, animals received systemic injections of dimethyl sulfoxide (vehicle), anandamide, SR141716A (cannabinoid receptor 1 [CB1] antagonist), or SR141716A and anandamide. One hour after injections, microdialysis samples were collected (5 microL) from the basal forebrain every hour over a 20-minute period for 5 hours. The samples were immediately analyzed via high-performance liquid chromatography for adenosine levels. Sleep was also recorded continuously over the same period. Anandamide increased adenosine levels compared to vehicle controls with the peak levels being reached during the third hour after drug injection. There was a significant increase in slow-wave sleep during the third hour. The induction in sleep and the rise in adenosine were blocked by the CB1-receptor antagonist, SR141716A. Anandamide increased adenosine levels in the basal forebrain and also increased sleep. The soporific effects of anandamide were mediated by the CB1 receptor, since the effects were blocked by the CB1-receptor antagonist. These findings identify a potential therapeutic use of endocannabinoids to induce sleep in conditions where sleep may be severely attenuated.
Article
The effects of cannabis extracts on nocturnal sleep, early-morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg Delta-9-tetrahydrocannabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm. The electroencephalogram was recorded during the sleep period (11 pm to 7 am). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 am (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combination, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC.
Article
Cannabinoid receptors in the brain (CB(1)) take part in modulation of learning, and are particularly important for working and short-term memory. Here, we employed a delayed-matching-to-place (DMTP) task in the open-field water maze and examined the effects of cannabis plant extracts rich in either Delta(9)-tetrahydrocannabinol (Delta(9)-THC), or rich in cannabidiol (CBD), on spatial working and short-term memory formation in rats. Delta(9)-THC-rich extracts impaired performance in the memory trial (trial 2) of the DMTP task in a dose-dependent but delay-independent manner. Deficits appeared at doses of 2 or 5 mg/kg (i.p.) at both 30 s and 4 h delays and were similar in severity compared with synthetic Delta(9)-THC. Despite considerable amounts of Delta(9)-THC present, CBD-rich extracts had no effect on spatial working/short-term memory, even at doses of up to 50 mg/kg. When given concomitantly, CBD-rich extracts did not reverse memory deficits of the additional Delta(9)-THC-rich extract. CBD-rich extracts also did not alter Delta(9)-THC-rich extract-induced catalepsy as revealed by the bar test. It appears that spatial working/short-term memory is not sensitive to CBD-rich extracts and that potentiation and antagonism of Delta(9)-THC-induced spatial memory deficits is dependent on the ratio between CBD and Delta(9)-THC.
Article
The neurochemical control of learning depends on several neurotransmitters, hormones, and neuropeptides. Cortistatin is a neuropeptide with sleep-modulating properties that regulates memory consolidation and evocation. Several reports have suggested that learning processes are expressed under diurnal variations; therefore, it seems that the efficiency to solve learning tasks is related to the arousal state. Although we know that cortistatin modulates learning, we do not know whether its effect is subjected to diurnal variations. Hence, we evaluated memory evocation and the sleep-waking cycle along the day. Additionally, we evaluated the effect of cortistatin on motor control and cyclic adenosine monophosphate (cAMP) concentration. Performance of rats was better at 01:00 h than at 13:00 h to solve the Barnes maze. Cortistatin impaired memory evocation, increased rapid-eye-movement (REM) sleep, and decreased wakefulness at 01:00 h, whereas increasing it at 13:00 h. Cortistatin blunts cAMP concentration and impairs motor control at 13:00 h. These results support further a cortistatin modulatory role in the memory process.
Article
Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by 6-hydroxydopamine, both in vivo and in vitro, which may be relevant to Parkinson's disease (PD). First, we evaluated whether the administration of cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of dopamine contents and a reduction of tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of delta9-tetrahydrocannabinol (delta9-THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of delta9-THC appeared to be irreversible since interruption of the daily administration of this cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same neuroprotective effect was also produced by cannabidiol (CBD), another plant-derived cannabinoid with negligible affinity for cannabinoid CB1 receptors, suggests that the antioxidant properties of both compounds, which are cannabinoid receptor-independent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether cannabinoids also provide neuroprotection against the in vitro toxicity of 6-hydroxydopamine. We found that the non-selective cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the cannabinoid was directly added to neuronal cultures than when these cultures were exposed to conditioned medium obtained from mixed glial cell cultures treated with HU-210, suggesting that the cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of cannabinoids against the in vivo and in vitro toxicity of 6-hydroxydopamine, which might be relevant for PD. Our data indicated that these neuroprotective effects might be due, among others, to the antioxidant properties of certain plant-derived cannabinoids, or exerted through the capability of cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms.
Article
Through their widespread projections to the entire brain, dorsal raphe cells participate in many physiological functions and are associated with neuropsychiatric disorders. In previous studies, the width of action potentials was used as a criterion to identify putative serotonergic neurons, and to demonstrate that cells with broad spikes were more active in wakefulness, slowed down their activity in slow wave sleep and became virtually silent during paradoxical sleep. However, recent studies reported that about half of these presumed serotonergic cells were not immunoreactive for tyrosine hydroxylase. Here, we re-examine the electrophysiological properties of dorsal raphe cells across the sleep-wake cycle in rats by the extracellular recording of a large sample of single units (n = 770). We identified two major types of cells, which differ in spike waveform: a first population characterized by broad, mostly positive spikes, and a second one displaying symmetrical positive-negative spikes with a large distribution of spike durations (0.6-3.2 ms). Although we found classical broad-spike cells that were more active in wakefulness, we also found that about one-third of these cells increased or did not change their firing rate during sleep compared with wakefulness. Moreover, 62% of the latter cells were active in paradoxical sleep when most of raphe cells were silent. Such a diversity in the neuronal firing behaviour is important in the light of the recent controversy regarding the neurochemical identity of dorsal raphe cells exhibiting broad spikes. Our results also suggest that the dorsal raphe contains subpopulations of neurons with reciprocal activity across the sleep-wake cycle.
Article
Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol (CBD) are two major constituents of Cannabis sativa. Delta(9)-THC modulates sleep, but no clear evidence on the role of CBD is available. In order to determine the effects of CBD on sleep, it was administered intracerebroventricular (icv) in a dose of 10 microg/5 microl at the beginning of either the lights-on or the lights-off period. We found that CBD administered during the lights-on period increased wakefulness (W) and decreased rapid eye movement sleep (REMS). No changes on sleep were observed during the dark phase. Icv injections of CBD (10 microg/5microl) induced an enhancement of c-Fos expression in waking-related brain areas such as hypothalamus and dorsal raphe nucleus (DRD). Microdialysis in unanesthetized rats was carried out to characterize the effects of icv administration of CBD (10 microg/5 microl) on extracellular levels of dopamine (DA) within the nucleus accumbens. CBD induced an increase in DA release. Finally, in order to test if the waking properties of CBD could be blocked by the sleep-inducing endocannabinoid anandamide (ANA), animals received ANA (10 microg/2.5 microl, icv) followed 15 min later by CBD (10 microg/2.5 microl). Results showed that the waking properties of CBD were not blocked by ANA. In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD. Both regions are apparently involved in the generation of alertness. Also, CBD increases DA levels as measured by microdialysis and HPLC procedures. Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence.
Article
Cannabidiol (CBD) is a major constituent of the Cannabis sativa plant. It inhibits the anxiogenic activity of high doses of Delta9-tetrahydrocannabinol and induces anxiolytic-like effects. However, the mechanisms underlying the actions of CBD are unknown. Therefore, the aim of the present study was to test the effects of CBD in the Vogel test, a widely used animal model of anxiety. In addition, it was verified if these effects would depend on benzodiazepine-receptor activation. After 24 h of water deprivation, male Wistar rats were subjected to an initial 3-min non-punished (pre-test) drinking session. This was followed by an additional 24-h period of water deprivation followed by a 3-min punished-licking session (test). Diazepam (3 mg/kg) or CBD (2.5, 5 or 10 mg/kg) were intraperitoneally injected 30 min before the test session. CBD (10 mg/kg) and diazepam had similar anticonflict effects, increasing the number of punished licks. The effect of diazepam, but not of CBD, was prevented by the benzodiazepine-receptor antagonist flumazenil (10 mg/kg). To exclude that the anticonflict effects were reflecting non-specific drug effects, we checked the effects of CBD on water consumption and nociceptive response. The drug did not interfere on the former variable in a non-punished test session. Moreover, contrary to morphine (5 mg/kg), CBD was ineffective in the tail-flick test. In conclusion, CBD induced an anticonflict effect not mediated by benzodiazepine receptors or by non-specific drug interference on nociceptive threshold or water consumption. These results reinforce the hypothesis that this cannabinoid has anxiolytic properties.
Article
A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2 receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells. The [35S]GTPS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB1 and the human CB2 receptor. This paper reports firstly that cannabidiol displays inverse agonism at the human CB2 receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB2 receptors. This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor. The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties.
Article
Our group has described previously that the endogenous cannabinoid anandamide induces sleep. The hydrolysis of this lipid involves the activity of the fatty acid amide hydrolase (FAAH), which additionally catalyzes the degradation of the satiety factor oleoylethanolamide and the analgesic-inducing lipid palmitoylethanolamide. It has been demonstrated that the inhibition of the FAAH by URB597 increases levels of anandamide, oleoylethanolamide and palmitoylethanolamide in the brain of rats. In order to determinate the physiological properties of the FAAH inhibition on the sleep modulation, we report the pharmacological effects on the sleep-wake cycle of the rat after i.c.v. administrations of URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl). Separate unilateral i.c.v. injections of 3 compounds during the lights-on period, increased wakefulness and decreased slow wave (SW) sleep in rats in a dose-dependent fashion. We additionally found out that, compared to controls, c-Fos immunoreactivity in hypothalamus and dorsal raphe nucleus was increased in rats that received URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl, i.c.v.). Next, we found that after an injection of the compounds, levels of dopamine were increased whereas extracellular levels of levodopa (l-DOPA) were decreased. These findings indicate that that inhibition of the FAAH, via URB597, modulates waking. These effects were mimicked separately by the administration of oleoylethanolamide or palmitoylethanolamide. The alertness induced by the compounds tested here activated wake-promoting brain regions and they also induced the release of dopamine. Our results suggest that FAAH activity as well as two molecules that are catalyzed by this enzyme, oleoylethanolamide and palmitoylethanolamide, participate in the regulation of the waking state. Alternative approaches to treat sleep disorders such as excessive somnolence might consider the use of the URB597, oleoylethanolamide or palmitoylethanolamide since all compounds enhance waking.
Article
Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.
Article
We investigated whether administration of MOD in rats during the lights-on period into wake-promoting areas, such as anterior hypothalamus (AH) or into the pedunculopontine tegmental nucleus (PPTg) would enhance waking. Results showed that microinjections of 1 microL of MOD (10, 20, or 30 microg) into both brain areas increased the total time of alertness and decreased sleep. Additionally, MOD-treated rats showed an enhancement in alpha power spectra but delta power spectra was diminished. Finally, c-Fos expression was found increased into either AH or the PPTg. Collectively, these results suggest that MOD induces waking via the activity of two wake-related brain areas such as AH and the PPTg.
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Pharmacokinetics of cannabinoids. Pain Research & Management
  • I J Mcgilveray
McGilveray, I. J. (2005). Pharmacokinetics of cannabinoids. Pain Research & Management, 10(Suppl. SA),15A-22A.