Article

Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats

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  • Universidad Anáhuac Mayab. Mérida, Yucatán. México
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Abstract

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.

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... 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
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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.
... 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]. ...
... 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]. 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]. ...
... 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]. ...
Article
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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
... Selective blocking of CB1 receptors in rats increased wake and decreased SWS and REM in a dose-dependent manner [18]. Intracerebroventricular (ICV) administration of anandamide in rats during the light-on period decreased wake and increased SWS and REM; while CBD increased wake and decreased REM sleep [19,20]. The effects of endocannabinoids on sleep are more prominent when injected into the REM regulating pedunculopontine tegmental nucleus [21]. ...
... In previous reports, administration of selective CB1 receptor blocker in a dosedependent manner via IP route enhanced arousal in the rats [18]. Rodriguez et al., have performed ICV injection of CBD, a CB1 receptor antagonist, during lights on period, and demonstrated an increase in wakefulness and a decrease in REM sleep in rats [19]. We applied the antagonist at the MS nucleus, while Rodriguez et al., applied at ICV. ...
... In some reports, the drug administration time to see the effect of the acute or sub-chronic effect of endocannabinoids on SW pattern has been done in both lights-on and lights-off period, and the researchers have observed the 24 h sleep pattern post-drug administration [17,38]. However, based on the protocols of many previous reports [3,19,20,26], we have observed the 4-hour post-injection effect of the drug on sleep in the present study. One of the limitations of our study is the lack of a dose-response curve, as it was beyond the scope of the current study. ...
Article
The role of medial septum in the genesis of slow-wave sleep and the inhibition of rapid eye movement sleep has been established using neurotoxic lesion and chemical stimulation of the medial septum. Intracerebroventricular injection of endocannabinoids (anandamide) decreases wake and increases slow-wave and rapid eye movement sleep in rats. Central cannabinoid (CB1) receptors are localized in the rat medial septum; however, the role of cannabinoid receptors at the medial septum on the regulation of sleep-wakefulness in rats lacks evidence. In this study, we have examined the changes in sleep architecture of 21 male Wistar rats, divided into three groups. Initially, 6 rats were used for dose standardization. Subsequently, one group (n=6) was microinjected with CB1 receptor agonist, R-(+)-WIN 55,212-2 mesylate salt, the second group (n=6) received microinjection of CB1 receptor antagonist LY 320135, and the third group (n=5) was microinjected with the vehicle, DMSO at the medial septum using stereotaxy. The sleep-wake cycle was recorded using electroencephalogram, electro-oculogram, and electromyogram. Microinjection of CB1 receptor agonist at the medial septum decreased slow-wave sleep and increased total sleep time. The increase in total sleep time was due to an increased percentage of rapid eye movement sleep. After the third and fourth hour of CB1 receptor antagonist microinjection at the medial septum, slow-wave sleep decreased when compared to vehicle injection, while rapid eye movement sleep decreased compared to baseline. We conclude that the endocannabinoid system at the septal nucleus acts through CB1 receptors to increase rapid eye movement sleep in rats.
... [1][2][3] Cannabis alters the sleep-wake cycle, increases the production of melatonin, and can inhibit the arousal system by activating cannabinoid type 1 (CB 1 ) receptors in the basal forebrain and other wakepromoting centers. [9][10][11][12] Investigations have shown that the major psychoactive compound in cannabis, ∆ 9 -tetrahydrocannabinol (THC), can decrease sleep onset latency in naïve users or at low doses in experienced users (eg, 70 mg/day); however, higher doses in experienced users increased sleep latency and wake after sleep onset. 9,13,14 Indeed, frequent cannabis users (≥5 uses/week for 3 months and lifetime use ≥2 years) are reported to have shorter total sleep duration, less slow wave sleep, worse sleep efficiency, and longer sleep onset compared to controls. ...
... [16][17][18][19] In addition to THC, hundreds of other compounds exist in cannabis products such as the non-psychoactive cannabidiol, cannabinol, and terpenes, which can also impact sleep and wakefulness. 9,12,20 Individuals who obtain cannabis at medical dispensaries or for recreational use are also more likely to use alternative ingestion methods including edibles, concentrates (eg, dabbing), or extracts applied topically as oils or balms. [21][22][23] Studies on the impact of these ingestion methods are limited, and the health consequences specific to vaping and dabbing remain largely unknown. ...
Article
Full-text available
Nicole P Bowles, Maya X Herzig, Steven A Shea Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USAThe recent legalization of cannabis for medical and recreational use in many states in the United States and internationally4,5 has resulted in a decrease in stigma and of perceived risk of cannabis use, more frequent use of cannabis, use of higher potency cannabis products, and increased dependence on cannabis use.6–8 Cannabis sativa and its derivatives are often used for improved sleep and relaxation; characteristics originally attributed to Indian hemp in the nineteenth century.1–3 Cannabis alters the sleep–wake cycle, increases the production of melatonin, and can inhibit the arousal system by activating cannabinoid type 1 (CB1) receptors in the basal forebrain and other wakepromoting centers.9–12 Investigations have shown that the major psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), can decrease sleep onset latency in naïve users or at low doses in experienced users (eg, 70 mg/day); however, higher doses in experienced users increased sleep latency and wake after sleep onset.9,13,14 Indeed, frequent cannabis users (≥5 uses/week for 3 months and lifetime use ≥2 years) are reported to have shorter total sleep duration, less slow wave sleep, worse sleep efficiency, and longer sleep onset compared to controls.15 The contrasting benefits of THC exposure may represent the biphasic influence of THC on CB1 receptors whereby acute use causes more activation of CB1 receptors and tendency toward sleep, but long-term use results in desensitization of the CB1 receptor and decreased downstream signaling.
... The same happens with CBD. An activating effect was demonstrated following intracerebroventricular CBD administration in rats (Murillo- Rodríguez et al., 2006), and after the application of an oromucosal spray with a combination of CBD and THC in humans ( Nicholson et al., 2004). However, intraperitoneal injection of CBD in rats had an hypnotic effect (Monti, 1977). ...
... Vaporization provides delivery characteristics that are similar to smoking, without the toxicants that are present due to combustion (Shiplo et al., 2016). While large amount of research has focused on the administration of smoked, oral or injected cannabinoids (Feinberg et al., 1976;Monti, 1977;Murillo-Rodríguez et al., 2006;Russo et al., 2007), at the moment, there is no published research about the effects of vaporized Cannabis on sleep, either in laboratory animals or in humans. ...
Article
Studies exploring the effect of compounds that modulate the endocannabinoid system on sexual behavior have yielded contradictory results. However, the effect of smoked Cannabis in women has been consistently associated with an increase in sexual drive. Therefore, it can be speculated that vaporized cannabis will augment sexually motivated components of the sexual behavior of female rats. To test this hypothesis, we compared the sexual behavior of late-proestrous female rats in a bilevel chamber after vaporizing 0, 200 or 400 mg of Cannabis flowers (containing 18% of delta-9-THC and undetectable levels of cannabidiol) during 10 min. We found that both doses of Cannabis increased the duration of the lordosis response, whereas the highest dose also reduced the lordosis quotient of females. The lowest dose of Cannabis augmented the display of hops and darts without altering the expression of sexual solicitations of females, while the highest one did not affect the expression of hops and darts but reduced sexual solicitations. These effects were not accompanied by alterations of females' ambulatory behavior. The increment of the duration of lordosis response produced by both doses of Cannabis could be associated to a general effect of this drug in sensory processing, as can be an enhancement of females' sensory reactivity to male's stimulation. However, the reduction in the display of solicitations and lordosis in response to mounting observed in females exposed to the highest dose when compared to control and 200 mg of Cannabis groups indicates a reduction of sexual receptivity and motivation. This differential effect of vaporized Cannabis according to the dose employed, suggests that it modulates sexual behavior in a complex way, impacting neural circuits that control different aspects of this social behavior.
... Accordingly, systemic administration of CB 1 /CB 2 receptor agonists increases TH, the enzyme that limits the synthesis of NA, and the synthesis of NA in the LC and its projection areas such as HC, cerebral cortex (CC), HT and cerebellum (Moranta et al. 2004;Page et al. 2007) (Table 8.2). However, activation of the CB 1 receptor by local administration of URB597 or application of the CB 1 receptor allosteric modulator cannabidiol (CBD) fails to significantly change c-Fos expression in the LC (Murillo-Rodríguez et al. 2006. The release of NA in noradrenergic terminals (i.e. ...
... Taking into account that the cannabinoid effect on serotonergic cells is stimulatory, these neurochemical actions could be the result of local inhibitory mechanisms related to the CB 1 receptor in the projection areas. On the other hand, the application of the non-psychoactive cannabinoid CBD enhances cFos expression in the DRN (Murillo-Rodríguez et al. 2006). However, in contrast to classical cannabinoids, CBD does not increase the firing activity of DRN serotonergic cells (see Sect. 8.3.3.1). ...
Chapter
The main noradrenergic and serotonergic nuclei in the central nervous system (CNS) are the locus coeruleus (LC) and the dorsal raphe nucleus (DRN). These brain areas, located in the brainstem, play a pivotal role in the control of various functions and behaviors that are altered by cannabinoids (i.e., pain, arousal, mood, anxiety, or sleep-wake cycle). Anatomical, neurochemical, and functional data suggest that cannabinoids regulate both central noradrenergic and serotonergic neurotransmission. Thus, strong evidence has shown that the firing activity of LC and DRN monoamine neurons or the synthesis/release of noradrenaline (NA) and serotonin (5-HT) in the projection areas are all affected by cannabinoid administration. Herein, we propose that interaction between the endocannabinoid system and the noradrenergic-serotonergic systems could account for some of the anxiolytic, antidepressant, and antinociceptive effects of cannabinoids or the disruption of attention/sleep induced by these drugs.
... The same happens with CBD. An activating effect was demonstrated following intracerebroventricular CBD administration in rats (Murillo-Rodríguez et al., 2006), and after the application of an oromucosal spray with a combination of CBD and THC in humans (Nicholson et al., 2004). However, intraperitoneal injection of CBD in rats had an hypnotic effect (Monti, 1977). ...
... Vaporization provides delivery characteristics that are similar to smoking, without the toxicants that are present due to combustion (Shiplo et al., 2016). While large amount of research has focused on the administration of smoked, oral or injected cannabinoids (Feinberg et al., 1976;Monti, 1977;Murillo-Rodríguez et al., 2006;Russo et al., 2007), at the moment, there is no published research about the effects of vaporized Cannabis on sleep, either in laboratory animals or in humans. ...
... Cannabidiol (CBD), a non-psychotropic compound derived from Cannabis sativa, shows positive therapeutic effects in the treatment of multiple health issues, such as epilepsy, pain, nausea, anxiety, among many others (Fraguas-Sánchez and Torres-Suárez, 2018;Friedman et al., 2019;Millar et al., 2019;Premoli et al., 2019;Pretzsch et al., 2019;Samanta, 2019). In addition, CBD exerts modulatory properties in the sleep-wake cycle by increasing alertness as well as wake-related neurochemicals (Murillo-Rodríguez et al., 2006, 2017. ...
... It cannot be discarded that the HU-580 could modify the activity of catechol-O-methyltransferase, adenosine monophosphate or choline acetyltransferase activity. Previous reports have demonstrated that CBD and CBDA modify enzymatic activities (Murillo-Rodríguez et al., 2006;De Petrocellis et al., 2011;Pellati et al., 2018) suggesting that HU-580 might display similar effects. We assume that in the near future, additional studies should address the effects of HU-580 on the enzymatic activity of synthesis and/or metabolism of DA, 5-HT, AD or ACh. ...
... Blockade of CB1 receptors inhibited apoptosis in β-cells under stress from obesity and STZ toxicity as described in a recent study, implicating CB1 receptor blockade is a useful strategy in preventing β-cell apoptosis in T1D [53]. The cannabinoids D9-THC and cannabidiol are unique terpenophenols isolated from Cannabis sativa [54]. NOD mice treated with either of these compounds exhibited a significant reduction in plasma levels of the pro-inflammatory cytokines, IFN-γ and TNF-α. ...
... Cuminaldehyde (54) and cuminol (55) isolated from Cuminum cyminum have long been known for their inhibitory activity against aldose reductase, and α-glucosidase [150]. Recently, cuminaldehyde and cuminol were shown to exert their protective action in β-cells by maintenance of the closure of the ATP-sensitive K (KATP) channel and by increasing intracellular Ca² + concentration in the islet T-cells, thus lowering glucose levels, without causing hypoglycemia [151]. ...
... Multiple experiments have suggested the key role of nucleus accumbens (AcbC) in sleep modulation (Lazarus et al., 2012Lazarus et al., , 2013Qiu et al., 2012;Zhang et al., 2013;Liu et al., 2016). Furthermore, previous studies from our laboratory have indicated reliable measurements of monoamines as well as AD from AcbC (Murillo-Rodríguez et al., 2006;MijangosMoreno et al., 2014). Thus, these evidences allowed us to collect microdialysis samples from AcbC to determine whether sleep changes provoked by AA-5-HT might be linked with effects in neurotransmitters contents. ...
... 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.
... 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. ...
... In addition, we have identified several limitations in our study. First, we assume that the increase in waking might be related to an enhancement in monoamines and/or acetylcholine availability as consequence of CBD treatment as previously reported [52,55]. Thus, the activity of the locus coeruleus (LC) and/or basal forebrain (BF) might play a central role in the effects described. ...
Article
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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.
... CBD as like as other cannabinoids can induce biphasic effects; stimulatory at low doses and sedating at high doses [90]. It has been shown that intraventricular administration of CBD increases waking and reduces REM sleep period [91]. Also, administration of CBD into the lateral hypothalamus increases waking, reduces REM sleep period, and reduces SWS [92]. ...
... It has been shown that administration of CBD enhances wakefulness in humans [100]. Furthermore, microinjection of CBD also increases waking in rats [91]. Administration of CBD at the beginning of the lights-on period increases waking and decreases REM sleep [101]. ...
Article
Cannabis sativa (Marijuana) has a long history as a medicinal plant and Δ9-tetrahydrocannabinol (Δ9-THC) is the most active component in this plant. Cannabinoids are interesting compounds with various modulatory effects on physiological processes and cognitive functions. The use of cannabinoids is a double-edged sword, because they induce both adverse and therapeutic properties. One of the most important roles of cannabinoids is modulating sleep-wake cycle. Sleep, its cycle, and its mechanism are highly unknown. Also, the effects of cannabinoids on sleep-wake cycle are so inconsistent. Thus, understanding the role of cannabinoids in modulating sleep-wake cycle is a critical scientific goal. Cannabinoids interact with many neurotransmitter systems. In this review article, we chose serotonin due to its important role in regulating sleep-wake cycle. We found that the interaction between cannabinoids and serotonergic signaling especially in the dorsal raphe is extensive, unknown, and controversial.
... Indeed, a recent study indicated that CBD (i.e. 30 mg/kg i.p.) enhances alertness, and decreases slow wave sleep and REM sleep during the 'lights-on' period in rats (101). These effects were associated with increases in neuronal activation of lateral hypothalamus and dorsal raphe nuclei (areas implicated in alertness control) and elevated extracellular dopamine concentrations (98,99), consistent with the well-documented role for dopamine in mediating wakefulness and arousal (102). Given the favourable safety profile of CBD in humans, this initial evidence provides impetus to translate the findings into a properly designed RCT of CBD as an adjunctive treatment in individuals with excessive daytime sleepiness such as in patients with narcolepsy, OSA, and idiopathic hypersomnolence. ...
Article
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.
... 403 This activity underlies its neutralizing actions on THC side effects such as anxiety, tachycardia, and sedation. [404][405][406][407][408][409] CBD seems to attenuate some of the negative side effects of THC when the CBD:THC ratio is at least 8:1 (± 11.1), but CBD may potentiate some of the THC side effects when the CBD:THC ratio is around 2:1 (± 1.4). 407,409 CBD was also shown to reduce cognitive and memory impairments that have been attributed to THC. 410 It is an inverse agonist at the CB2 receptor, which may contribute to its anti-inflammatory effects. ...
Article
Background.—Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/ cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described. Most of the existing literature reports on the cannabinoids Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain. Objective.—Review the medical literature for the use of cannabis/cannabinoids in the treatment of migraine, headache, facial pain, and other chronic pain syndromes, and for supporting evidence of a potential role in combatting the opioid epidemic. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis. Summarize the individual medicinal benefits of these substances, including analgesic and anti-inflammatory properties. Conclusion.—There is accumulating evidence for various therapeutic benefits of cannabis/cannabinoids, especially in the treatment of pain, which may also apply to the treatment of migraine and headache. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards. Further research is anticipated to optimize breeding of strain-specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and diseasetargeted therapies.
... CBD may possibly act on circadian clock genes and melatonin production (Lafaye et al., 2018). Moreover, preclinical intracerebral perfusion of CBD could prevent sleep rebound after total sleep deprivation (Murillo-Rodríguez et al., 2011) and increase wakefulness in the lights-on period, supporting a clinical alerting effect for this agent in managing somnolence (Babson et al., 2017;Murillo-Rodríguez et al., 2006;Scuderi et al., 2009). On the other hand, CBD-induced sedation has been shown both in animal and human studies, supposedly because of a corticotropin releasing hormone (CRH)-related gene downregulation (Lafaye et al., 2018;Russo et al., 2007). ...
Article
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the most represented phytocannabinoids in Cannabis sativa plants. However, CBD may present with a different activity compared with the psychotomimetic THC. Most typically, CBD is reported to be used in some medical conditions, including chronic pain. Conversely, the main aim of this systematic review is to assess and summarise the available body of evidence relating to both efficacy and safety of CBD as a treatment for psychiatric disorders, alone and/or in combination with other treatments. Eligible studies included randomized controlled trials (RCT) assessing the effect of CBD in a range of psychopathological conditions, such as substance use; psychosis, anxiety, mood disturbances, and other psychiatric (e.g., cognitive impairment; sleep; personality; eating; obsessive-compulsive; post-traumatic stress/PTSD; dissociative; and somatic) disorders. For data gathering purposes, the PRISMA guidelines were followed. The initial search strategy identified some n = 1301 papers; n = 190 studies were included after the abstract's screening and n = 27 articles met the inclusion criteria. There is currently limited evidence regarding the safety and efficacy of CBD for the treatment of psychiatric disorders. However, available trials reported potential therapeutic effects for specific psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety. Further large-scale RCTs are required to better evaluate the efficacy of CBD in both acute and chronic illnesses, special categories, as well as to exclude any possible abuse liability.
... While CBD seems unlikely to directly influence sleep in healthy humans [115] (and may be "sleep-promoting" in those with certain comorbid conditions) [26,32,157], a small number of rodent studies suggest that the cannabinoid could actually be "wake-inducing" [128,132,204]. One placebo-controlled, double-blinded (single-dose) crossover trial of healthy individuals (n = 8) [137] also found that low-dose CBD (15 mg) counteracted some of the sedative effects of co-administered Δ 9 -THC (15 mg), i.e. increasing overnight wakefulness; although, this effect could be due to CBD acting as a NAM of CB 1 R, thereby attenuating Δ 9 -THCs effects on that receptor [92]. ...
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Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.
... Sleep Disorders: There is limited preclinical or clinical evidence for supporting the use of cannabinoids for treating sleep disorders. CBD promoted wakefulness in rats [86], possibly via increasing levels of dopamine in brain regions responsible for wakefulness [87], suggesting that CBD could be further developed for treating narcolepsy. In a case report, CBD administration was linked to improved quality and quantity of sleep of a 10-year-old patient with PTSD, perhaps due to CBD's anxiolytic effects [88]. ...
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Purpose of review There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines. Recent findings Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity. Summary Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.
... Interestingly, previous studies using systemic CBD administration have reported both effects of CBD on spontaneous activity patterns in VTA neuronal populations (French et al, 1997) or increases in mesolimbic DA release (Murillo-Rodríguez et al, 2006). These discrepancies are likely due to differences in administration routes, as the present study exclusively used targeted microinfusions into the NASh vs systemic administration. ...
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Emerging evidence suggests that the largest phytochemical component of cannabis, cannabidiol (CBD), may possess pharmacotherapeutic properties in the treatment of neuropsychiatric disorders. CBD has been reported to functionally interact with both the mesolimbic dopamine (DA) and serotonergic (5-HT) receptor systems. However, the underlying mechanisms by which CBD may modulate emotional processing are not currently understood. Using a combination of in vivo electrophysiological recording and fear conditioning in rats, the present study aimed to characterize the behavioral, neuroanatomical, and pharmacological effects of CBD within the mesolimbic pathway, and its possible functional interactions with 5-HT and DAergic transmission. Using targeted microinfusions of CBD into the shell region of the mesolimbic nucleus accumbens (NASh), we report that intra-NASh CBD potently blocks the formation of conditioned freezing behaviors. These effects were challenged with DAergic, cannabinoid CB1 receptor, and serotonergic (5-HT 1A) transmission blockade, but only 5-HT 1A blockade restored associative conditioned freezing behaviors. In vivo intra-ventral tegmental area (VTA) electrophysiological recordings revealed that behaviorally effective doses of intra-NASh CBD elicited a predominant decrease in spontaneous DAergic neuronal frequency and bursting activity. These neuronal effects were reversed by simultaneous blockade of 5-HT 1A receptor transmission. Finally, using a functional contralateral disconnection procedure, we demonstrated that the ability of intra-NASh CBD to block the formation of conditioned freezing behaviors was dependent on intra-VTA GABAergic transmission substrates. Our findings demonstrate a novel NAc → VTA circuit responsible for the behavioral and neuronal effects of CBD within the mesolimbic system via functional interactions with serotonergic 5-HT 1A receptor signaling.
... Moreover, previous reports have shown that histones are engaged in CBD-related effects [7,8]. Since we have previously reported that CBD promotes wakefulness [9][10][11][12], thus it was reasonable to hypothesize that this cannabinoid could exert influence on the histone activity in wake-related brain areas specially since histones have been linked to sleep modulation [13][14][15][16][17][18]. Therefore, we investigated the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels after systemic injections of CBD (20mg/Kg/i.p.) in the cerebral cortex, hypothalamus and pons of rats. ...
Article
Background: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity. Aim: This study assessed the changes on the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20mg/Kg/i.p.). Objective: To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats. Method: Ten adult rats were randomly assigned into 2 groups: Control or CBD (20mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure. Results: CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD-treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2. Conclusion: The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.
... Higher CBD content may thus increase therapeutic effects and potentially protect against THC-induced adverse effects ( McPartland et al., 2015;Niesink & van Laar, 2013); however, as yet, no outcome studies exist specifically addressing links between CBD:THC content and anxiety ( Blessing et al., 2015;Haney & Evins, 2015). Preclinical literature also suggests beneficial effects in treating comorbid depression ( Zanelati, Biojone, & Moreira, 2010) although effects of CBD on sleep quality may not necessarily be beneficial, potentially increasing alertness ( Murillo-Rodriguez, Millan-Aldaco, & Palomero-Rivero, 2006;Nicholson, Turner, Stone, & Robson, 2004). Regarding the potential propsychotic effects of marijuana, CBD has been associated with antipsychotic effects, both preclinically, and in human trials ( Leweke, Mueller, Lange, & Rohleder, 2016). ...
Article
Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first-line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids’ potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids’ effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research.
... CBD has been proposed as a negative allosteric modulator of CB 1 -mediated signaling (Laprairie et al., 2015;Pertwee et al., 2002;Straiker et al., 2018). However, CBD could indirectly increase anandamide levels through inhibition of its metabolism/uptake (Bisogno et al., 2001;Murillo-Rodriguez et al., 2006;Pertwee, 2008). CBD and anandamide, therefore, could activate TRPV1 receptors, facilitating glutamate release. ...
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An ever‐increasing body of preclinical studies has shown the multifaceted neuroprotective profile of cannabidiol (CBD) against impairments caused by cerebral ischemia. In this study, we have explored the neuropharmacological mechanisms of CBD action and its impact on functional recovery using a model of transient global cerebral ischemia in mice. C57BL/6J mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min and received vehicle or CBD (10 mg/Kg) 0.5 h before and 3, 24, and 48 h after reperfusion. To investigate the neuropharmacological mechanisms of CBD, the animals were injected with CB1 (AM251, 1 mg/kg), CB2 (AM630, 1 mg/kg), 5‐HT1A (WAY‐100635, 10 mg/kg) or PPAR‐γ (GW9662, 3 mg/kg) receptor antagonists 0.5 h prior to each injection of CBD. The animals were evaluated using a multi‐task testing battery that included the open field (OF), elevated zero maze (EZM), Y‐maze (YM), and forced swim test (FST). CBD prevented anxiety‐like behavior, memory impairments, and despair‐like behaviors induced by BCCAO in mice. The anxiolytic‐like effects of CBD in BCCAO mice were attenuated by CB1, CB2, 5‐HT1A, and PPAR‐γ receptor antagonists. In the YM, both CBD and the CB1 receptor antagonist AM251 increased the exploration of the novel arm in ischemic animals, indicating beneficial effects of these treatments in the spatial memory performance. Together, these findings indicate the involvement of CB1, CB2, 5‐HT1A, and PPAR‐γ receptors in the functional recovery induced by CBD in BCCAO mice.
... It has been reported that in both humans and animals, CBD increases the wakefulness state. These apparently antagonistic results regarding CBD in anxiety and sleep may be explained by the biphasic nature of its effects, producing alertness properties at low doses and sedative actions at higher doses [34][35][36]. Thus, it is possible that in a new environment, as was the arena used to assess sexual behavior in our study, the CBD 30 group may have exhibited the anxiolytic properties of CBD, which may have contributed to the improved sexual performance of the animals. ...
... CBD has much lower affinity for CB1 or CB2 receptors, and acts as an antagonist of CB1 and CB2 agonists such as THC [276]. At low concentrations, its antagonism of CB1 underlies its neutralizing effects on the CB1 agonist THC side effects such as anxiety, tachycardia, and sedation [283][284][285][286][287][288]. CBD appears to attenuate some of these negative side effects of THC when the CBD:THC ratio is at least 8:1 (± 11.1), but may potentiate some of the THC side effects when the CBD:THC ratio is around 2:1 (± 1.4) [286,288]. ...
Article
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Background Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis. Methods Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded. Cannabis use for migraine among headache patients was assessed via the ID Migraine™ questionnaire, a validated screen used to predict the probability of migraine. Results Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 “Yes” responses, 20% (n = 102) giving 2 “Yes” responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with “OG Shark” the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2–59.5%), most commonly opiates/opioids (40.5–72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%). Conclusions Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with “OG Shark”, a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes β-caryophyllene and β-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.
... PhyCBs have been shown to exhibit promising efficacy towards many conditions including, i) CNS disorders (Hill, Williams, Whalley, & Stephens, 2012); ii) convulsions (Hill et al., 2010); iii) neurodegeneration (Gilbert, Kim, Waataja, & Thayer, 2007;Zani, Braida, Capurro, & Sala, 2007), iv) epilepsy (Cunha et al., 1980;dos Santos, Hallak, Leite, Zuardi, & Crippa, 2015); v) sleep disorders (Murillo-Rodríguez (Murillo-Rodriguez, Millan-Aldaco, Palomero-Rivero, Mechoulam, & Drucker-Colin, 2006) and vi) inflammation (Costa et al., 2004). ...
Article
Opioid receptors (ORs), μOR, δOR, κOR and ORL1 mediate numerous signaling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly μOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a μOR antagonist (for example. naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signaling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signaling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the 'Holy Grail' of analgesics, for example, ignavine, the natural μOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and ҡ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.
... Prior findings have demonstrated that systemic and central administrations of CBD increase alertness. However, it is worthy to mention that these studies were developed in adult animals and under acute pharmacological experimental trials (Murillo-Rodríguez et al. 2006, 2011Mijangos-Moreno et al. 2014). Clearly, these data provide great significance for public health in regard to the long-term effects of CBD in adulthood if they are relevant to chronic uses in adolescents. ...
Article
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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.
... Diverse effects of CBD were over time detected depending on medication doses, with higher doses up to 160 mg/day increasing sedative-hypnotic effects [69,70]. Such effects were hypothesized to be mediated by the monoaminergic system since CBD appeared to increase the expression of c-Fos in the dorsal raphe nuclei [71]. Furthermore, CBD can increase Anandamide (AEA) concentration by blocking the AEA membrane transporter (AMT) or the Fatty Acid Amide Hydrolase (FAAH) enzyme, which catalyzes AEA hydrolysis, increasing time of sleep and of slow-wave phase that is physiologically fostered by this endogenous CB1 ligand [72]. ...
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Post-Traumatic Stress Disorder (PTSD) is a complex disorder involving dysregulation of stress-related hormones and neurotransmitter systems. Research focused on the endocannabinoid system (eCBS) for anxiety and stress regulation, cognitive and emotional responses modulation and aversive memories extinction, leading to the hypothesis that it could represent a possible alternative treatment target for PTSD. In this systematic review, we summarize evidence about the efficacy and safety of medicinal cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), and nabilone in PTSD treatment. The PRISMA statement guidelines were followed. A systematic literature search was conducted in MEDLINE/PubMed, Scopus and Web of Science by two independent researchers, who also performed data extraction and quality assessment. Among the initial 495 papers, 234 were screened for eligibility and 10 were included. Studies suggested that different medicinal cannabinoids at distinct doses and formulations could represent promising treatment strategies for the improvement of overall PTSD symptomatology as well as specific symptom domains (e.g., sleep disorders, arousal disturbances, suicidal thoughts), also influencing quality of life, pain and social impact. Although there is a robust rationale for treatment with drugs that target the eCBS and the results are promising, further studies are needed to investigate the safety and efficacy profile of their prolonged use.
... In the CNS, CBD has been shown to possess antiinflammatory actions, thus being useful for neuroinflammatory diseases [119], and therapy of spasticity and pain [120]. Based on its anticonvulsant roles, CBD has been used as a therapy for epilepsy [121], and also for the therapy for sleep disorders [122] due to its capability to control serotonin transmission [123]. CBD possesses interesting roles for psychiatric disorders, such as schizophrenia [124], but it also presents other possible actions, such as anxiolytic and antidepressant roles [125,126]. ...
Article
Parkinson's disease (PD) is a major neurodegenerative disease (ND), presenting a progressive degeneration of the nervous system characterized by a loss of dopamine in the substantia nigra pars compacta. Recent findings have shown that oxidative stress and inflammation play key roles in the development of PD. However, therapies remain uncertain and research for new treatment is of the utmost importance. This review focuses on the potential effects of using cannabidiol (CBD) as a potential therapeutic strategy for the treatment of PD and on some of the presumed mechanisms by which CBD provides its beneficial properties. CBD medication downregulates GSK-3β, the main inhibitor of the WNT/β-catenin pathway. Activation of the WNT/β-catenin could be associated with the control of oxidative stress and inflammation. Future prospective clinical trials should focus on CBD and its multiple interactions in the treatment of PD.
... CBD possesses the unique ability to counteract the intoxicating and adverse effects of cannabis, such as anxiety, tachycardia, hunger, and sedation in rats and humans (Murillo-Rodriguez, Millan-Aldaco, Palomero-Rivero, Mechoulam, & Drucker-Colin, 2006;Nicholson, Turner, Stone, & Robson, 2004;Russo, 2011;Russo & Guy, 2006). The benefits of CBD include reducing the unwanted side effects of THC, a dynamic pharmaco- logical effect that has been fairly well studied in clinical trials. ...
Chapter
The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed “pharmacological treasure trove.”
... PhyCBs have been shown to exhibit promising efficacy towards many conditions including, i) CNS disorders (Hill, Williams, Whalley, & Stephens, 2012); ii) convulsions (Hill et al., 2010); iii) neurodegeneration (Gilbert, Kim, Waataja, & Thayer, 2007;Zani, Braida, Capurro, & Sala, 2007), iv) epilepsy (Cunha et al., 1980;dos Santos, Hallak, Leite, Zuardi, & Crippa, 2015); v) sleep disorders (Murillo-Rodríguez (Murillo-Rodriguez, Millan-Aldaco, Palomero-Rivero, Mechoulam, & Drucker-Colin, 2006) and vi) inflammation (Costa et al., 2004). ...
Article
The organized tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without the unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB2 selective affinity, the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from market for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules.
... CBD shows lower CB 1 and CB 2 receptor affinity with respect to Δ9-THC. In the presence of Δ 9 -THC, it is able to antagonize CB 1 at low nanomolar concentrations, finding that supports its regulatory properties on Δ 9 -THC related adverse effects like tachycardia, anxiety, sedation and hunger in humans and rats (Murillo-Rodríguez, Millán-Aldaco, Palomero-Rivero, Mechoulam, & Drucker-Colín, 2006;Nicholson, Turner, Stone, & Robson, 2004;Russo & Guy, 2006). Indeed, both human and animal studies suggest anxiolytic properties associated with CBD. ...
... The sleep-wake cycle is controlled by multiple neurochemical substrates, including exogenous and endogenous cannabinoids (Buonamici et al. 1982;Carlini and Cunha 1981;Feinberg et al. 1975Feinberg et al. , 1976Freemon 1972;Monti 1977;Murillo-Rodríguez et al. 2006a, b, 2008, 2011aNicholson et al. 2004;Pivik et al. 1972). In this chapter, we revised that phytocannabinoids modulate the sleep-wake cycle. ...
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.
Article
Methamphetamine (METH) is a widely abused and a severely addictive psychostimulant. Relapse is the main cause of concern when treating addiction. It could manifest after a long period of abstinence. Previous studies showed that there is a strong connection between sleep impairment and relapse. Also, it has been reported that cannabidiol might be a potential treatment for drug craving and relapse. In this study, we used conditioned place preference (CPP) to investigate whether Cannabidiol (CBD), a phytocannabinoid, can prevent METH-induced reinstatement in Rapid Eye Movement Sleep Deprived (RSD) rats. In order to induce CPP, the animals were given METH (1mg/kg; sc) for five days. The effective priming dose of METH (0.5mg/kg, sc) reinstated the extinguished METH-induced CPP. In order to investigate the effect of RSD on METH-induced reinstatement, we used the inverted flowerpot technique to deprive the rats of REM sleep. We found that 24h-RSD could facilitate priming-induced reinstatement of METH. In addition to this, the ICV administration of CBD 10μg/5μl could suppress the METH-induced reinstatement even in RSD rats. In conclusion, the administration of CBD 10μg/5μl effectively prevents METH-induced CPP, even in a condition of stress. CBD can be considered an agent that reduces the risk of the relapse; however, this requires more investigation.
Article
Despite increasing use of Medical Cannabis (MC) among posttraumatic stress disorder (PTSD) patients, research is lacking on how MC treatment relates to PTSD symptomatology, in particular sleep disturbances. This study examines the time gap between MC use and sleep onset and its association with (1) number of awakenings throughout the night, (2) early awakenings, (3) nightmares. Each morning over a two week period, 77 licensed MC patients suffering from PTSD reported on the timing of previous night MC use and sleep disturbances. Within-person analyses found that shorter time gaps between previous night MC use and sleep start time was associated with lower likelihood of experiencing nightmares throughout the night, but it was not associated with nightly awakenings or waking up too early. Between-person analyses showed that individuals who used MC products with higher CBD concentrations reported fewer early awakenings. These preliminary results indicate that future research should test causal relations between MC use and sleep problems in PTSD patients. Future research is warranted in order to explore causal relationships between MC use, nightmares and insomnia in PTSD patients.
Article
Most of the drugs of abuse affect the brain by interacting with naturally expressed molecular receptors. Marihuana affects a series of receptors including cannabinoid receptor 1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid system modulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. However, this very same anatomical and physiological distribution makes this system a useful target for therapeutic endeavors. In this review, we briefly discuss the potential of small molecules that target the endocannabinoids as therapeutic tools to improve behaviors and treat illnesses. We believe that under medical supervision, endocannabinoid targets offer new advantages for patients for controlling multiple medical disorders.
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Background: There is a growing interest in the use of cannabis (and its extracts), as well as CBD oil (hemp extracts containing cannabidiol), for therapeutic purposes. While there is reason to believe that cannabinoids may be efficacious for a number of different diseases and syndromes, there exist limited objective data supporting the use of crude materials (CBD oil, cannabis extracts, and/or cannabis itself). Summary: In the present review, we examined data for pure cannabinoid compounds (dronabinol, nabilone, and CBD), as well as partially purified medicinal cannabis extracts (nabiximols), to provide guidance on the potential therapeutic uses of high-THC cannabis and CBD oil. In general, data support a role for cannabis/cannabinoids in pain, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting. Given the biological activities of the cannabinoids, there may be utility in treatment of central nervous system disorders (such as neurodegenerative diseases, PTSD, and addiction) or for the treatment of cancer. However, those data are much less compelling. Key Message: On balance, there are reasons to support the potential use of medical cannabis and cannabis extract (Δ9-THC-dominant or CBD-dominant), but much more careful research is required.
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A complex neurobiological network drives the sleep-wake cycle. In addition, external stimuli, including stimulants or depressor drugs, also influence the control of sleep. Here we review the recent advances that contribute to the comprehensive understanding of the actions of stimulants and depressor compounds, such as alcohol and cannabis, in sleep regulation. The objective of this review is to highlight the neurobiological mechanism engaged by alcohol and cannabis in sleep control.
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The endocannabinoid system (ECS) is a widespread cell signaling network that maintains homeostasis in response to endogenous and exogenous stressors. This has made the ECS an attractive therapeutic target for various disease states. The ECS is a well-known target of exogenous phytocannabinoids derived from cannabis plants, the most well characterized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, the therapeutic efficacy of cannabis products comes with a risk of toxicity and high abuse potential due to the psychoactivity of THC. CBD, on the other hand, is reported to have beneficial medicinal properties including analgesic, neuroprotective, anxiolytic, anticonvulsant, and antipsychotic activities, while apparently lacking the toxicity of THC. Nevertheless, not only is the currently available scientific data concerning CBD’s efficacy insufficient, there is also ambiguity surrounding its regulatory status and safety in humans that brings inherent risks to manufacturers. There is a demand for alternative compounds combining similar effects with a robust safety profile and regulatory approval. Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator, primarily known for its anti-inflammatory, analgesic and neuroprotective properties. It appears to have a multi-modal mechanism of action, by primarily activating the nuclear receptor PPAR-α while also potentially working through the ECS, thus targeting similar pathways as CBD. With proven efficacy in several therapeutic areas, its safety and tolerability profile and the development of formulations that maximize its bioavailability, PEA is a promising alternative to CBD.
Chapter
Good sleep is vital for good health, and poor sleep, in particular insomnia, is associated with a range of poor health outcomes. Sleep disorders are common and a key reason why people self-medicate with cannabis. We have two key biological mechanisms which work together to regulate our sleep-wake cycle, the processes of sleep-wake homeostasis and our circadian rhythms. The endocannabinoid system is involved in the circadian sleep-wake cycle, including maintenance and promotion of sleep, and may provide the link between the circadian regulation systems and the physiological process of sleep. Cannabis has been used for centuries to treat sleep disorders. Preclinical and clinical evidence indicate that cannabidiol and tetrahydrocannabinol may have a role to play in the treatment of sleep disorders.
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The popularity of cannabidiol (CBD) in consumer products is soaring as consumers are using CBD for general health and well-being as well as to seek relief from ailments especially pain, inflammation, anxiety, depression, and sleep disorders. However, there is limited data currently in the public domain that provide support for these benefits. By contrast, a significant amount of safety evaluation data for CBD has been obtained recently from pre-clinical and clinical studies of the CBD therapeutic Epidiolex®. Yet some key data gaps concerning the safe use of CBD still remain. Furthermore, current regulations on CBD use in consumer products remain uncertain and often conflict between the state and federal level. In light of the rapidly expanding popularity of CBD-related products in the marketplace, here we review the current understanding of the benefits, safety, and regulations surrounding CBD in consumer products. This review does not advocate for or against the use of CBD in consumer products. Rather this review seeks to assess the state-of-the-science on the health effects and safety of CBD, to identify critical knowledge gaps for future studies, and to raise the awareness of the current regulations that govern CBD use in consumer products.
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Despite the fact that medical properties of Cannabis have been recognized for more than 5000 years, the use of Cannabis for medical purposes have recently reemerged and became more accessible. Cannabis is usually employed as a self-medication for the treatment of insomnia disorder. However, the effects of Cannabis on sleep depend on multiple factors such as metabolomic composition of the plant, dosage and route of administration. In the present chapter, we reviewed the main effect Cannabis on sleep. We focused on the effect of “crude or whole plant” Cannabis consumption (i.e., smoked, oral or vaporized) both in humans and experimental animal models.
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Cannabis has been shown to be beneficial in the treatment of pain and inflammatory diseases. The biological effect of cannabis is mainly attributed to two major cannabinoids, tetrahydrocannabinol and cannabidiol. In the majority of studies to-date, a purified tetrahydrocannabinol and cannabidiol alone or in combination have been extensively examined in many studies for the treatment of numerous disorders including pain and inflammation. However, few studies have investigated the biological benefits of full-spectrum cannabis plant extract. Given that cannabis is known to generate a large number of cannabinoids along with numerous other biologically relevant products including terpenes, studies involving purified tetrahydrocannabinol and/or cannabidiol may not precisely consider the potential biological benefits of the full-spectrum cannabis extracts. This may be especially true in the role of cannabis as a treatment of pain and inflammation. Herein, we review the pre-clinical physiological and molecular mechanisms in biological systems that are affected by cannabis.
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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.
Chapter
The cannabinoids are a family of chemical compounds that can be either synthesized or naturally derived. These compounds have been shown to modulate a wide variety of biological processes. In this chapter, the studies detailing the effects of cannabinoids on sleep in laboratory animals are reviewed. Both exogenous and endogenous cannabinoids generally appear to decrease wakefulness and alter rapid eye movement (REM) and non-REM sleep in animal models. In addition, cannabinoids potentiate the effects of sedative-hypnotic drugs. However, the individual contributions of each cannabinoid on sleep processes is more nuanced and may depend on the site of action in the central nervous system. Many studies investigating the mechanism of cannabinoid effects on sleep suggest that the effects of cannabinoids on sleep are mediated via cannabinoid receptors; however, some evidence suggests that some sleep effects may be elicited via non-cannabinoid receptor-dependent mechanisms. More research is necessary to fully elucidate the role of each compound in modulating sleep processes.
Chapter
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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Medical marijuana and the promise of medical advances with cannabinoids is a controversial topic. This book provides clinicians with credible, peer-reviewed science to advise patients on the use of cannabinoids in practice. From the history of cannabis to the recent discoveries, chapters include the science of cannabinoids, changes in the legal and regulatory landscape, and the emerging area of endocannabinoids. The book differentiates approved cannabinoids from cannabis and medical marijuana and stimulates clinicians to think about the risks and benefits of these two drugs. It provides the factual background for clinicians to lead the discussion on the continued use of marijuana, ongoing areas of research and future advances and development of new medications for treatment. An invaluable guide for all specialists in the pharmaceutical sciences, toxicologists, biochemists, neurologists, psychiatrists, addiction specialists, as well as primary care physicians, nurse practitioners, and regulators and policymakers.
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Five new compounds including three new cannabinoids, cannabisativas A–C (1–3), two new phenolic acids, (7Z,9Z)-cannabiphenolic acid A (4) and (8S,9Z)-cannabiphenolic acid B (5), together with twelve known compounds (6–17), were isolated from the aerial parts of Cannabis sativa L. subsp. sativa. The structures of 1–5 were established on the basis of extensive 1D, 2D NMR and HRESIMS analysis. The absolute configurations were determined by comparison between their experimental and calculated spectra of electronic circular dichroism (ECD) or the modified Mosher's method. The neuroprotective effects of the compounds 1–17 were evaluated on PC 12 cells. Compounds 12, 13 and 15 showed potential protective effects against H2O2-induced damage.
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Objective Interest in the use of cannabidiol (CBD) is increasing worldwide as its therapeutic effects are established and legal restrictions moderated. Unlike Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC), CBD does not appear to cause cognitive or psychomotor impairment. However, further assessment of its effects on cognitively demanding day‐to‐day activities, such as driving, is warranted. Here, we describe a study investigating the effects of CBD on simulated driving and cognitive performance. Methods Thirty healthy individuals will be recruited to participate in this randomised, double‐blind, placebo‐controlled crossover trial. Participants will complete four research sessions each involving two 30‐min simulated driving performance tests completed 45 and 210 min following oral ingestion of placebo or 15, 300, or 1,500 mg CBD. Cognitive function and subjective drug effects will be measured, and blood and oral fluid sampled, at regular intervals. Oral fluid drug testing will be performed using the Securetec DrugWipe® 5S and Dräger DrugTest® 5000 devices to determine whether CBD increases the risk of “false‐positive” roadside tests to Δ⁹‐THC. Noninferiority analyses will test the hypothesis that CBD is no more impairing than placebo. Conclusion This study will clarify the risks involved in driving following CBD use and assist in ensuring the safe use of CBD by drivers.
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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.
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. A central tenet underlying the use of botanical remedies is that herbs contain many active ingredients. Primary active ingredients may be enhanced by secondary compounds, which act in beneficial syn-ergy. Other herbal constituents may mitigate the side effects of dominant active ingredients. We reviewed the literature concerning medical can-nabis and its primary active ingredient, ∆ 9 -tetrahydrocannabinol (THC). Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC. Other cannabinoid and non-cannabinoid compounds in herbal cannabis or its extracts may reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activ-ity. [Article copies available for a fee from The Haworth Document Delivery Service: and: Cannabis Therapeutics in HIV/AIDS (ed: Ethan Russo) The Haworth Integrative Healing Press, an imprint of The Haworth Press, Inc., 2001, pp. 103-132. Single or multiple copies of this arti-cle are available for a fee from The Haworth Document Delivery Service [1-800-342-9678, 9:00 a.m. -5:00 p.m. (EST). E-mail address: getinfo@haworthpressinc.com].
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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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The antinociceptive effects of various cannabinoids, alone and in combination with opiates, were evaluated in antinociceptive tests in mice. The cannabinoids tested produce marked antinociceptive effects after i.t. administration to mice. The rank order of potency for the drugs using the tail-flick test was levonantradol greater than CP-55,940 = CP-56,667 greater than 11-hydroxy-delta 9-THC greater than delta 9-THC greater than delta 8-THC; dextronantradol was inactive at a dose of 25 micrograms/mouse. Respective ED50 values in the tail-flick test were 0.4, 12.3, 4.2, 15, 45 and 72 micrograms/mouse. Although pretreatment with morphine somewhat enhanced the effects of delta 9-THC, pretreatment of the mice with naloxone (1 mg/kg s.c. or 1 micrograms/mouse i.t.) failed to block the antinociceptive effects of the cannabinoids, indicating that the cannabinoid-induced antinociception does not occur due to direct interaction with the opiate receptor. Pretreatment of mice with 3.13 micrograms/mouse and 6.25 micrograms/mouse of delta 9-THC shifted the ED50 of morphine to 0.15 and 0.05 micrograms/mouse, respectively (a 4-and a 12-fold shift). The shifts in the dose-response curve of the morphine were parallel. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of the combination of 6.25 micrograms of delta 9-THC with morphine. The AD50 for naloxone blockade of the drug combination was 0.24 (0.06-0.94) mg/kg s.c. and the pA2 was 7.7 (6.7-8.9). The pA2 for naloxone blockade of the dimethylsulfoxide-morphine combination was 6.9 (5.7-8.1).(ABSTRACT TRUNCATED AT 250 WORDS)
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Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
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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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A series of experiments was conducted to determine the effects of orally administered 1-trans-Δ-9-tetrahydrocannabinol (THC) on both undisturbed and experimentally altered (by rapid eye movement [REM] deprivation) sleep patterns of young adult male volunteers. In the deprivation experiments, the effects of a semisynthetic Δ-6a-10-THC homologue, synhexl, were also studied. In the normative studies, 4 subjects received THC in doses ranging from 61 to 258 μg per kilogram shortly before sleep onset, while in the deprivation experiments 2 subjects received either THC (244 μg per kilogram and 259 μg per kilogram) or synhexl (733 μg per kilogram and 777 μg per kilogram) the morning after the second of 2 consecutive nights of REM deprivation. In both normative and deprivation experiments, all-night sleep recordings were taken during base-line, drug, and postdrug conditions. The results of both types of experiments were consistent in demonstrating increments in Stage 4 sleep and decrements in REM sleep. In the normative experiments, reduction in Stage 1 and time awake after sleep onset were observed at the highest dose level. Interpretation of these results and their relation to the effects of other psychoactive compounds upon sleep pattern are discussed.
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In order to determine the specific catecholamine content of catecholamine-containing neurons of the pons and mesencephalon and to investigate their role in mechanisms of waking, electroylitic lesions of these neurons were performed in 19 cats which were subsequently continously recorded and simultaneously observed for 8–13 days after surgery. Following sacrifice, monoamine levels of dopamine, noradrenaline, and serotonin were assayed in the diencephalon and telencephalon by spectrofluorimetric technique, and the extent of the lesions was determined by histological preparation and examination of the pons and mesencephalon. A quantitative analysis of the relationships among the percentage of area destroyed, the percentage of monoamine in the rostral brain and percentage of electrocortical waking (of total recording time) was performed by multiple correlations. The behavioral state of the animal was classified into 3 categories which were compared according to the variables mentioned above.
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The effects of the active ingredient of Cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), and of the highly addictive drug heroin on in vivo dopamine transmission in the nucleus accumbens were compared in Sprague-Dawley rats by brain microdialysis. Δ9-THC and heroin increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2. SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of Δ9-THC but not those of heroin. Naloxone, a generic opioid antagonist, administered systemically, or naloxonazine, an antagonist of μ1 opioid receptors, infused into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopamine transmission. Thus, Δ9-THC and heroin exert similar effects on mesolimbic dopamine transmission through a common μ1 opioid receptor mechanism located in the ventral mesencephalic tegmentum.
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The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (-)Delta9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-D-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-D-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.
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The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-gamma production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.
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Preclinical and clinical studies suggest that cannabidiol (CBD), a major component of Cannabis sativa, could produce antipsychotic effects without causing extra-pyramidal side-effects. In the present paper we employed the detection of Fos protein to investigate neuronal activation in the dorsal striatum and nucleus accumbens of male Wistar rats after systemic administration of CBD (120 mg/kg), haloperidol (1 mg/kg) or clozapine (20 mg/kg). Only haloperidol was able to increase the number of Fos immunoreactive neurons (FIr) in the dorsal striatum (vehicle: 0.07 ± 0.07/0.1 mm², haloperidol: 28.3 ± 8.9/0.1 mm², p < 0.01). In contrast, both haloperidol and CBD significantly increased FIr in the nucleus accumbens (Vehicle: 0 ± 0/0.1 mm², haloperidol: 7.2 ± 2.7/0.1 mm², CBD: 4.0 ± 1.9/0.1 mm², p < 0.05). Clozapine also produced a barely significant increase in FIr (3.0 ± 1.7/0.1 mm², p = 0.062). These results show that CBD is able to induce FIr in a limbic- but not in a motor-related area.
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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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To study the putative association of dopamine agonists with sleep attacks in patients with Parkinson's disease (PD) and their relation to daytime sleepiness, we performed a survey of 2,952 PD patients in two German counties. In 177 patients, sudden, unexpected, and irresistible sleep episodes while engaged in some activity were identified in a structured telephone interview. Ninety-one of these patients denied the occurrence of appropriate warning signs. A total of 133 patients (75%) had an Epworth Sleepiness Scale (ESS) score >10; 65 (37%) >15. Thirty-one patients (18%) had an ESS score ≤10 and yet experienced sleep attacks without warning signs. Thus, although a significant proportion of patients at risk for sleep attacks might be identified using the ESS, roughly 1% of the PD patient population seems to be at risk for sleep attacks without appropriate warning signs and without accompanying daytime sleepiness. Sleep attacks occurred with all dopamine agonists marketed in Germany (α-dihydroergocryptine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole), and no significant difference between ergot and nonergot drugs was evident. Levodopa (L-dopa) monotherapy carried the lowest risk for sleep attacks (2.9%; 95% confidence interval [CI], 1.7–4.0%) followed by dopamine agonist monotherapy (5.3%; 95% CI, 1.5–9.2%) and combination of L-dopa and a dopamine agonist (7.3%; 95% CI, 6.1–8.5%). Neither selegeline nor amantadine or entacapone appeared to influence the occurrence of sleep attacks. A high ESS score, intake of dopamine agonists, and duration of PD were the main influencing factors for the occurrence of sleep attacks. The odds ratio for dopamine agonist therapy was 2.9 compared to 1.9 with L-dopa therapy and 1.05 for a 1-year-longer disease duration. © 2003 Movement Disorder Society
Article
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327
Article
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.
Extremely low frequency magnetic fields (ELF MF) have a wide variety of effects in biological systems. Rat chromaffin cells in vitro show morphological and biochemical changes when exposed to ELF MF similar to those produced by nerve growth factor (NGF). To determine whether ELF MF alters catecholamine (CA) release, we used a culture of postnatal rat chromaffin cells which was differentiated by NGF or ELF MF for 7 days. Levels of catecholamine on media culture were detected by high pressure liquid chromatography with electrochemical detection (HPLC-ED) analysis. The results showed that differentiated cells released more dopamine than adrenaline, while chromaffin undifferentiated cells released more adrenaline than dopamine. In both cases noradrenaline release did not change. The results are discussed in terms of the role of Ca2+ or some enzymes in the changes in messenger ratios.
Article
As VLSI progresses, it is becoming increasingly difficult to use current methods from input-output theories to detect faults in circuits. This paper will discuss a method for detecting faults at the board level, using the temperature of the thermal image of the IC obtained with infrared cameras. This method is based on the point of view that the result would be equivalent to measuring the supply current flowing through each IC. A comparison was made with the fault detection method that allows the supply current to flow throughout the board. Based on the results, we were able to demonstrate that our method is more advantageous in an environment where VLSI is advancing. © 1998 Scripta Technica, Syst Comp Jpn, 29(5): 49–61, 1998
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
In order to study putative hypothalamic mechanisms of sleep waking cycle regulation we destroyed, by electrolytic coagulation, a large part of the medial hypothalamus overlapping the paraventricular nucleus in 6 adult cats. We never observed any modification of light slow wave sleep. Three of the six cats presented no paradoxical sleep (PS) impairment, despite an almost total destruction of neurophysin-immunoreactive cells of PVN in two cats and marked signs of diabetes insipidus in the third. Further, in the other three animals a statistically significant decrease of daily quantities of PS and deep slow wave sleep (SWS2) were related to an extensive destruction of the anterior hypothalamic area. These results suggest lack of influence of the PVN in sleep regulation and an involvement of the anterior hypothalamus in the onset of SWS2 and PS.