Article

Effect of Δ-9-Tetrahydrocannabinol and Cannabidiol on Nocturnal Sleep and Early-Morning Behavior in Young Adults

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

The effects of cannabis extracts on nocturnal sleep, early-morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg Delta-9-tetrahydrocannabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm. The electroencephalogram was recorded during the sleep period (11 pm to 7 am). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 am (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combination, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... The main psychoactive constituents of cannabis are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) . Several studies show circadian changes after chronic administration of THC (Gorelick et al., 2013;Perron et al., 2001;Nicholson et al., 2004). A study by Gorelick et al. (2013) showed that the use of higher THC concentrations by healthy men (increasing from 40 to 120 mg per day for 7 days) was significantly associated with lower sleep latency, daytime sleepiness, and less difficulty falling asleep. ...
... A study by Gorelick et al. (2013) showed that the use of higher THC concentrations by healthy men (increasing from 40 to 120 mg per day for 7 days) was significantly associated with lower sleep latency, daytime sleepiness, and less difficulty falling asleep. In addition, circadian rhythms were less pronounced (Perron et al., 2001) and sedative effects were observed after chronic administration of 15 mg of THC (Nicholson et al., 2004). On the other hand, 15 mg of CBD increases wakefulness during sleep and neutralizes the residual activity of 15 mg of THC (Nicholson et al., 2004). ...
... In addition, circadian rhythms were less pronounced (Perron et al., 2001) and sedative effects were observed after chronic administration of 15 mg of THC (Nicholson et al., 2004). On the other hand, 15 mg of CBD increases wakefulness during sleep and neutralizes the residual activity of 15 mg of THC (Nicholson et al., 2004). ...
Article
The circadian system organizes circadian rhythms (biological cycles that occur around 24 h) that couple environmental cues (zeitgebers) with internal functions of the organism. The misalignment between circadian rhythms and external cues is known as chronodisruption and contributes to the development of mental, metabolic and other disorders, including cancer, cardiovascular diseases and addictive disorders. Drug addiction represents a global public health concern and affects the health and well-being of individuals, families and communities. In this manuscript, we reviewed evidence indicating a bidirectional relationship between the circadian system and the development of addictive disorders. We provide information on the interaction between the circadian system and drug addiction for each drug or drug class (alcohol, cannabis, hallucinogens, psychostimulants and opioids). We also describe evidence showing that drug use follows a circadian pattern, which changes with the progression of addiction. Furthermore, clock gene expression is also altered during the development of drug addiction in many brain areas related to drug reward, drug seeking and relapse. The regulation of the glutamatergic and dopaminergic neurocircuitry by clock genes is postulated to be the main circadian mechanism underlying the escalation of drug addiction. The bidirectional interaction between the circadian system and drug addiction seems to be mediated by the effects caused by each drug or class of drugs of abuse. These studies provide new insights on the development of successful strategies aimed at restoring/stabilizing circadian rhythms to reduce the risk for addiction development and relapse.
... However, dronabinol (a cannabinoid receptor agonist with a preference for CB1r over CB2r) decreases the percent time spent in REM sleep in Sprague-Dawley rats [72]. It has been shown that administration of CBD enhances wakefulness in humans [100]. Furthermore, microinjection of CBD also increases waking in rats [91]. ...
... It has also been reported that Sativex (containing approximately equal doses of THC and CBD) improves sleep in subjects with pain-related sleep disturbances [127]. However, it has been revealed that CBD at lower doses co-administered with Δ9-THC increases waking [100]. In addition to basic studies, inconsistent effects of cannabinoids on sleep have been observed in clinical studies [128]. ...
... In addition to basic studies, inconsistent effects of cannabinoids on sleep have been observed in clinical studies [128]. It has been shown that cannabinoid consumption decreases REM sleep [129] or has no effect [100,130,131]. Also, cannabinoids induce various effects on sleep latency including decrease [100], increase [132], or no effect [133]. ...
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.
... Therefore, this section of the review focuses on controlled, cross-over design studies that have included predominantly non-experienced cannabis users and objective measures of sleep quality and architecture (Table 1). 19,[30][31][32][33] The majority of studies have focused on the effects of a THC dominant cannabinoid formulation, 19,[30][31][32] although one study investigated the effects of THC alone as well as two doses of a balanced THC:CBD formulation. 31 Another study investigated the effects of CBD alone. ...
... Therefore, this section of the review focuses on controlled, cross-over design studies that have included predominantly non-experienced cannabis users and objective measures of sleep quality and architecture (Table 1). 19,[30][31][32][33] The majority of studies have focused on the effects of a THC dominant cannabinoid formulation, 19,[30][31][32] although one study investigated the effects of THC alone as well as two doses of a balanced THC:CBD formulation. 31 Another study investigated the effects of CBD alone. ...
... 19,[30][31][32][33] The majority of studies have focused on the effects of a THC dominant cannabinoid formulation, 19,[30][31][32] although one study investigated the effects of THC alone as well as two doses of a balanced THC:CBD formulation. 31 Another study investigated the effects of CBD alone. 33 The largest and most recent study on effects of cannabinoids on sleep, by Linares et al, identified no change in any measure of sleep quantity or architecture when 27 healthy young volunteers took a single 300mg dose of CBD compared to placebo. ...
Article
Full-text available
The legalization of cannabis for medicinal, and in some countries, recreational, purposes in addition to growth in the cannabis industry has meant that cannabis use and interest in the area has increased rapidly over the past 20 years. Treatment of poor sleep and sleep disorders are two of the most common reasons for the current use of medicinal cannabis. However, evidence for the role of medical cannabis in the treatment of sleep disorders has not been clearly established, thus making it challenging for clinicians to make evidence-based decisions regarding efficacy and safety. This narrative review summarizes the highest quality clinical evidence currently available in relation to the use of medicinal cannabis for the treatment of sleep disorders including insomnia, obstructive sleep apnea, restless legs syndrome, rapid eye movement sleep behavior disorder, nightmare disorder and narcolepsy. A summary of the effect of cannabis on sleep quality and architecture is also presented. Currently, there is insufficient evidence to support the routine use of medicinal cannabis as an effective and safe treatment option for any sleep disorder. Nevertheless, emerging evidence is promising and warrants further investigation using standardized cannabinoid products and validated quantitative measurement techniques.
... Another study investigating multiple doses of cannabinoids for sleep reported that administration of both 5 mg/5 mg and 15 mg/15 mg of THC/CBD demonstrated a decrease in stage 3 sleep when compared with placebo, with the higher dose also showing increased states of wakefulness [22]. THC administration on its own demonstrated no significant changes to sleep architecture from placebo; however, the same study found that high doses of THC alone or in combination with CBD resulted in increased subjective sleepiness [22]. ...
... Another study investigating multiple doses of cannabinoids for sleep reported that administration of both 5 mg/5 mg and 15 mg/15 mg of THC/CBD demonstrated a decrease in stage 3 sleep when compared with placebo, with the higher dose also showing increased states of wakefulness [22]. THC administration on its own demonstrated no significant changes to sleep architecture from placebo; however, the same study found that high doses of THC alone or in combination with CBD resulted in increased subjective sleepiness [22]. From this, the researchers concluded that CBD may have dose-dependent effects on alertness and that the activating and sedating properties of CBD and THC, respectively, could work together to induce sleep and counteract daytime sleepiness [22]. ...
... THC administration on its own demonstrated no significant changes to sleep architecture from placebo; however, the same study found that high doses of THC alone or in combination with CBD resulted in increased subjective sleepiness [22]. From this, the researchers concluded that CBD may have dose-dependent effects on alertness and that the activating and sedating properties of CBD and THC, respectively, could work together to induce sleep and counteract daytime sleepiness [22]. Although few clinical trials have objectively analyzed cannabinoids for sleep with sleep outcomes as primary measures, some preliminary trials have shown that administration of THC and THC-derivatives, alone or in combination with CBD, were associated with subjective improvement in sleep outcomes [11][12][13]. ...
Article
Background Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. Objective We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. Methods Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. Results Overall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P<.001) and predominant sativa strains (estimated mean difference 0.74, SE 0.16; 95% CI 0.43-1.06; adjusted P<.001). Indica hybrid strains also presented a greater reduction in insomnia symptomology than CBD strains (mean difference 0.52, SE 0.12; 95% CI 0.29-0.74; adjusted P<.001) and predominant sativa strains (mean difference 0.67, SE 0.16; 95% CI 0.34-1.00; adjusted P=.002). Conclusions Medicinal cannabis users perceive a significant improvement in insomnia with cannabinoid use, and this study suggests a possible advantage with the use of predominant indica strains compared with predominant sativa strains and exclusively CBD in this population. This study emphasizes the need for randomized placebo-controlled trials assessing the efficacy and safety profile of cannabinoids for the treatment of insomnia.
... Another study investigating multiple doses of cannabinoids for sleep reported that administration of both 5 mg/5 mg and 15 mg/15 mg of THC/CBD demonstrated a decrease in stage 3 sleep when compared with placebo, with the higher dose also showing increased states of wakefulness [22]. THC administration on its own demonstrated no significant changes to sleep architecture from placebo; however, the same study found that high doses of THC alone or in combination with CBD resulted in increased subjective sleepiness [22]. ...
... Another study investigating multiple doses of cannabinoids for sleep reported that administration of both 5 mg/5 mg and 15 mg/15 mg of THC/CBD demonstrated a decrease in stage 3 sleep when compared with placebo, with the higher dose also showing increased states of wakefulness [22]. THC administration on its own demonstrated no significant changes to sleep architecture from placebo; however, the same study found that high doses of THC alone or in combination with CBD resulted in increased subjective sleepiness [22]. From this, the researchers concluded that CBD may have dose-dependent effects on alertness and that the activating and sedating properties of CBD and THC, respectively, could work together to induce sleep and counteract daytime sleepiness [22]. ...
... THC administration on its own demonstrated no significant changes to sleep architecture from placebo; however, the same study found that high doses of THC alone or in combination with CBD resulted in increased subjective sleepiness [22]. From this, the researchers concluded that CBD may have dose-dependent effects on alertness and that the activating and sedating properties of CBD and THC, respectively, could work together to induce sleep and counteract daytime sleepiness [22]. Although few clinical trials have objectively analyzed cannabinoids for sleep with sleep outcomes as primary measures, some preliminary trials have shown that administration of THC and THC-derivatives, alone or in combination with CBD, were associated with subjective improvement in sleep outcomes [11][12][13]. ...
Preprint
BACKGROUND Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. OBJECTIVE We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. METHODS Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. RESULTS Overall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P <.001) and predominant sativa strains (estimated mean difference 0.74, SE 0.16; 95% CI 0.43-1.06; adjusted P <.001). Indica hybrid strains also presented a greater reduction in insomnia symptomology than CBD strains (mean difference 0.52, SE 0.12; 95% CI 0.29-0.74; adjusted P <.001) and predominant sativa strains (mean difference 0.67, SE 0.16; 95% CI 0.34-1.00; adjusted P =.002). CONCLUSIONS Medicinal cannabis users perceive a significant improvement in insomnia with cannabinoid use, and this study suggests a possible advantage with the use of predominant indica strains compared with predominant sativa strains and exclusively CBD in this population. This study emphasizes the need for randomized placebo-controlled trials assessing the efficacy and safety profile of cannabinoids for the treatment of insomnia.
... The effect of cannabis on sleep is mixed, which may in part be due to varying doses and cannabis composition (Babson et al. 2017). However, sleep disturbances are the most consistent symptom of cannabis withdrawal and poor sleep can predict relapse (Babson et al. 2017 Different cannabinoids may have opposing effects on sleep, which may lead to conflicting data on cannabis in human studies: Acute THC decreases REM sleep and increases slow-wave sleep (Vaughn et al. 2010), decreases stage-3 sleep, and may increase sleepiness the next day (Nicholson et al. 2004). However, in patients with posttraumatic stress disorder, chronic THC led to a reduction in the frequency of nightmares (Roitman et al. 2014). ...
... CBD on the other hand elicits differential effects on sleep, based on its dose, in both, humans and rodents: Low-dose CBD has a stimulating effect, while high-dose CBD has a sedating effect (Nicholson et al. 2004;Zuardi 2008;Carlini and Cunha 2013;Chagas et al. 2013). Similar to THC, CBD can improve sleep disturbances related to posttraumatic stress disorder (Shannon and Opila-Lehman 2015). ...
Chapter
Psychoactive drugs are a popular way to induce pleasant feelings, but also to modify wakefulness and sleep. In turn, insomnia and circadian often impact on drug-taking behavior. This book chapter explores the interplay between drugs and the circadian system. The reader will be introduced to the main classes of psychoactive drugs and the role they play in circadian pathways and behaviors. The importance of circadian interventions on drug-taking and implications for our society are discussed.
... Other effects attributed to CBD, such as sedative effects, are thought to be biphasic. Larger doses have been shown to exert sedative effects in both rats and humans, whereas low doses of CBD may increase wakefulness (40)(41)(42). While the effect of CBD on sedation has not been specifically investigated in a canine model, a preliminary investigation of the safety of escalating CBD doses in 20 healthy dogs reported mild constitutional adverse events recorded for dogs receiving 1.7-64.7 mg/kg CBD oil, which included both lethargy and hyperesthesia (43). ...
... In humans and rats, CBD doses ranging from ∼2 to 40 mg/kg BW/day have been reported to induce sedative effects, improve sleep quality, and increase total sleep time (41,46,47). However, more recent work has reported CBD to have no influence on the sleep cycle in humans (48), and others argue that CBD by itself does not produce sedative effects but rather modulates the sedative effect of 9 -tetrahydrocannabinol (THC), even if THC is only present in minute amounts (42,49,50). ...
Article
Full-text available
Growing public interest in the use of cannabidiol (CBD) for companion animals has amplified the need to elucidate potential impacts. The purpose of this investigation was to determine the influence of CBD on the daily activity of adult dogs. Twenty-four dogs (18.0 ± 3.4 kg, 9 months−4 years old) of various mixed breeds were utilized in a randomized complete block design with treatments targeted at 0 and 2.5 mg (LOW) and at 5.0 mg (HIGH) CBD/kg body weight (BW) per day split between two treats administered after twice-daily exercise (0700-0900 and 1,700-1,900 h). Four hours each day [1,000-1,200 h (a.m.) and 1,330-1,530 h (p.m.)] were designated as times when no people entered the kennels, with 2 h designated as Quiet time and the other 2 h as Music time, when calming music played over speakers. Quiet and Music sessions were randomly allotted to daily a.m. or p.m. times. Activity monitors were fitted to dogs' collars for continuous collection of activity data. Data were collected over a 14-day baseline period to establish the activity patterns and block dogs by activity level (high or low) before randomly assigning dogs within each block to treatments. After 7 days of treatment acclimation, activity data were collected for 14 days. Data were examined for differences using the MIXED procedure in SAS including effects of treatment, day, session (Quiet or Music), time of day (a.m. or p.m.), and accompanying interactions. CBD (LOW and HIGH) did not alter the total daily activity points (P = 0.985) or activity duration (P = 0.882). CBD tended (P = 0.071) to reduce total daily scratching compared with the control. Dogs were more active in p.m. sessions than in a.m. sessions (P < 0.001). During the p.m. session, dogs receiving HIGH tended (P = 0.091) to be less active than the control (CON). During the a.m. and p.m. sessions, CBD reduced scratching compared with CON (P = 0.030). CBD did not affect the activity duration during exercise periods (P = 0.143). These results indicate that, when supplemented with up to 4.5 mg CBD/kg BW/day, CBD does not impact the daily activity of adult dogs, but may exert an antipruritic effect.
... 38 High doses of THC have been associated with changes in sleep architecture such as reduced REM and reduced stage 3 sleep as well as subjective changes such as increased sleepiness. 35,39 High doses of THC administered throughout the day for 7 days to chronic cannabis users were associated with more daytime sleepiness. 40 Of interest, subjects also reported less difficulty falling asleep and had shorter sleep latencies, suggesting that heavy cannabis users may build a tolerance to the adverse consequences of daily high-dose THC consumption. ...
... Higher doses of THC and CBD were associated with a decrease in slow-wave sleep and reduced sleep latency compared with lower doses. 39 This dose-response relationship is also illustrated in a study where severity of insomnia using the Insomnia Severity Index was greater among daily cannabis users compared with both infrequent users and non-users. 66 In a sample of 20 inpatient cannabis users, greater volume and 8 EDWARDS AND FILBEY duration of cannabis use were correlated with greater reduction in sleep quality. ...
Article
Introduction: There is widespread literature on the interaction between cannabis use and sleep, yet the mechanisms that underlie this relationship are not well understood. Several factors lead to inconsistencies in this relationship suggesting a nuanced interaction between cannabis and sleep. An important question that remains to be addressed is the temporal relationship between disrupted sleep and cannabis use. This literature review summarizes the existing literature on the association between disrupted sleep and cannabis toward the goal of addressing the question of the chronology of these reported effects. Materials and Methods: We conducted a review of the literature using PubMed to summarize current knowledge on the association between cannabis use and sleep in humans. Results: We identified 31 studies on the association of cannabis use and sleep. The findings from these studies were mixed. Cannabis was associated with a variety of impacts on sleep ranging from beneficial effects, such as reduced sleep-onset latency, to negative outcomes, such as reduced sleep duration and suppressed rapid eye movement oscillations. The chronology of the interaction of cannabis and sleep was unclear, although much of the current literature focus on factors that modulate how cannabis impairs sleep after initial use. Conclusion: There was sufficient evidence to suggest that cannabis use alters circadian rhythms, and hence, negatively impacts sleep. The current literature is largely from studies utilizing self-report measures of sleep; thus, objective measures of sleep are needed. In addition, although there were no empirical studies on the temporal relationship between cannabis use and sleep, the majority of the literature focused on characterizing sleep impairment after cannabis use.
... En effet, chez le sujet sain, le CBD ne semble pas modifier le temps total de sommeil ni les différentes phases du sommeil [78]. Par contre, chez des personnes insomniaques ou sédatées au 9-THC, il est possible d'observer des modifications du cycle veille-sommeil [74,79]. Ces modifications de cycle semblent dépendre de la présence de troubles (insomnie, somnolence) mais également de la dose de CBD administrée. ...
... Ces modifications de cycle semblent dépendre de la présence de troubles (insomnie, somnolence) mais également de la dose de CBD administrée. Ainsi, Carlini et al. [74] ont observé une augmentation du temps de sommeil avec une seule dose de 160 mg de CBD chez des sujets insomniaques alors que Nicholson et al. [79] ont rapporté une augmentation du temps d'éveil après l'administration de 15 mg par spray oromucosal chez des individus sous 9-THC. Les individus semblent réagir de manière biphasique avec un effet stimulant pour de faibles doses et un effet sédatif avec des fortes doses qui facilitent l'endormissement comme c'est le cas chez l'animal [80]. ...
Article
Résumé Objectifs Dans cet article, nous souhaitons faire le point sur les différentes propriétés du cannabidiol (CBD) potentiellement intéressantes pour le sportif. Actualités Le CBD est, avec le Δ9-tetrahydrocannabinol, l’un des phytocannabinoïdes les plus abondants du Cannabis Sativa L. Avec la levée de l’interdiction en 2018 du CBD par l’Agence mondiale anti-dopage, il est probable que les sportifs se tournent davantage vers les produits au CBD dérivés du Cannabis Sativa L. Perspectives et projets Des études précliniques sur le CBD ont montré des effets anxiolytiques, analgésiques, anti-inflammatoires, neuroprotecteurs mais également sur le sommeil. Ces propriétés pourraient être intéressantes dans la gestion des blessures, des commotions, de l’anxiété et des troubles du sommeil. Si le CBD paraît être une molécule sûre, les effets secondaires indésirables existent bel et bien et notamment pour les produits non réglementés. Conclusion Le manque de preuves scientifiques et le trop peu d’études cliniques appliquées aux sportifs ne permettent pas, pour le moment, de recommander l’utilisation du CBD aux athlètes.
... Earlier studies have shown that THC produced a somnolent effect in humans [260][261][262][263]. However, in recent studies THC produced no effect on nocturnal sleep, reduced sleep expectancy as well as increased daytime sleep [264]. THC also significantly decreased duration of nighttime sleep, suggesting development of tolerance to the sedative effect [265]. ...
... 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]. ...
Article
Full-text available
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
... Animal studies suggest that CBD may act as an antagonist at CB -1 [21], raising the possibility of CBD reducing the sedative effects of THC. The specific action of other exogenous CBs such as terpenes, with or without THC and CBD, on the ECS is uncertain and a developing area of research [22]. ...
Article
Background Insomnia is associated with significant comorbidity, disability and impact on quality of life and, despite advances in pharmacotherapy and psychotherapy, remains a significant burden to society. Cannabinoids are gaining acceptance for use as medicines in the treatment of insomnia disorder.Objective We conducted a systematic review and meta-analysis to evaluate the efficacy of cannabinoids in the treatment of insomnia disorder.Methods We performed a systematic review of the PubMed, Cochrane Library, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature Complete databases from inception to 5 December 2019, and again prior to data abstraction, for studies of cannabis-based products for the treatment of insomnia disorder in adults. Inclusion criteria were (1) clinical studies, (2) participants aged ≥ 18 years, (3) insomnia disorder either formally diagnosed against contemporaneous diagnostic criteria or quantified with validated instruments and (4) compared cannabis-based products with the standard of care, placebo or a sedative. No language restrictions were imposed. Non-primary research, animal studies and studies of cannabis-induced insomnia were excluded. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials (RCTs) and Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) tool for non-randomized trials. Heterogeneity was assessed with the I2 statistic.ResultsA total of five studies (two RCTs and three non-randomised studies) with 219 study participants were included, of which three could be combined. The three non-randomised studies contributed data on the Pittsburgh Sleep Quality Index Questionnaire score, showing a favourable effect of cannabinoids at ≤ 4 weeks of follow-up (mean difference − 1.89 [95% confidence interval {CI} − 2.68 to − 1.10]; n = 176) and at 8 weeks of follow-up (mean difference − 2.41 [95% CI − 3.36 to − 1.46]; n = 166). One double-blind crossover RCT (n = 32) reported that, compared with amitriptyline, nabilone—a synthetic analogue to tetrahydrocannabinol (THC)—improved Insomnia Severity Index scores after 2 weeks of treatment (adjusted difference − 3.25 [95% CI − 5.26 to − 1.24]) and resulted in a more restful sleep as a sub-measure of the Leeds Sleep Evaluation Questionnaire (LSEQ) (difference 0.48 [95% CI 0.01–0.95]) but with no effect on overall sleep quality as measured by the LSEQ. In a single ascending-dose RCT (n = 9), THC reduced sleep-onset latency compared with placebo at 10 mg, 20 mg and 30 mg doses (mean difference − 43.00 min [95% CI − 82.76 to − 3.24], − 62.00 [95% CI − 103.60 to − 20.40] and − 54.00 [95% CI − 103.93 to − 4.07], respectively). All the included studies were assessed as poor quality, mainly due to small sample sizes, short treatment periods, uncertain clinical significance and high risk of bias.Conclusions Few studies have examined the efficacy of cannabinoids in the treatment of insomnia disorder. Despite some possible signals for efficacy, the heterogeneity of participants, interventions, efficacy outcomes and results, and the high risk of bias across included trials, do not reliably inform evidence-based practice. This review highlights shortcomings in the existing literature, including lack of diagnostic clarity, poorly defined participant groups, non-standardised interventions and studies of inappropriate design, duration and power to detect clinically meaningful outcomes. Further research in the form of high-quality RCTs are required before drawing any conclusions about the efficacy of cannabinoids in the treatment of insomnia disorder.Trial RegistrationPROSPERO registration number, CRD42020161043.
... Acute withdrawal from cannabis can contribute to objective and subjective sleep disturbances, which are more common in chronic users (29,30). Acutely cannabis can decrease sleep latency, making it easier to fall asleep (31,32); however, long-term sleep quality is negatively impacted (15). In fact, roughly half of adults with CUD reported that cannabis use had caused them difficulty sleeping in the past 90 days (33). ...
Article
Full-text available
Background: There are known sex differences in behavioral and clinical outcomes associated with drugs of abuse, including cannabis. However, little is known about how chronic cannabis use and sex interact to affect brain structure, particularly in regions with high cannabinoid receptor expression, such as the cerebellum, amygdala, and hippocampus. Based on behavioral data suggesting that females may be particularly vulnerable to the effects of chronic cannabis use, we hypothesized lower volumes in these regions in female cannabis users. We also hypothesized poorer sleep quality among female cannabis users, given recent findings highlighting the importance of sleep for many outcomes related to cannabis use disorder. Methods: Using data from the Human Connectome Project, we examined 170 chronic cannabis users (>100 lifetime uses and/or a lifetime diagnosis of cannabis dependence) and 170 controls that we attempted to match on age, sex, BMI, race, tobacco use, and alcohol use. We performed group-by-sex ANOVAs, testing for an interaction in subcortical volumes, and in self-reported sleep quality (Pittsburgh Sleep Questionnaire Inventory). Results: After controlling for total intracranial volume and past/current tobacco usage, we found that cannabis users relative to controls had smaller cerebellum volume and poorer sleep quality, and these effects were driven by the female cannabis users (i.e., a group-by-sex interaction). Among cannabis users, there was an age of first use-by-sex interaction in sleep quality, such that females with earlier age of first cannabis use tended to have more self-reported sleep issues, whereas this trend was not present among male cannabis users. The amygdala volume was smaller in cannabis users than in non-users but the group by sex interaction was not significant. Conclusions: These data corroborate prior findings that females may be more sensitive to the neural and behavioral effects of chronic cannabis use than males. Further work is needed to determine if reduced cerebellar and amygdala volumes contribute to sleep impairments in cannabis users.
... In experimental studies, CBD has been safely administered to healthy humans in doses ranging from 15 mg to 600mg (oral) per day (20,(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97) alone and in combination with THC and is known to have been tolerated well with no significant adverse effects. Previous studies have also demonstrated that IV CBD is well . ...
Preprint
Full-text available
Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience investigations. In this double-blind randomized placebo-controlled counterbalanced human laboratory experiment, we examined the effects of three different dose ratios of CBD: THC (1:1, 2:1 and 3:1) on neural noise, an electrophysiological biomarker of psychosis known to be sensitive to cannabinoids as well as subjective and psychotomimetic effects. Interestingly, the lowest CBD:THC ratio (1:1) resulted in maximal attenuation of both THC induced psychotomimetic effects (PANSS positive - ATS = 7.83, df = 1, pcorr = 0.015) and neural noise (ATS = 8.83, df = 1, pcorr = 0.009) with an inverse-linear dose response relationship. Further, in line with previous studies, addition of CBD did not reduce the subjective experience of THC induced high (p > 0.05 for all CBD doses). These novel results demonstrate that CBD attenuates THC induced subjective and objective effects relevant to psychosis- but in a dose/ratio dependent manner. Given the increasing global trend of cannabis liberalization and application for medical indications, these results assume considerable significance given the potential dose related interactions of these key phyto-cannabinoids.
... However, when taken in combination CBD is known to attenuate the potential psychotropic effects of THC [9] although high doses of CBD have been reported to have potential alerting properties. [10] Greater drowsiness has been reported with the addition of cannabinol (CBN) and THC than with THC alone. [11] A c c e p t e d M a n u s c r i p t This study therefore employed a double-blind, randomized, placebo-controlled, cross-over design to evaluate the safety and efficacy of a cannabinoid formulation which included THC, CBD and CBN (ZTL-101), for treating insomnia symptoms in patients with chronic insomnia disorder. ...
Article
Full-text available
Study Objectives This randomized, double-blind, placebo-controlled, cross-over study was conducted to evaluate the safety and efficacy of two-weeks of nightly sublingual cannabinoid extract (ZTL-101) in treating chronic insomnia (symptoms ≥three months). Methods Co-primary study endpoints were safety of the medication based on adverse event reporting and global insomnia symptoms (Insomnia Severity Index; ISI). Secondary endpoints included: self-reported (sleep diary), actigraphy-derived and polysomnography measurements of sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE); and self-reported assessments of sleep quality (sSQ) and feeling rested upon waking. Adjusted mean differences between placebo and ZTL-101 were calculated. Results Twenty-three of 24 randomized participants (n=20 female, mean age 53±9years) completed the protocol. No serious adverse events were reported. Forty mild, non-serious, adverse events were reported (36 during ZTL-101) with all but one resolving overnight or soon after waking. Compared to placebo, ZTL-101 decreased ISI (-5.07units [95%CI: -7.28 to -2.86]; p=0.0001) and self-reported SOL (-8.45mins [95%CI: -16.33 to -0.57]; p=0.04) and increased self-reported TST (64.6mins [95%CI: 41.70 to 87.46]; p<.0001), sSQ, (0.74units [95%CI: 0.51 to 0.97]; p<0.0001) and feeling of being rested on waking (0.51units [95%CI: 0.24 to 0.78]; p=0.0007). ZTL-101 also decreased actigraphy-derived WASO (-10.2mins [95%CI: -16.2 to -4.2]; p=0.002), and increased actigraphy-derived TST (33.4mins [95%CI: 23.07 to 43.76]; p<0.001) and SE (2.9% [95%CI: 2.0 to 3.8]; p=0.005). Conclusion Two-weeks of nightly sublingual administration of a cannabinoid extract (ZTL-101) is well tolerated and improves insomnia symptoms and sleep quality in individuals with chronic insomnia symptoms.
... Acute THC administration (15 mg) to young healthy adults produced minimal changes in nocturnal objective sleep parameters, but on the following day participants exhibited reduced SL and reported more subjective sleepiness (Nicholson et al., 2004). When combined with 15 mg of CBD, however, the sedating effects of THC were seemingly offset, pointing to the contrasting alerting properties of CBD at this dose. ...
Chapter
Sleep disturbances are common in substance-related disorders and may play significant roles in their initiation, maintenance, and relapse. In this chapter, we review the effects of the most commonly used substances of abuse on sleep, circadian rhythms, and sleep disorders, discuss potential mechanisms connecting sleep disturbances and substance use disorders (SUD), and outline current best practices for identifying and managing sleep disturbances in patients with SUD. Future basic and clinical research is needed to delineate further the critical role of sleep and circadian disturbances in SUD and novel approaches to treating sleep disturbances in patients with SUD.
... Two studies have reported on the effects of CBD on PSG defined sleep in healthy normal volunteers. Eight subjects in a double-blind crossover study received placebo, 15 mg THC, 5 mg THC combined with 5 mg CBD, and 15 mg THC combined with 15 mg CBD (Nicholson et al., 2004). The treatments were administered as an oromucusal spray 30 min before the 8 h NPSG. ...
Chapter
Alcohol and caffeine are widely used legal drugs across the world which are principally used in social and recreational contexts. There is a large literature that has documented the effects of alcohol and caffeine on sleep and daytime alertness. While at low doses they initially improve sleep (alcohol) or daytime alertness (caffeine), ultimately they both disrupt either the initiation, maintenance, or staging of sleep and diminish daytime alertness. Cannabidiol is one of the two most biologically active compounds of the cannabis plant. It's use has increased over the last five years and is primarily used for its medicinal effects, among them insomnia. While now legal (2018) in the US, it falls under varying governmental controls in other countries across the world. The literature on the effect of cannabidiol on sleep, either beneficial or disruptive, is very limited. Further clarification of the risks versus benefits of these three widely used substances will improve our understanding of their effects on sleep and daytime alertness and strengthen public health guidance and messaging.
... In individuals with insomnia, pioneer studies indicated that CBD (160 mg/day) increases total sleep time and decreases the frequency of arousals during the night (Carlini and Cunha 1981). Interestingly, low-dose CBD increases wakefulness (Nicholson et al. 2004;Zuardi 2008). According to other studies (Gorelick et al. 2013), THC decreases sleep latency albeit tolerance to this effect is developed (Figs. ...
Chapter
The sleep-wake cycle is a complex process that includes wake (W), non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Each phase is regulated by specialized brain structures that, by means of different neurotransmitters, maintain the constant expression of the sleep-wake cycle. Molecules like orexin, serotonin, noradrenaline, histamine, for waking; GABA, adenosine, prostaglandins, for NREM sleep and acetylcholine and glutamate for REM sleep, among other molecules are responsible for the expression and maintenance of each phase. When the endocannabinoid system was being described for the first time, almost three decades ago, oleamide’s sleep promoting properties were highlighted. Nowadays, enough evidence has been cumulated to support the endocannabinoid system role in the sleep-wake cycle regulation. The endocannabinoids oleamide anandamide, and 2-arachidonylglycerol promote NREM and/or REM sleep via the CB1R, thereby making this system a target to treat sleep disorders, such as insomnia.
... THC-treated, but not control or THC + CBD-treated subjects showed a tendency to increased total night-time activity and fragmented nighttime activity over time, overlapping with some parameters of sleep compromised by marijuana use in human adolescents (Maultsby et al., 2021). The inter-subject variability in the present study, and the inconsistent data on sleep patterns of human exposed to cannabinoids (Babson et al., 2017;Kuhathasan et al., 2019;Nicholson et al., 2004), highlight the need for well-designed trials in adolescents to objectively measure the effects of long-term daily use marijuana with varying potencies and CBD on parameters of sleep. ...
Article
Background: Daily use of marijuana is rising in adolescents, along with consumption of high potency marijuana products (high % Δ-9-tetrahydrocannabinol or THC). These dual, related trends have opened gaps in understanding the long-term effects of daily consumption of a high dose of THC in adolescents and whether a therapeutic dose of cannabidiol (CBD) modulates THC effects. Methods: Adolescent squirrel monkeys (Saimiri boliviensis) were treated daily for four months with vehicle (n = 4), a high THC dose (1 mg/kg i.m.; n = 4), or THC + CBD (1 mg/kg +3 mg/kg i.m.; n = 4), to investigate whether: (1) a daily high THC dose affects performance in tasks of cognition (repeated acquisition, discrimination reversal); (2) a daily high THC dose affects spontaneous behavior and day/night activity (3) tolerance develops to the behavioral effects of THC; (4) whether CBD modulates THC effects. Results: THC impaired performance of adolescent monkeys in a cognitive test initially, but not performance on a task of cognitive flexibility. THC reduced motor activity and increased sedentary behavior, with tolerance developing after weeks of daily treatment. Co-administered with THC, CBD did not modulate THC effects on cognitive performance, activity or tolerance, but prevented THC-induced emesis on the first day of daily treatment. Conclusions: Daily high dosing with THC compromised performance on a task of cognition, and reduced activity in adolescent primates, with tolerance developing within weeks. Whether our observations are relevant to a broader range of cognitive tasks vital for daily function in in human adolescents is uncertain.
... Certainly, derivatives of cannabis with relaxing and sleep promoting effects can be legally purchased in many countries (Bowles et al., 2017). These derivatives can increase melatonin production and inhibit wakefulness by activating the cannabinoid type-1 (CB1) receptors in the wake promoting regions of the brain (Nicholson et al., 2004;Lissoni et al., 1986;Murillo-Rodrigez et al., 2003). ...
Preprint
Full-text available
This study examined the prevalence of illegal drug use in UK students and motivators behind such behaviour. Additionally, we explored possible relationships between substance use, psychosocial motivators, and psychiatric distress. N=543 students completed online measures of substance use, anxiety, depression, perceived stress, insomnia. A series of reasons behind their use were ranked based on importance. Reported cannabis, cocaine, nitrous oxide, ketamine and MDMA use were most prevalent based on lifetime, past year, and month assessments. The experience of anxiety, depression, perceived stress, and insomnia were related to increased reports of substance use. Poor self-confidence and self-medication were key motivators of illicit drug use in those presenting greater psychiatric distress. These outcomes add to the sparse body of literature concerning illicit substance use in relation to psychiatric distress amongst UK students. Furthermore, we provided novel insight into the psychosocial motivators of such use.
... Other studies, however, have had mixed findings for sleep outcomes. One study found that THC in combination with CBD may decrease stage 3 sleep, whilst THC in isolation may decrease sleep latency, measures that reflect sleep quantity and quality [55]. The combined findings may reflect the high degree of heterogeneity in studied CBMPs across studies. ...
Article
Full-text available
Objectives Anxiety disorders are one of the most common reasons for seeking treatment with cannabis-based medicinal products (CBMPs). Current pharmacological treatments are variable in efficacy and the endocannabinoid system has been identified as a potential therapeutic target. This study aims to detail the changes in health-related quality-of-life (HRQoL) and clinical safety following CBMP therapy for generalised anxiety disorder. Methods A case series of the UK Medical Cannabis Registry was performed. Primary outcomes included change from baseline in patient-reported outcome measures (the General Anxiety Disorder Scale (GAD-7), EQ-5D-5L (a measure of health-related quality of life), and Sleep Quality Scale (SQS)) at 1, 3 and 6 months. Statistical significance was defined as p<0.050. Results 67 patients were treated for generalised anxiety disorder. Statistically significant improvements were observed in GAD-7, EQ-5D-5L Index Value, EQ5D Visual Analogue Scale, and SQS scores at 1, 3 and 6 months (p<0.050). 25 (39.1%) patients reported adverse events during the follow-up period. Conclusion This study suggests that CBMPs may be associated with improvement in HRQoL outcomes when used as a treatment for generalised anxiety disorder. These findings must be treated with caution considering limitations of study design; however this data may help inform future clinical studies and practice.
... Concerning sleep architecture, the administration of combinations of THC and CBD (5-mg THC plus 5-mg CBD, and 15-mg THC plus 15-mg CBD) were associated with decreases in stage 3 sleep and increases in wakefulness. 29 ...
Article
Full-text available
Phytocannabinoid derivatives are among the several compounds found in the cannabis plant. The phytocannabinoid chemicals Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are mostly responsible for the drug's behavioural effects. Chronic cannabis administration has been shown to disrupt circadian rhythms and reduce the duration of the deepest phase (Stage N3) of non-rapid eye movement (NREM) sleep. Cannabidiol is thought to be responsible for the disruption of the circadian rhythm, while THC is thought to be accountable for the changes in sleep architecture. The quality of one's sleep has a significant impact on cannabis abstinence or relapse. As a result, the diminished sleep-promoting efficiency of cannabis in chronic users, as well as the resulting sleep difficulties once cannabis use is stopped, may sabotage attempts to quit and raise the risk of relapse. In individuals with obstructive sleep apnea (OSA) who do not complain about the treatment process known as continuous positive airway pressure (CPAP), cannabinoids are one of the treatments being considered. In this regard, preclinical investigations have demonstrated that combining the agent oleamide and THC aids in the stabilisation of respiration in all stages of sleep as well as the maintenance of autonomic stability during sleep. The synthetic THC dronabinol was found to lower the apnea-hypopnea index (AHI) in a clinical investigation and is regarded safe for the short-term treatment of OSA. Patients experiencing nightmares who had been diagnosed with posttraumatic stress disorder (PTSD) were given the synthetic endocannabinoid receptor agonist nabilone. When compared to a placebo, the chemical proved helpful in reducing the frequency of nightmares. It's worth noting that a single study that looked at the effects of CBD on REM behavior disorder (RBD) found that symptoms improved. Based on the available findings, cannabinoids can be utilised as an alternate treatment for various sleep disorders. However, additional research is needed to corroborate the conclusions of these investigations.
... Another advantage of CBD is related to the absence of psychotic effects during administration. Some studies showed that CBD might be used for the patient suffering from schizophrenia while others pointed out the fact that THC might induce sleepiness (Nicholson et al. 2004;Mao et al. 2015). ...
Article
Full-text available
Cannabidiol (CBD) is an alkaloid present in Cannabis sativa, along with tetrahydrocannabinol (THC) and more than 100 other substances belonging to a group of compounds called cannabinoids. Whereas the legal status and medical use of Cannabis is a controversial issue in many countries, inconsistent legislation makes CBD status even more complicated. Some CBD products are legal in some countries, while banned in other countries , further compounding the confusion. In 2018, the Food and Drug Administration (FDA) approved the first CBD containing medical product, Epidiolex ® , for the treatment of paediatric seizures. Currently, several clinical trials are in progress for the potential treatment of neurologic and behavioural disorders. CBD's current legal and regulatory status is a continuously evolving issue; the current review is presenting historical and present information regarding the use of CBD products worldwide.
... Interestingly, THC and CBD have been associated with the induction of sleeping due to their psychoactive and non-psychoactive actions, which promotes a probable interaction of both cannabis components (Belendiuk et al. 2015). A study carried out by Nicholson et al. (2004) indicated that both THC and CBD could provide better balance in sleep promotion due to their different activities. Further, a literature survey reveals that cannabis is efficient in insomnia treatment since its phytoproducts also play an important role in inducing effects under sleep deprivation (Tringale and Jensen 2011). ...
... Interestingly, THC and CBD have been associated with the induction of sleeping due to their psychoactive and non-psychoactive actions, which promotes a probable interaction of both cannabis components (Belendiuk et al. 2015). A study carried out by Nicholson et al. (2004) indicated that both THC and CBD could provide better balance in sleep promotion due to their different activities. Further, a literature survey reveals that cannabis is efficient in insomnia treatment since its phytoproducts also play an important role in inducing effects under sleep deprivation (Tringale and Jensen 2011). ...
Chapter
Bhanga (Cannabis) has been reported with numerous therapeutic, traditional, commercial, and sacred uses in India and across the globe. Its uses are deeply rooted in the cultural, social, and economic lives of the people. The inclusion of Cannabis under ‘Scheduled E1’ drugs in India restricts its use. However, being a crop of economic and medicinal importance, the pharmaceutical and various other sectors are showing much interest in the plant. The present review article delineates traditional, culinary, cosmetic, ritual, social, spiritual, recreational, economic, and therapeutic uses of Cannabis. The review illustrates various uses of Cannabis across the globe; noted from articles, publications, and books providing description of various parts, viz. leaves and seeds (Bhanga), flowering and fruiting tops (Ganja), resin (Charas), extract, tincture, and whole plant, stalks (Fibers). The review may be helpful to researchers, clinicians, and pharmaceutical companies to carry out further research for developing cost-effective healthcare options.
... The observed effects on sleep, especially in male mice, are generally consistent with our hypothesis that chronic THC administration would cause sleep disruption that mirrors the transient changes observed in the clinical setting, and are consistent with a study using the synthetic CB1 agonist AM2389 [78] that was published while the present study was under consideration for publication. The observations that acute THC treatment enhanced NREM while REM sleep was fragmented in male mice during abstinence are consistent with previous reports of single THC or cannabis exposures in animal models [79][80][81] and humans [32,[82][83][84][85][86]. The finding that THC tolerance following chronic treatment diminishes the drug's effect on sleep is also consistent with past findings in animals [80,81,[87][88][89] and regular human cannabis users [34,82,85,[90][91][92]. ...
Article
Full-text available
Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors like irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during abstinence in a mouse model of chronic THC exposure. Using a THC treatment regimen known to produce tolerance, we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance to THC. Altered striatal DA release, sleep, and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. These findings provide a foundation for preclinical study of directly translatable non-precipitated THC withdrawal symptoms and the neural mechanisms that affect them.
... Quanto à administração do CBD, constatou-se que 15 mg foram capazes de neutralizar a atividade sedativa residual do THC (Conroy & Arnedt, 2014;Nicholson, Turner, Stone & Robson, 2004). Entretanto, apesar do CBD em baixas doses possuir efeito estimulante, em altas doses (160 mg/dia), seu efeito é sedativo (Babson et al., 2017). ...
Article
Full-text available
Alterações nos padrões normais de sono, quando comprometem o desempenho do indivíduo, em esfera comportamental e/ou social, recebem a nomenclatura de "distúrbios" ou "transtornos" do sono e mostram-se, muitas vezes, preditoras da procura por substâncias paliativas, capazes de atenuar, a curto prazo, os sintomas da condição. A Cannabis sativa L. apresenta alto consumo mundial no tratamento de diversas patologias, sendo utilizada, com ou sem supervisão médica, inclusive, com o intuito de minimizar a manifestação dos sintomas da insônia. Esta revisão bibliográfica buscou delimitar o mecanismo de ação da C. sativa no sono e expor as vantagens e desvantagens-principalmente, neuropsicológicas-de seu uso enquanto substância indutora do sono. Por meio de pesquisa bibliográfica realizada através de buscas pelos descritores "Cannabis e fisiologia do sono (sleep physiology/ fisiología del sueño)/ fitoterapia (phytotherapy/ fitoterapía)/ insônia (insomnia/ insomnio)/ mecanismo de ação (mechanism of action/ mecanismo de acción)/ transtornos psicológicos (psychological disorders/ desórdenes psicológicos)", nas bases de dados SciELO (Scientific Eletronic Library Online), PuBMeD, ResearchGate e Science Direct, foram selecionados 49 artigos científicos, que fundamentaram o presente trabalho. Constatou-se que os efeitos benéficos da C. sativa no sono limitam-se a usuários em seu primeiro episódio de uso, visto que há o desenvolvimento de tolerância ao THC (Δ9-tetrahidrocanabinol). Além disso, há a possibilidade de agravo ou desencadeamento de novas patologias, sobretudo, quando a C. sativa é administrada através do fumo, que, pela combustão, libera toxinas prejudiciais à saúde. Desta forma, a vaporização surge como via de administração a ser explorada, por apresentar menores riscos e maiores benefícios aos sujeitos.
... One study examined the effects of THC and CBD versus placebo in young adults on subjective measures of nighttime sleep as well as morning sleepiness assessed for 30 min after rising and 9 h after administration of THC and/or CBD. 48 This study showed that 15 mg of THC was sedating, whereas 15 mg of CBD increased wake activity during sleep and counteracted the sedating properties of THC. A metaanalysis showed a significant increased risk (OR 2.10; 95% CI: 1.36-3.31) of fatal motor vehicle collisions with the use of THC. ...
Article
Full-text available
The use of cannabis products to help with sleep and various other medical conditions by the public has increased significantly in recent years. Withdrawal from cannabinoids can lead to sleep disturbance. Here, we describe a patient who developed significant insomnia leading to worsening anxiety, mood, and suicidal ideation in the setting of medical cannabis withdrawal, prompting presentation to the Emergency Department and inpatient admission. There is a limited evidence base for the use of cannabis products for sleep. We provide a comprehensive review evaluating the literature on the use of cannabis products on sleep, including an overview of cannabis and related psychoactive compounds, the current state of the law as it pertains to the prescribing and use of these substances, and potential side effects and drug interactions. We specifically discuss the impact of cannabis products on normal sleep and circadian sleep-wake rhythms, insomnia, excessive daytime sleepiness, sleep apnea, parasomnias, and restless legs syndrome. We also describe the effects of cannabis withdrawal on sleep and how this increases relapse to cannabis use. Most of the studies are observational but the few published randomized controlled trials are reviewed. Our comprehensive review of the effects of cannabis products on normal sleep and sleep disorders, relevant to primary care providers and other clinicians evaluating and treating patients who use these types of products, shows that cannabis products have minimal to no effects on sleep disorders and may have deleterious effects in some individuals. Further research examining the differential impact of the various types of cannabinoids that are currently available on each of these sleep disorders is required.
... However, finding the right chemovar and the right dose is essential to having sedation without the impairment from THC. For example, research using THC with 1-2 mg CBD found CBD could mitigate the memory-impairing effects of THC but using CBD doses as small as 5-15 mg was found to interfere with stage 3 sleep (Nicholson et al., 2004). A recent RCT with 23 patients showed promising results using a cannabinoid formulation with 10 mg THC/1mg CBD and 0.5 mg CBN, 0.5 mL sublingual administered one hour to desired sleep time for two weeks. ...
Article
Medical Cannabis is receiving renewed interest in clinical practice due to the gradual increase over the last few decades of cannabis legalization and high-quality research on the potential benefits of cannabis for treating a variety of conditions (NASEM, 2017; Nursing Care of the Patient, 2018). However, the pace of medical cannabis legalization and research are outpacing the training for medical providers, leaving gaps in their confidence and ability to safely guide patients using medical cannabis (NCSBN, 2018). Medical providers are increasingly fielding questions from patients regarding the use of medical cannabis for conditions commonly seen in clinical practice, but many are uncertain of if and how they should guide patients on this use. The aim of this research is two-fold: to assess current barriers to medical providers discussing medical cannabis with their patients; and to assess the impact a one-hour educational presentation can have on addressing these barriers and increasing the likelihood of providers engaging in discussions. Though the results of this research may be limited by the small sample size surveyed, they could highlight barriers present in clinical practice and indicate possible areas for future research in expanding cannabis education for medical providers.
... There are a few studies including case reports [139,168], case series [140], and randomized controlled trials [169,170] that indicate that CBD may be efficacious in promoting sleep. Yet, there is some contention in the literature, with some studies suggesting CBD has a stimulating or alerting effect [171,172], and others suggest CBD has a sedating effect [169,170] and one which found no effect in terms of sleepiness [173]. There is a need for research into the potential effects of CBD on sleep in cancer patients, since the benefits of improved sleep would be tremendous. ...
Article
Full-text available
The plant Cannabis sativa has been in use medicinally for several thousand years. It has over 540 metabolites thought to be responsible for its therapeutic effects. Two of the key phytocannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). Unlike THC, CBD does not have potentially intoxicating effects. Preclinical and clinical research indicates that CBD has a wide range of therapeutic effects, and many of them are relevant to the management of cancer. In this article, we explore some of the potential mechanisms of action of CBD in cancer, and evidence of its efficacy in the integrative management of cancer including the side effects associated with its treatment, demonstrating its potential for integration with orthodox cancer care.
Chapter
Cannabidiol (CBD), a naturally occurring constituent compound isolated from cannabis and hemp, has been the subject of basic science research since 1940. Over the past 5 years, CBD has entered the everyday lexicon of health advocates for nutraceutical products, federal regulators, and legislative authorities. While CBD nutraceutical food products have grown rapidly in North American markets to meet demand with safe supply chain distribution and finished products, acceptance of CBD globally by foreign governments has been slower due to increased scrutiny over safety. Some countries have recently opined on safe levels permitted for use in foods, removing regulatory barriers that once prevented their lawful entry. While the safety of CBD has been established to a degree that permits its endorsement by the WHO and marketing as a prescription drug, there remain significant gaps in the understanding of its toxicity in the context of use in conventional food, dietary supplements, and health and wellness products. Assessing the safety of CBD as a nutraceutical ingredient, this chapter provides an analysis of the available literature from genotoxicity to human clinical trials, with a focus on utilizing appropriate preclinical models and interpreting safety data to establish safe exposure levels.
Conference Paper
Full-text available
The discovery of the endocannabinoid system (ECS) has not only increased our understanding of the effects of plant cannabinoids, but also increased our understanding of human biochemistry as well as opened up avenues towards new therapeutic targets. Phytocannabinoids as well as their synthetic counterparts are known to engage with our endocannabinoid system ; hence our understanding of the basic biochemistry of this pivotal signaling system offers insights into beneficial and therapeutic uses of these molecules. There is a plethora of research data and scientific peer-reviewed papers on the topic of cannabinoids, the ECS and health/disease. Much data has been gathered from epidemiological and biomedical research, thus providing patients and medical professionals with good foundations for the use of cannabinoids in medicine. But understanding the biochemistry of the ECS and the role this signaling system plays in human physiology is the key to the proper use of these potent molecules.
Chapter
Shared neurophysiology of addiction and sleep disorders results in a bidirectional interplay. Diagnosing and treating primary sleep disorders, particularly in adolescents, can prevent the development of addiction in susceptible individuals. Addressing sleep issues in early recovery, and throughout maintenance, can prevent relapse. Cannabis use for insomnia shows mixed results; assisting with onset sleep latency in early use, this subsides with chronic use and holds addiction risk. Insomnia is a primary complaint of cannabis withdrawal syndrome and a primary cause of relapse in cannabis use disorder. An ideal sleep aid would prevent relapse and have low abuse potential. Pharmaceutical and behavioral options include suvorexant, mirtazapine, trazodone, and aerobic exercise, but clinical trials are lacking to demonstrate efficacy.
Chapter
The worldwide interest and push for the legalization of cannabis/marijuana, especially in the United States, are increasing with each passing day. The present article deals with the concise yet broad review of chemical, medicinal (neuroprotection), and adverse psychotic aspects of cannabis (marijuana or marihuana). The emphasis is made to understand the influence of tetrahydrocannabinol (THC) on a broad spectrum of properties ranging from psychosis, neuroprotection, neurotoxicity to medicinal. The reason why THC shows psychoactivity, but cannabidiol (CBD) does not, has been elucidated based on the minor difference in their chemical structures inhibiting CBD to bind with cannabinoid receptors due to steric hindrance. The distribution of cannabinoid receptors (namely, CB1 and CB2) in the human body and the role of endocannabinoids (namely, anandamide and 2-arachidonoyl glycerol) throughout the human system are described. The effect of the method of consumption (inhalation vs. ingestion) on the psychotropicity of cannabis/THC has also been discussed. Additionally, the effect of the use of synthetic endocannabinoid receptor blocker (antagonist) as a drug molecule for a specific purpose, such as for reducing the appetite, to treat obesity, or for the treatment of tobacco, alcohol, and other hard drugs induced addiction, and their potential adverse effects are also the focus of the article. Both the benefits and the risks of consuming cannabinoids are mainly dose-dependent, just like any other legal or prescription pharma products or regulated/unregulated psychotropic substances. Moderation is the right old prescription for a healthy and long productive life, and it applies to the use of medicinal, cultural, and/or recreational products like cannabis/cannabinoids. The traditional use of cannabis leaves (bhang) in India for medical as well as cultural purposes has been discussed from the modern scientific perspective. Lastly, the rapidly growing trend of the number of the publication of both the scientific research papers and the patent applications on cannabis, along with the market trend of cannabis-derived products, has been provided, showing quite high and promising growth.
Chapter
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.
Article
Full-text available
The increasing legal availability of cannabis has important implications for road safety. This systematic review characterised the acute effects of Δ⁹-THC on driving performance and driving-related cognitive skills, with a particular focus on the duration of Δ⁹-THC-induced impairment. Eighty publications and 1534 outcomes were reviewed. Several measures of driving performance and driving-related cognitive skills (e.g. lateral control, tracking, divided attention) demonstrated impairment in meta-analyses of “peak” Δ⁹-THC effects (p’s<0.05). Multiple meta-regression analyses further found that regular cannabis use was associated with less impairment than ‘other’ (mostly occasional) cannabis use (p = 0.003) and that the magnitude of oral (n = 243 effect estimates [EE]) and inhaled (n = 481 EEs) Δ⁹-THC-induced impairment depended on various factors (dose, post-treatment time interval, the performance domain (skill) assessed) in other cannabis users (p’s<0.05). The latter model predicted impairment would take ∼7 -hs to subside (Hedges’ g=–0.25) after inhaling 20 mg of Δ⁹-THC; oral Δ⁹-THC-induced impairment may take longer to subside. These results suggest individuals should wait at least 7 -hs following inhaled cannabis use before performing safety-sensitive tasks.
Article
The recent trend for legalization of medicinal cannabis and cannabinoid-containing products, together with their soporific effects, has led to a surge of interest of their potential therapeutic role in the management of some common sleep disorders, such as insomnia, sleep disordered breathing, and restless legs syndrome, and less common disorders such as narcolepsy and parasomnias. Although much of the pre-clinical and clinical data were derived from studies with relatively small sample sizes and limited by biases in assessment, and in clinical trials lack of allocation concealment, as a whole, the results indicate a potential therapeutic role for cannabinoids in the management of some sleep disorders. Clinical trials are underway for insomnia and obstructive sleep apnea management, but there remains a substantial need for rigorous large multi-center studies to assess the dose, efficacy, and safety of the various types of cannabinoids on sleep disorders. This review aims to summarize the modulatory effects of cannabinoids on sleep physiology and provide a critical evaluation of the research on their potential therapeutic benefit in various sleep disorders.
Article
Nearly one third of Americans experience poor sleep, which is associated with numerous deleterious health outcomes. Poor sleep may be exacerbated when an individual attends college, as they experience drastic shifts in lifestyle and sleep patterns. Previous research suggests cannabis has therapeutic potential for sleep disorders but may also impair sleep quality long-term. However, no study has examined the differences in sleep quality within individuals who meet criteria for Cannabis Use Disorder (CUD). The purpose of the current study was to determine differences in sleep quality among undergraduate students who met criteria for mild CUD (n=18), moderate CUD (n=22), severe CUD (n=16) and students who did not meet criteria for CUD (n=244). Participants included 300 predominantly Black/African American undergraduate students (79% female), aged between 18-25 years. Each participant completed an online survey that included measures assessing sleep quality and CUD criteria. Employing analysis of covariance, the moderate CUD subgroup (M=9.00, SD=3.32) reported poorer sleep quality than individuals who did not meet criteria for CUD (M=6.93, SD=3.03). Interestingly, the severe CUD subgroup (M=6.75, SD=2.52) reported similar sleep quality to individuals who did not meet criteria for CUD (M=6.93, SD=3.03). Individuals meeting criteria for mild and moderate CUD reported the poorest sleep quality among the groups, suggesting a differentiation within CUD severity. Future research should assess withdrawal and cannabis use frequency among individuals who meet criteria for CUD to further elucidate disturbances in sleep quality among those with CUD.
Article
The medicolegal landscape of cannabis continues to change, and with ever increasing access there has been a concurrent proliferation of research seeking to understand the utility of cannabinoids in treating innumerable conditions with pain at the forefront. This article seeks to summarize clinically relevant findings in cannabinoid research to better prepare clinicians in the utility of cannabis in the treatment of pain.
Article
Cannabidiol, commonly abbreviated CBD, is one of the hundreds of compounds present in the flowering cannabis plant, along with its more well-known structural isomer, Δ9-tetrahydrocannabinol or THC. CBD can be extracted from the plant and utilized in many forms, from topical oils to smokable flowers. Recently, availability, interest in and use of CBD across the nation have grown exponentially, with internet searches for CBD increasing 160% between 2017 and 2018 and 14% of Americans citing current CBD use. Users of this compound endorse numerous perceived benefits, including anxiolysis, analgesia and much more. Most users claim to employ CBD to treat specific medical conditions spanning from autoimmune, to psychiatric, to musculoskeletal. Evidence supports some of these reported effects in recent studies, as CBD has demonstrated anticonvulsant, antipsychotic and antinociceptive properties, among others. However, the implications of these findings are still in their infancy. As of June 2018, one FDA-approved pure CBD product for seizure treatment, Epidolex®, is available for prescription use and many more are in various stages of testing. However, numerous safety and legal concerns remain regarding off-label and over-the-counter CBD usage. Physicians and other health care professionals are likely to encounter CBD use by their patients. As usage continues to grow, so does the duty of care providers to understand its role and serve as a source of evidence-b
Article
Full-text available
Terpenoids, also referred as terpenes have been used extensively in drug related industry due to pharmaceutical properties. These have driven the emergence of studies on terpenoid from plant. Cannabis sativa plant is one of the common natural sources of terpenoids and cannabinoids. The cannabis produces and accumulates terpenoids in grandular trichomes. The grandular trichomes are abundant on the surface of female inflorescence. About 140 terpenoids are known in cannabis and some of them have medicinal potential in treatment of pain, inflammatory, cognition, epilepsy and immune functioning. The biological effect of terpenoid from cannabis is mainly attributed to limonene, myrcene, pinene, linalool, ß-caryophyllene, caryophyllene oxide, nerolidol and phytol. The different composition of terpenoids are responsible in exhibit the unique organoleptic properties and influence the medicinal qualities of difference cannabis strains and varieties. This article aims to review the cannabis plant for terpenoid, terpenoid biosynthesis and its pharmacological activities. The terpenoids from cannabis could be valuable natural resources for drug development.
Article
Objective: The objective of this study was to evaluate the safety and efficacy of medications commonly used in autism spectrum disorder (ASD) and compare this to what current research has shown regarding medical cannabis use in this population. Methods: Searches were performed to collect information surrounding currently used medications and their safety and efficacy profiles, biologic plausibility of cannabis use for symptoms of ASD, and studies detailing cannabis' safety and efficacy profile for use in the ASD population. Results were used to compare medications to cannabis as a proposed treatment. Results: The heterogeneity of ASD produces great difficulties in finding appropriate treatment, leading to many medication changes or treatment trials throughout a patient's life. Commonly prescribed medications display varying levels of efficacy, safety, and tolerability between patients and symptoms targeted. Some of the most common side effects cited are also considered the most troubling symptoms associated with ASD; aggression, anxiety, irritability, and a negative effect on cognition, leading many patients to discontinue use as the side effects outweigh benefits. Recent case reports and retrospective studies have displayed the potential efficacy, safety, and tolerability of cannabidiol (CBD)-rich medical cannabis use for treating both core symptoms of ASD and many comorbid symptoms such as irritability and sleep problems. Studies have also identified circulating endocannabinoids as a possible biomarker for ASD, providing another possible method of diagnosis. Conclusions: Currently, there are no approved medications for the core symptoms of ASD and only two medications Food and Drug Administration approved for associated irritability. Prescribed medications for symptoms associated with ASD display varying levels of efficacy, safety, and tolerability among the heterogeneous ASD population. At the time of this study there are no published placebo-controlled trials of medical cannabis for ASD and the observational studies have limitations. CBD-rich medical cannabis seems to be an effective, tolerable, and relatively safe option for many symptoms associated with ASD, however, the long-term safety is unknown at this time.
Article
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.
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.
Technical Report
Full-text available
Sleep is an important physiological function that represents about a third of our daily lives. This function can be altered by several sleep disorders with varying prevalence. Cannabis is often viewed as a hypnotic drug, based on user’s reports or objective measurements. The two main cannabinoids of the plant are THC and CBD. They both act differently on the endocannabinoid system, which is itself involved in regulating the sleep-wake cycle. In acute exposure, THC has sleep-promoting properties (decreasing sleep onset latency and wake after sleep onset ; increasing total sleep time and slow wave sleep). Data on CBD is inconsistent, it is sometimes presented as a wakepromoting drug. These effects of cannabinoids on sleep raise questions about the relevance of their use in the pharmacological treatment of certain sleep disorders. Among the seven medical situations for which there is literature, the best – yet weak – data relate to sleep apnea and PTSD-related nightmares. Further work should shed light on this field of research in the future. (text in French)
Article
For a good night's sleep, we consensually recommend avoiding alcohol, smoking and drugs. However, these addictions are highly prevalent in the general population, and it is difficult to estimate their real impact on sleep. The aim of this study is to clarify the association between sleep habits and disorders, and addictions. The design was a telephone crossover national recurrent health poll survey (Santé publique France, Baromètre santé, 2017; Questionnaire, pp. 53; Saint Maurice) in a representative sample of French adults. There were 12,367 subjects (18-75 years old) who answered the survey. Sleep log items assessed sleep schedules (total sleep time) on work and leisure days: at night, while napping, and over 24 hr using a sleep log. Retained items include: (1) short sleep (≤ 6 hr/24 hr); (2) chronic insomnia (International Classification of Sleep Disorders, 3rd edition criteria); and (3) chronotype (evening-morning-neutral). Psychoactive substances retained included tobacco (current or former users), alcohol (daily consumption and weekly binge drinking), cannabis (Cannabis Abuse Screening Test), and other drugs (consumption during the past year). We found that: (1) daily smokers (lightly or heavily dependent) were more frequently short sleepers than occasional smokers and non-smokers; (2) heavily dependent daily smokers were more likely to suffer from insomnia than other smokers or non-smokers; (3) short sleep and insomnia were not significantly associated with the consumption of alcohol, cannabis or any other drug; (4) the evening chronotype was significantly associated with the consumption of tobacco, alcohol and cannabis. In conclusion, our study highlights significant relationships between the use of psychoactive substances and sleep characteristics among adults, emphasizing the need to take into account each subject individually.
Chapter
Cannabis or marijuana is comprised of over 100 known sub-chemicals or cannabinoids. Two of these, delta-9-Tehtrahydrocannabinol (THC) and cannabidiol (CBD), have received increasing scrutiny regarding their effects on sleep-wake physiology and their potential for treating a wide variety of sleep disorders. The limited data available suggest there may be initial improvement in several sleep parameters but also a tendency toward tolerance with long-term use. Withdrawal effects following chronic use can be significant. There is presently little high-quality evidence currently available on the remedial properties of cannabinoids for primary sleep disorders. Large-scale, randomized, controlled studies in humans are needed.
Chapter
Cannabis has been well known for centuries due to its medicinal properties. In recent decades, the inclination of researchers towards its important phytoconstituents as a potential therapeutic alternative has been propounded due to the discovery of its major active constituent, i.e., Δ9-tetrahydrocannabinol (Δ9-THC). Besides this, the presence of other phytoproducts, including cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), etc., also contribute towards its medicinal importance. Interestingly, due to the effectiveness of cannabis against various pathological conditions, its use for medicinal purposes has been revolutionized worldwide. Despite these facts, it has become obligatory to explore synergistic interactions and mode of action of its phytoconstituents involving various biological pathways. Current advancements have allowed medical practitioners to better understand cannabis-derived products as a pharmacological choice in several conditions, including pain treatment, stress, anxiety, neurodegenerative disorders, and cancer. However, there exists a lacuna in the literature regarding its beneficial doses. Since medicinal exploration and the legalization of cannabis depend upon various factors, the present review deals with the important phytocannabinoids, their biogenesis, types of drugs obtained, mode of action, therapeutic implications, and new approaches for supporting this plant as a critical therapeutic agent for pharmaceutical drugs. Overall, this may provide an insight into the role of cannabis as a potent candidate for future drug discovery and generate efficient products for human welfare.
Article
Full-text available
This report proposes a method of assessing aircrew fatigue based on work/rest profiles. Possible circadian desynchronization and cumulative fatigue an aircrew may have experienced are considered. The method was used to assess aircrew fatigue during computer-simulated airlift operations. It shows quantitatively how flying-hour limitations can affect average aircrew fatigue and system performance.
Article
Full-text available
The advent of hand-held computers means that it is now feasible to administer standard measures of affect and cognitive performance in field studies without the direct intervention of the investigator. The functional requirements for such an instrument are set out, and a set of programs developed for an electronic Organiser to meet those requirements are described. The programs include alarm scheduling, subjective rating scales, a sleep diary, and choice reaction time and memory search tasks. Compliance rates and usability of the instrument are assessed and judged satisfactory on the basis of examples from three field studies of shiftworkers.
Article
Full-text available
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.
Article
Full-text available
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.
Article
Full-text available
Although some aspects of memory functions are known to be acutely impaired by delta(9)-tetrahydrocannabinol (delta(9)-THC; the main active constituent of marijuana), effects on other aspects of memory are not known and the time course of functional impairments is unclear. The present study aimed to detail the acute and residual cognitive effects of delta(9)-THC in infrequent cannabis users. A balanced, double-blind cross-over design was used to compare the effects of 7.5 mg and 15 mg delta(9)-THC with matched placebo in 15 male volunteers. Participants were assessed pre and 1, 2, 4, 6, 8, 24 and 48 h post-drug. Delta(9)-THC 15 mg impaired performance on two explicit memory tasks at the time of peak plasma concentration (2 h post-drug). At the same time point, performance on an implicit memory task was preserved intact. The higher dose of delta(9)-THC resulted in no learning whatsoever occurring over a three-trial selective reminding task at 2 h. Working memory was generally unaffected by delta(9)-THC. In several tasks, delta(9)-THC increased both speed and error rates, reflecting "riskier" speed-accuracy trade-offs. Subjective effects were also most marked at 2 h but often persisted longer, with participants rating themselves as "stoned" for 8 h. Participants experienced a strong drug effect, liked this effect and, until 4 h, wanted more oral delta(9)-THC. No effects of delta(9)-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral delta(9)-THC are minimal. These data demonstrate that oral delta(9)-THC impairs episodic memory and learning in a dose-dependent manner whilst sparing perceptual priming and working memory.
Article
Some time ago, a multiple comparison procedure for comparing several treatments simultaneously with a control or standard treatment was introduced by the present author (Dunnett [1955]). The procedure was designed to be used either to test the significance of the differences between each of the treatments and the control with a stated value 1 - P for the joint significance level, or to set confidence limits on the true values of the treatment differences from the control with a stated value P for the joint confidence coefficient. Thus the procedure has the property of controlling the experimentwise, rather than the per-comparison, error rate associated with the comparisons, in common with the multiple comparison procedures of Tukey [unpublished] and Scheffe [1953]. In the earlier paper, tables were provided enabling up to nine treatments to be compared with a control with joint confidence coefficient either .95 or .99. Tables for both one-sided and two-sided comparisons were given but, as explained in the paper, the two-sided values were inexact for the case of more than two comparisons as a result of an approximation which had to be made in the computations. The main purpose of the present paper is to give the exact tables for making two-sided comparisons. The necessary computations were done on a General Precision LGP-30 electronic computer, by a method described in section 3 below. The tables are given here as Tables II and III; these replace Tables 2a and 2b, respectively, of the previous paper. In addition to providing the exact values, a method is given for adjusting the tabulated values to cover the situation where the variance of the control mean is smaller than the variance of the treatment means, as occurs for example when a greater number of observations is allocated to the control than to any of the test treatments. Furthermore, the number of treatments which may be simultaneously compared with a control has been extended to twenty. 482
Article
Five volunteers slept 8 to 15 consecutive nights in the laboratory with electroencephalogram, chin electromyogram, and eye movements monitored by the method originated by Dement and Kleitman. d9-tetrahydrocannabinol (THC), 20 mg administered at bedtime decreased the amount of time spent in the REM or paradoxical phase of sleep. Abrupt withdrawal of THC after 4 to 6 consecutive nights of use produced a mild insomnia characterized by difficulty in falling and staying asleep but did not produce a marked REM rebound.
Article
The Criterion Task Set (CTS), V1.0 is a battery of human performance tests designed to place selective demands on the elementary mental resources and information processing functions of the human operator. Currently under development as a general purpose research tool for applied investigations of human performance capabilities, the CTS V1.0 includes nine standardized tasks which are implemented in user-friendly software on an inexpensive microcomputer system. This interim report describes the theoretical basis of the CTS, the rationale used in its construction, and the parametric research conducted to establish standard loading levels, pacing rates, and training requirements for each of the tasks. Potential research applications of the CTS are discussed as well as planned developmental efforts intended to enhance it utility. Documentation for the CTS V1.0 is provided in the form of detailed individual task descriptions and brief summaries of hardware requirements and software characteristics.
Article
Primary objectives of this study were to assess the pharmacokinetic characteristics of CBME when administered sublingually in different ratios, to determine if the pharmacokinetic profiles of THC and its metabolite 11-hydroxy-THC are different when administered sublingually in different formulations, and to characterise the pharmacokinetic profile of CBD when administered with THC in equal amounts. Secondary objectives were to determine if there was a correlation between intoxication levels and plasma concentrations of THC and/or its metabolite 11-hydroxy-THC, and to assess safety and tolerability of CBME when administered sublingually.Methodology employed a double-blind, randomised, three-way crossover study of placebo, High THC and CBD:THC administered sublingually as a liquid spray. Twenty-four subjects were planned, dosed, completed the study and were analysed.Test products were Δ-tetrahydrocannabinol (THC, formulated as 25 mg THC per ml) with or without cannabidiol (CBD) (formulated as 25 mg CBD + 25 mg THC per ml) formulated in ethanol (Eth):propylene glycol (PG) with peppermint (ppmt) flavouring or matching placebo, administered with a 100 μl pump. Each subject received one single dose of 10 mg THC and one single dose of 10 mg CBD + 10 mg THC plus a single dose of placebo in a randomised manner on three separate occasions. The washout period was six days between each dose. Placebo was Eth:PG in a 50:50 ratio with ppmt flavouring, administered with a 100 μl actuator pump.Mean plasma concentrations show that following administration of both High THC and CBD:THC formulations CBD and or THC was detectable in plasma in measurable concentrations 15–30 minutes after dosing, although individual subjects showed quite wide variability, 15 to 135 minutes, to appearance measurable concentrations. At all time points up to 180 minutes after dosing mean concentrations of THC were greater following the High THC formulation than CBD:THC. Concentrations of THC were also greater than corresponding concentrations of CBD following the CBD:THC treatment.There were no statistically significant differences in mean Cmax, t1/2, AUC0-t and AUC0-∞of both THC and 11-hydroxy-THC between the High THC and CBD:THC formulations. THC Tmax was statistically significantly later following CBD:THC than High THC (p = 0.014) and this was the only statistically significant difference in pharmacokinetic parameters between the treatments. The AUC values (AUC0-t and AUC0-∞) for THC show an approximate 8 to 10-fold difference between the lowest and highest subject values while the difference for CBD was approximately 3.5 to 4-fold. Differences in Cmax were 20 to 30 fold for THC and approximately 14-fold for CBD. Intra-subject differences in values for THC between treatments were smaller though differences in Cmax of up to 5-fold and 3-fold in AUC (AUC0-t and AUC0-∞) were observed. Other than a single isolated significant difference in Tmax there were no significant differences in pharmacokinetic parameters between the CBD:THC and High THC formulations. The bioavailability of THC appears to be greater than that of CBD.Mean intoxication scores on both CBME treatments were very low throughout the observation period. The majority of subjects scored zero for the majority of assessment points and there were few scores greater than three on the Box Scale 11 (BS-11). Recorded intoxication scores do not seem to show a direct relationship to plasma concentrations of THC and/or 11-hydroxy-THC either within or between subjects. The time of intoxication scores in individual subjects do not seem to relate consistently with the timing of increases in plasma concentrations or maximal concentrations of THC or 11-hydroxy-THC. Neither is there an apparent relationship between subjects reporting intoxication and those with the highest plasma levels of THC or 11-hydroxy-THC.No subjects withdrew from the study as a result of adverse events and both active and the placebo test treatments were well tolerated. The treatment with the least number of treatment related adverse events was placebo. High THC and CBD:THC had a greater number of subjects who experienced intoxication type adverse events and application site type reactions. The most common overall adverse event experienced was throat irritation, followed by dizziness, somnolence, oral paraesthesia and then headache. All the events were mild and only two events needed any treatment. There were no clinically significant changes from baseline for haematology, biochemistry, vital signs or ECGs.There was wide inter- and intra-subject variability in pharmacokinetic parameters with up to 10-fold differences in THC AUC between subjects and even greater differences in Cmax. Results suggest that there are no overall statistically significant differences between the pharmacokinetic parameters of High THC and CBD:THC other than a delay in Tmax. Considering the wide inter- and intra-subject variability in pharmacokinetic parameters including Tmax this is unlikely to be clinically important in a medication that is self titrated by the patient.
Article
The first two volumes are complete revisions of Kendall's two volumes, written in 1943 and 1946. Harvard Book List (edited) 1971 #77 (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Based on previous observations that cannabidiol (CBD) blocks some effects of Δ9-tetrahydrocannabinol (Δ9-THC) in laboratory animals, the present work was carried out to study possible interaction between CBD and Δ9-THC in human beings. In a double blind procedure, 40 healthy male volunteers were assigned to 1 of 8 experimental groups, receiving per oral route, placebe, 30 mg Δ9-THC, 15 30 or 60 mg of CBD, and mixtures of 30 mg of Δ9-THC plus either 15, 30 or 60 mg of CBD respectively. Pulse rate, time production tasks and psychological logical reactions were measured at several time intervals after drug ingestion. 30 mg Δ9-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects. 15–60 mg of CBD alone provoked no effects. On the other hand, CBD was efficient in blocking most of the effects of Δ9-THC when both drugs were given together. CBD also decreased the anxiety component of Δ9-THC effects, in such a way that the subjects reported more pleasurable effects.
Article
The Multi-Attribute Task (MAT) Battery provides a benchmark set of tasks for use in a wide range of lab studies of operator performance and workload. The battery incorporates tasks analogous to activities that aircraft crewmembers perform in flight, while providing a high degree of experimenter control, performance data on each subtask, and freedom to use nonpilot test subjects. Features not found in existing computer based tasks include an auditory communication task (to simulate Air Traffic Control communication), a resource management task permitting many avenues or strategies of maintaining target performance, a scheduling window which gives the operator information about future task demands, and the option of manual or automated control of tasks. Performance data are generated for each subtask. In addition, the task battery may be paused and onscreen workload rating scales presented to the subject. The MAT Battery requires a desktop computer with color graphics. The communication task requires a serial link to a second desktop computer with a voice synthesizer or digitizer card.
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
Experiments investigating the possible interaction of tetrahydrocannabinol (THC) and cannabidiol (CBD), two major components of marihuana, were conducted under controlled laboratory conditions in a double-blind manner. In one study, 15 male volunteers were given placebo or 25 mug/kg of THC together with either placebo or 150 mug/kg of CBD by inhalation of the smoke of a single cigarette. All four treatments were assigned to each subject according to a series of Latin-square designs. CBD significantly attenuated the subjective euphoria of THC. Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD, but a trend indicating a decrease in THC-like effects was observed after the combination. When administered alone CBD was inactive for all the parameters measured. In a second study, 8 male subjects were given CBD (0 or 150 mug/kg) by smoke inhalation 30 min before THC (0 or 25 mug/kg) in a second cigarette. In contrast to the simultaneous administration of both drugs, CBD pretreatment did not alter the effects of THC on the parameters observed.
Article
Cannabidiol (CBD), a nonpsychoactive cannabinoid of Cannabis, was given to 5 patients with dystonic movement disorders in a preliminary open pilot study. Oral doses of CBD rising from 100 to 600 mg/day over a 6 week period were administered along with standard medication. Dose-related improvement in dystonia was observed in all patients and ranged from 20 to 50%. Side-effects of CBD were mild and included hypotension, dry mouth, psychomotor slowing, lightheadedness, and sedation. In 2 patients with coexisting Parkinsonian features, CBD at doses over 300 mg/day exacerbated the hypokinesia and resting tremor. CBD appears to have antidystonic and Parkinsonism-aggravating effects in humans.
Article
Performance was measured during the day (0800-1700 hours) and during the night (1700-0800 hours) of a day-night schedule, and the effect of caffeine (300 mg) was studied during the overnight periods of work. The sleep electroencephalogram was recorded together with oral temperature and urinary electrolyte excretion. Impairment of performance within 9 h after the beginning of the daytime work period was minimal, and was limited to a test of continuous performance, but impairment of performance within 9 h after the beginning of the overnight work period was more pronounced and included lowered vigilance. Impaired performance overnight was related to time on task and circadian rhythmicity, and was alleviated to some extent by the use of caffeine.
Article
The effects of Δ9-tetrahydrocannabinol (Δ9-THC) administered orally at 2 dose levels were studied in a group o f 7 healthy young adult males. Each subject was studied for 7 nights (2 drug, 5 placebo). Vital signs, subjective feelings, deep tendon reflexes, electrocardiogram, electroencephalogram, visual evoked responses, postural responses, time estimation and reaction time and sleep patterns were studied. At the doses studied, Δ9-THC increased pulse rate, altered subjective feelings, and caused hyperreflexia and upset postural responses in the absence of visual cues. Some subjects also exhibited lowered oral temperature, changes in averaged visual evoked response, and alteration of sleep patterns.
Article
Investigated whether the Stanford Sleepiness Scale (SSS), a self-rating scale used to quantify progressive steps in sleepiness, cross-validates with performance on mental tasks and whether the SSS demonstrates changes in sleepiness with sleep loss. 5 undergraduates were given a brief test of memory and the Wilkinson Addition Test in 2 test sessions and the Wilkinson Vigilance Test in 2 other sessions spaced throughout a 16-hr day for 6 days. Ss made SSS ratings every 15 min during their waking activities. On Night 4, Ss underwent all-night sleep deprivation. On all other nights, Ss were allowed only 8 hrs in bed. Mean SSS ratings correlated r = .68 with performance on the Wilkinson tests. Discrete SSS ratings correlated r = .47 with performance on the memory test. Moreover, mean baseline SSS ratings were found to be significantly lower than corresponding ratings of the deprivation period. (PsycINFO Database Record (c) 2005 APA, all rights reserved)
Article
This study describes the effect of two weeks of delta-9-tetrahydrocannabinol (THC) administration upon normal sleep. The two subjects, two brothers in their 20s, slept in the laboratory for 27 consecutive nights and then, after four nights at home, for four additional nights. One subject, after an adaption night, received placebo for four baseline nights, 30 mg of THC for the next 14 nights, and placebo during four withdrawal nights. The other subject received placebo during this entire period. One year later the subjects alternated these conditions. The subjects had difficulty falling and staying asleep during the first two nights of placebo after 14 consecutive drug nights. This mild drug withdrawal insomnia was not accompanied by the increase of REM sleep which frequently accompanies withdrawal of other drugs. Starting after about a week of THC administration, and continuing for a week after drug discontinuance, there was a marked decrease in the type of sleep associated with slow waves in the electroencephalogram, nonREM sleep stages 3 and 4. The fact that prolonged, but not acute use, suppresses slow wave sleep indicates that this commonly used drug produces a poorly understood change in brain physiology.
Article
Examined adaptation to a 9-day schedule of irregular rest and activity in 3 26–32 yr old males through EEG, EOG, and EMG sleep recordings; periodic measurement of temperature and urinary constituents; performance on tasks including auditory vigilance and tracking, choice RT, a color discrimination test, and CFF; and subjective assessments of mood, arousal, and task performance. The relationships between circadian rhythmicity, time on task, and cumulative sleep loss are examined. (22 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
The aim of this study was to establish whether fexofenadine hydrochloride, an antihistamine, modulates daytime sleepiness or performance. The effects of fexofenadine (120, 180, and 240 mg) on digit symbol substitution, tracking, and vigilance tasks, and on objective (multiple sleep latency test) and subjective sleepiness, were studied in six healthy volunteers (two males, four females, aged 20-34 [mean 26.5] yr) from 1 h pre-ingestion to 8 h post-ingestion. The study was placebo-controlled and double-blind with a six-way cross-over design. The centrally acting antihistamine, promethazine (10 mg), was used as an active control to confirm the sensitivity of the experimental procedures. There were no changes in performance or sleepiness with any dose of fexofenadine at any time, compared with placebo. Promethazine, compared with both placebo and fexofenadine, impaired performance on the digit symbol substitution task (2.5 h post-ingestion), vigilance task (2.5-5h post-ingestion) and tracking task (2.5-3.5 h post-ingestion), increased objective sleepiness (1.5-2.5 h post-ingestion) and subjective sleepiness (1.5-8h post-ingestion). Consideration may be given to the clinical use of currently licensed doses of fexofenadine (120-180 mg) by individuals involved in skilled activity. Fexofenadine may be potentially useful for aircrew.
Article
To establish the effect of melatonin upon nocturnal and evening sleep. Experiment I: The effect of melatonin (0.1, 0.5, 1.0, 5.0, and 10 mg), ingested at 23:30, was studied on nocturnal sleep (23:30-07:30) and core body temperature in 8 healthy volunteers. Performance was measured 8.5 h post-ingestion. On completion of the experiment dim light melatonin onsets (DLMO) were determined. Experiment II: The effect of melatonin (0.5, 1.0, 5.0, and 10 mg), ingested at 18:00, was studied on evening sleep (18:00-24:00) and core body temperature in 6 healthy volunteers. Performance was measured 6.5 h post-ingestion. Each experiment was placebo-controlled and double-blind with a cross-over design with temazepam (20 mg) as an active control. Experiment I: Melatonin (5 mg) reduced the duration of stage 3 in the first 100 min of sleep. Melatonin (0.1 mg) reduced body temperature 6.5 to 7 h post-ingestion. Temazepam increased stage 2, reduced wakefulness and stage 1, and increased the latency to REM sleep. Temazepam reduced body temperature 4.5 to 6.5 h post-ingestion. There were no changes in performance compared with placebo. DLMO occurred between 20:40 and 23:15. Experiment II: Melatonin (all doses) increased total sleep time (TST), sleep efficiency index (SEI) and stage 2, and reduced wakefulness. Temazepam increased TST, SEI, stage 2 and slow-wave sleep, and reduced wakefulness. There were no changes in body temperature or performance compared with placebo. Melatonin given at 23:30 has no significant clinical effect on nocturnal sleep in healthy individuals. Hypnotic activity of melatonin when given in the early evening (presumably in the absence of endogenous melatonin) is similar to 20 mg temazepam.
Article
Increasing prevalence of recreational cannabis use among the young population has stimulated debate on the possible effects of acute and longterm use. To highlight recent knowledge of mechanisms of action, effects on psychomotor and cognitive performance, and health risks associated with cannabis consumption. A brief review of recent literature on the prevalence of recreational cannabis use, the potency of modern cannabis preparations and the pharmacological actions of cannabis. Cannabinoids derived from herbal cannabis interact with endogenous cannabinoid systems in the body. Actions on specific brain receptors cause dose-related impairments of psychomotor performance with implications for car and train driving, aeroplane piloting and academic performance. Other constituents of cannabis smoke carry respiratory and cardiovascular health risks similar to those of tobacco smoke. Cannabis is not, as widely perceived, a harmless drug but poses risks to the individual and to society.
Quantification of sleepiness: a new approach Unauthorized reproduction of this article is prohibited. 16. Wechsler D. A Manual for the Wechsler Adult Intelligence Scale (Revised)
  • E Hoddes
  • V Zarcone
  • H Smythe
Hoddes E, Zarcone V, Smythe H, et al. Quantification of sleepiness: a new approach. Psychophysiology. 1973;10:431 –436. 312 n 2004 Lippincott Williams & Wilkins Nicholson and Associates Journal of Clinical Psychopharmacology Volume 24, Number 3, June 2004 Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 16. Wechsler D. A Manual for the Wechsler Adult Intelligence Scale (Revised). New York: Psychological Corporation; 1981.
A Task Battery for Applied Human Performance Assessment Research. Ohio Air Force Aerospace Medical Research Laboratories, Dayton, Ohio: Wright-Patterson Air Force Base
  • Shingledecker
  • Ca
Shingledecker CA. A Task Battery for Applied Human Performance Assessment Research. Ohio Air Force Aerospace Medical Research Laboratories, Dayton, Ohio: Wright-Patterson Air Force Base; 1984. Report No. AFAMRL-TR-84-071.
Open label evaluation of cannabidiol in dystonic movement disorders
  • Consroe P R Sandyk
  • Snider
  • Sr
Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders. Int J Neurosci. 1986;30(4):277–282.
Address correspondence and reprint requests to Prof Anthony N. Nicholson, QinetiQ Ltd E-mail: annicholson@QinetiQ.com
  • Ltd
  • Human Centre
  • Cody Sciences
  • Park
  • Farnborough
  • Uk Hampshire
  • Warneford Psychiatry
  • Hospital
  • Uk Oxford
*QinetiQ Ltd, Centre for Human Sciences, Cody Technology Park, Farnborough, Hampshire, UK; yDepartment of Psychiatry, Warneford Hospital, Oxford, UK. Received May 5, 2003; accepted after revision December 23, 2003. Address correspondence and reprint requests to Prof Anthony N. Nicholson, QinetiQ Ltd, Centre for Human Sciences, Ively Road, Farnborough, Hampshire GU14 0LX, UK. E-mail: annicholson@QinetiQ.com. Copyright n 2004 by Lippincott Williams & Wilkins ISSN: 0271-0749/04/2403-0305 DOI: 10.1097/01.jcp.0000125688.05091.8f Original Contribution Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. REFERENCES
The actions of cannabis in man
  • W D Paton
  • R G Pertwee
Paton WD, Pertwee RG. The actions of cannabis in man. In: Mechoulam R, eds. Marijuana: Chemistry, Pharmacology, Metabolism and Clinical Effects. New York: Academic Press. 1973:288-334.
Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents
  • Ea Carlini
  • Jr Leiter
  • M Tannhauser
Carlini EA, Leiter JR, Tannhauser M, et al. Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. J Pharm Pharmacol. 1973;25:664-665.
Neuilly Sur Seine, France: NATO Advisory Group for Aerospace Research and Development
  • A H Roscoe
Roscoe AH. Assessing pilot workload in flight. Neuilly Sur Seine, France: NATO Advisory Group for Aerospace Research and Development; 1984. NATO-AGARD CP No. 373 on Flight Test Technique. 12-1-12-13.
Order statistics in estimation and hypothesis testing
  • H A David
David HA. Order statistics in estimation and hypothesis testing. New York: Wiley; 1970:93-136.
Pharmacology and effects of cannabis: a brief review.
  • Ashton
Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry. 2001;178:101-106.
The advanced theory of statistics
  • M G Kendall
  • A Stewart
Kendall MG, Stewart A. The advanced theory of statistics. London: Griffin & Co.; 1967:44-46.
Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents.
  • Carlini