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Phytocannabinoids as NovelTherapeutic Agents for Sleep Disorders
Abstract
Sleep is a universal phenomenon that occurs in every species studied so far. A normal sleep period fluctuates in a regular cycle of two basic forms: slow wave sleep (SWS) and rapid eye movement (REM) sleep. The sleep–wake cycle is modulated by diverse brain circuits and neuromodulators as well as by several endogenous and exogenous molecules, including cannabinoids. Here, we describe the effects of certain cannabis-derived and synthetic cannabinoids on sleep. Additionally, we provide an overview of current knowledge about potential uses of natural or synthetic cannabinoids for the treatment of sleep disorders.
Cannabinoids promote non-rapid eye movement (NREM) sleep, but its underlying mechanism is not known. Here we find that cannabinoid promotion of NREM sleep is inhibited by cannabinoid antagonist injection systemically or into the dorsomedial hypothalamus (DMH), where cannabinoids selectively inhibit glutamatergic inputs synapsing with glutamatergic but not GABAergic neurons. Photoactivation of DMH-projecting ventromedial prefrontal cortical (vmPFC) neurons, their terminals, or their postsynaptic DMH neurons rapidly switches NREM sleep to wakefulness, which is blocked by photoinhibition of DMH outputs. Chemoactivation of DMH glutamatergic but not GABAergic neurons innervated by vmPFCs promotes wakefulness and suppresses NREM sleep, whereas chemoinhibition of vmPFC projections in DMHs produces opposite effects by mimicking cannabinoid effects. DMH-projecting vmPFC neurons are inhibited during NREM sleep and activated during wakefulness. Chemoactivation of DMH-projecting vmPFC neurons blocks cannabinoid promotion of NREM sleep and suppression of wakefulness. Thus, vmPFC neurons innervating DMHs represent the first identified set of cerebral cortical neurons for promotion of physiological wakefulness and suppression of NREM sleep, while cannabinoid inhibition of vmPFC projections in DMHs promotes NREM sleep and suppresses wakefulness.
Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany.
Selective literature review
Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting.
There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.
Recent advances in understanding of the mode of action of tetrahydrocannabinol and related cannabinoid in-gredients of marijuana, plus the accumulating anecdotal reports on potential medical benefits have spurred increasing re-search into possible medicinal uses of cannabis. Recent clinical trials with smoked and vaporized marijuana, as well as other botanical extracts indicate the likelihood that the cannabinoids can be useful in the management of neuropathic pain, spasticity due to multiple sclerosis, and possibly other indications. As with all medications, benefits and risks need to be weighed in recommending cannabis to patients. We present an algorithm that may be useful to physicians in determining whether cannabis might be recommended as a treatment in jurisdictions where such use is permitted.
Background
Insomnia is common in primary care, can persist after co-morbid conditions are treated, and may require long-term medication treatment. A potential alternative to medications is cognitive behavioral therapy for insomnia (CBT-I).
Methods
In accordance with PRISMA guidelines, we systematically reviewed MEDLINE, EMBASE, the Cochrane Central Register, and PsycINFO for randomized controlled trials (RCTs) comparing CBT-I to any prescription or non-prescription medication in patients with primary or comorbid insomnia. Trials had to report quantitative sleep outcomes (e.g. sleep latency) in order to be included in the analysis. Extracted results included quantitative sleep outcomes, as well as psychological outcomes and adverse effects when available. Evidence base quality was assessed using GRADE.
Results
Five studies met criteria for analysis. Low to moderate grade evidence suggests CBT-I has superior effectiveness to benzodiazepine and non-benzodiazepine drugs in the long term, while very low grade evidence suggests benzodiazepines are more effective in the short term. Very low grade evidence supports use of CBT-I to improve psychological outcomes.
Conclusions
CBT-I is effective for treating insomnia when compared with medications, and its effects may be more durable than medications. Primary care providers should consider CBT-I as a first-line treatment option for insomnia.
Cannabis intoxication is related to a number of physical and mental health risks with ensuing social costs. However, little attention has been given to the investigation of possible pharmacological interactions in this condition.
To review the available scientific literature concerning pharmacological interventions for the treatment of the acute effects of cannabis.
A search was performed on the Pubmed, Lilacs, and Scielo online databases by combining the terms cannabis, intoxication, psychosis, anxiety, and treatment. The articles selected from this search had their reference lists checked for additional publications related to the topic of the review.
The reviewed articles consisted of case reports and controlled clinical trials and are presented according to interventions targeting the physiological, psychiatric, and cognitive symptoms provoked by cannabis. The pharmacological interventions reported in these studies include: beta-blockers, antiarrhythmic agents, antagonists of CB-1 and GABA-benzodiazepine receptors, antipsychotics, and cannabidiol.
Although scarce, the evidence on pharmacological interventions for the management of cannabis intoxication suggests that propanolol and rimonabant are the most effective compounds currently available to treat the physiological and subjective effects of the drug. Further studies are necessary to establish the real effectiveness of these two medications, as well as the effectiveness of other candidate compounds to counteract the effects of cannabis intoxication, such as cannabidiol and flumazenil.
Aim. To compare the efficacy and safety of armodafinil, the R-enantiomer of modafinil, with modafinil in patients of shift work sleep disorder (SWSD). Material and Methods. This was a 12-week, randomized, comparative, double-blind, multicentric, parallel-group study in 211 patients of SWSD, receiving armodafinil (150 mg) or modafinil (200 mg) one hour prior to the night shift. Outcome Measures. Efficacy was assessed by change in stanford sleepiness score (SSS) by at least 2 grades (responder) and global assessment for efficacy. Safety was assessed by incidence of adverse events, change in laboratory parameters, ECG, and global assessment of tolerability. Results. Both modafinil and armodafinil significantly improved sleepiness mean grades as compared to baseline (P < .0001). Responder rates with armodafinil (72.12%) and modafinil (74.29%) were comparable (P = .76). Adverse event incidences were comparable. Conclusion. Armodafinil was found to be safe and effective in the treatment of SWSD in Indian patients. The study did not demonstrate any difference in efficacy and safety of armodafinil 150 mg and modafinil 200 mg.
Insomnia is a symptom, a syndrome and a comorbid disorder. Its diagnosis relies on subjective reports from the afflicted individual and is defined as difficulties in initiating sleep, maintaining sleep, waking up too early or non-restorative sleep. However, insomnia and especially, primary insomnia, has received much attention in insomnia research with the use of objective measures. Insomnia, its peculiarities, most frequent subtypes and two most prominent models will first be briefly introduced. Then, insomnia will be reviewed according to results obtained with the use of neurophysiological measures as basic/traditional as polysomnography to more sophisticated ones such as power spectral analysis, neuroimaging, cyclic alternating patterns and event-related potentials. In addition, a review of the discrepancies between subjective and objective reports of cognitive alterations through neuropsychological testing is offered. The need to combine measures is then highlighted in conclusion.
The rise of authorized marijuana use in the U.S. means that many individuals are using cannabis as they concurrently engage in other forms of treatment, such as substance abuse counseling and psychotherapy. Clinical and legal decisions may be influenced by findings that suggest marijuana use during treatment serves as an obstacle to treatment success, compromises treatment integrity, or increases the prevalence or severity of relapse. In this paper, the author reviews the relationship between authorized marijuana use and substance abuse treatment utilizing data from a preliminary pilot study that, for the first time, uses a systematic methodology to collect data examining possible effects on treatment.
Data from the California Outcomes Measurement System (CalOMS) were compared for medical (authorized) marijuana users and non-marijuana users who were admitted to a public substance abuse treatment program in California. Behavioral and social treatment outcomes recorded by clinical staff at discharge and reported to the California Department of Alcohol and Drug Programs were assessed for both groups, which included a sample of 18 reported medical marijuana users.
While the findings described here are preliminary and very limited due to the small sample size, the study demonstrates that questions about the relationship between medical marijuana use and involvement in drug treatment can be systematically evaluated. In this small sample, cannabis use did not seem to compromise substance abuse treatment amongst the medical marijuana using group, who (based on these preliminary data) fared equal to or better than non-medical marijuana users in several important outcome categories (e.g., treatment completion, criminal justice involvement, medical concerns).
This exploratory study suggests that medical marijuana is consistent with participation in other forms of drug treatment and may not adversely affect positive treatment outcomes. These findings call for more extensive sampling in future research to allow for more rigorous research on the growing population of medical marijuana users and non-marijuana users who are engaged in substance abuse treatment.
Cannabidiol (CBD) is a constituent of Cannabis sativa that induces nonpsychotropic effects, and some of its biological actions in sleep have been described by the authors' group. Here, the authors report that when administered 10 or 20 microg/1 microl during the lights-on period directly into either lateral hypothalamus (LH) or dorsal raphe nuclei (DRN), which are wake-inducing brain areas, CBD enhanced wakefulness and decreased slow wave sleep and REM sleep. Furthermore, CBD increased alpha and theta power spectra but diminished delta power spectra. Additionally, CBD increased c-Fos expression in LH or DRN. These findings suggest that this cannabinoid is a wake-inducing compound that presumably activates neurons in LH and DRN.
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.
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.
To provide an overview of the history and pharmacology of cannabis in relation to current scientific knowledge concerning actual and potential therapeutic uses of cannabis preparations and pure cannabinoids.
The literature on therapeutic uses of cannabis and cannabinoids was assessed with respect to type of study design, quality and variability of data, independent replications by the same or other investigators, magnitude of effects, comparison with other available treatments and reported adverse effects. The results of this review were also compared with those of major international reviews of this topic in the past five years.
Pure tetrahydrocannabinol and several analogues have shown significant therapeutic benefits in the relief of nausea and vomiting, and stimulation of appetite in patients with wasting syndrome. Recent evidence clearly demonstrates analgesic and anti-spasticity effects that will probably prove to be clinically useful. Reduction of intraocular pressure in glaucoma and bronchodilation in asthma are not sufficiently strong, long lasting or reliable to provide a valid basis for therapeutic use. The anticonvulsant effect of cannabidiol is sufficiently promising to warrant further properly designed clinical trials. There is still a major lack of long term pharmacokinetic data and information on drug interactions. For all the present and probable future uses, pure cannabinoids, administered orally, rectally or parenterally, have been shown to be effective, and they are free of the risks of chronic inflammatory disease of the airways and upper respiratory cancer that are associated with the smoking of crude cannabis. Smoking might be justified on compassionate grounds in terminally ill patients who are already accustomed to using cannabis in this manner. Future research will probably yield new synthetic analogues with better separation of therapeutic effects from undesired psychoactivity and other side effects, and with solubility properties that may permit topical administration in the eye, or aerosol inhalation for rapid systemic effect without the risks associated with smoke inhalation.
Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis-derived pharmaceuticals. Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB(1) and CB(2) ) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ(9) -tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended. Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use.
To provide an overview of foundational theories on the psychosocial and neurobiological mechanisms that underlie the pathophysiology of insomnia, a review of recent findings from across the spectrum of sleep sciences that are germane to conceptualizations of insomnia, and how such findings contribute to newer integrative models.
Recent findings come from a broad diversity of the sleep research spectrum including basic animal science, sleep neuroscience, especially sleep-wake regulation, psychoneuroimmunology, human genetics, epidemiology, psychology, and from the clinical research realm.
Our review focuses on the factors contributing to insomnia and to its maintenance over time as well as the theoretical models developed (and developing) to explain this pathophysiology. Early theoretical contributions have provided a backbone for insomnia research; the sleep sciences, in turn, have supported novel and increasingly complex theoretical models of insomnia. The overarching contention is that integrative models are needed that are fully comprehensive in scope.
Systemic hypertension is prevalent among patients with obstructive sleep apnea (OSA). Short-term studies indicate that continuous positive airway pressure (CPAP) therapy reduces blood pressure in patients with hypertension and OSA.
To determine whether CPAP therapy is associated with a lower risk of incident hypertension.
A prospective cohort study of 1889 participants without hypertension who were referred to a sleep center in Zaragoza, Spain, for nocturnal polysomnography between January 1, 1994, and December 31, 2000. Incident hypertension was documented at annual follow-up visits up to January 1, 2011. Multivariable models adjusted for confounding factors, including change in body mass index from baseline to censored time, were used to calculate hazard ratios (HRs) of incident hypertension in participants without OSA (controls), with untreated OSA, and in those treated with CPAP therapy according to national guidelines.
Incidence of new-onset hypertension.
During 21,003 person-years of follow-up (median, 12.2 years), 705 cases (37.3%) of incident hypertension were observed. The crude incidence of hypertension per 100 person-years was 2.19 (95% CI, 1.71-2.67) in controls, 3.34 (95% CI, 2.85-3.82) in patients with OSA ineligible for CPAP therapy, 5.84 (95% CI, 4.82-6.86) in patients with OSA who declined CPAP therapy, 5.12 (95% CI, 3.76-6.47) in patients with OSA nonadherent to CPAP therapy, and 3.06 (95% CI, 2.70-3.41) in patients with OSA and treated with CPAP therapy. Compared with controls, the adjusted HRs for incident hypertension were greater among patients with OSA ineligible for CPAP therapy (1.33; 95% CI, 1.01-1.75), among those who declined CPAP therapy (1.96; 95% CI, 1.44-2.66), and among those nonadherent to CPAP therapy (1.78; 95% CI, 1.23-2.58), whereas the HR was lower in patients with OSA who were treated with CPAP therapy (0.71; 95% CI, 0.53-0.94).
Compared with participants without OSA, the presence of OSA was associated with increased adjusted risk of incident hypertension; however, treatment with CPAP therapy was associated with a lower risk of hypertension.
Interactions among REM-ON and REM-OFF neurons form the basic scaffold for rapid eye movement sleep (REMS) regulation; however, precise mechanism of their activation and cessation, respectively, was unclear. Locus coeruleus (LC) noradrenalin (NA)-ergic neurons are REM-OFF type and receive GABA-ergic inputs among others. GABA acts postsynaptically on the NA-ergic REM-OFF neurons in the LC and presynaptically on the latter's projection terminals and modulates NA-release on the REM-ON neurons. Normally during wakefulness and non-REMS continuous release of NA from the REM-OFF neurons, which however, is reduced during the latter phase, inhibits the REM-ON neurons and prevents REMS. At this stage GABA from substantia nigra pars reticulate acting presynaptically on NA-ergic terminals on REM-ON neurons withdraws NA-release causing the REM-ON neurons to escape inhibition and being active, may be even momentarily. A working-model showing neurochemical-map explaining activation of inactivation process, showing contribution of GABA-ergic presynaptic inhibition in withdrawing NA-release and dis-inhibition induced activation of REM-ON neurons, which in turn activates other GABA-ergic neurons and shutting-off REM-OFF neurons for the initiation of REMS-generation has been explained. Our model satisfactorily explains yet unexplained puzzles (i) why normally REMS does not appear during waking, rather, appears following non-REMS; (ii) why cessation of LC-NA-ergic-REM-OFF neurons is essential for REMS-generation; (iii) factor(s) which does not allow cessation of REM-OFF neurons causes REMS-loss; (iv) the association of changes in levels of GABA and NA in the brain during REMS and its deprivation and associated symptoms; v) why often dreams are associated with REMS.
Regulation of the sleep-waking cycle is complex and involves diverse brain circuits and molecules. On one hand, an interplay among many neuroanatomical and neurochemical systems including acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin has been shown to control the waking state. On the other hand the sleep-onset is governed by the activity of sleep-promoting neurons placed in the anterior hypothalamus that utilize GABA to inhibit wake-promoting regions. Moreover, brainstem regions inhibited during wakefulness (W) and slow wave sleeps (SWS) become active during rapid eye movement (REM) sleep. Further complexity has been introduced by the recognition of sleep-promoting molecules that accumulate in the brain in prolonged W as well as the physiological role of gene expression during sleep. The sleep-wake cycle is currently undergoing intense research with many new findings leading to new paradigms concerning sleep regulation, brain organization and sleep function. This review provides a broader understanding of our present knowledge in the field of sleep research.
Armodafinil, the longer lasting R-isomer of racemic modafinil, improves wakefulness in patients with excessive sleepiness associated with shift work disorder (SWD). Pharmacokinetic studies suggest that armodafinil achieves higher plasma concentrations than modafinil late in a dose interval following equal oral doses. Pooled Multiple Sleep Latency Test (MSLT) data from 2 randomized, double-blind, placebo-controlled trials in 463 patients with SWD, 1 with armodafinil 150 mg/d and 1 with modafinil 200 mg/d (both administered around 2200 h before night shifts), were used to build a pharmacokinetic/pharmacodynamic model. Predicted plasma drug concentrations were obtained by developing and applying a population pharmacokinetic model using nonlinear mixed-effects modeling. Armodafinil 200 mg produced a plasma concentration above the EC(50) (4.6 µg/mL) for 9 hours, whereas modafinil 200 mg did not exceed the EC(50). Consequently, armodafinil produced greater increases in predicted placebo-subtracted MSLT times of 0.5-1 minute (up to 10 hours after dosing) compared with modafinil. On a milligram-to-milligram basis, armodafinil 200 mg consistently increased wakefulness more than modafinil 200 mg, including times late in the 8-hour shift.
Marijuana is a currently illegal psychoactive drug that many physicians believe has substantial therapeutic uses. The medical literature contains a growing number of studies on cannabinoids as well as case studies and anecdotal reports suggesting therapeutic potential. Fifteen states have passed medical marijuana laws, but little is known about the growing population of patients who use marijuana medicinally. This article reports on a sample of 1,746 patients from a network of nine medical marijuana evaluation clinics in California. Patients completed a standardized medical history form; evaluating physicians completed standardized evaluation forms. From this data we describe patient characteristics, self-reported presenting symptoms, physician evaluations, other treatments tried, other drug use, and medical marijuana use practices. Pain, insomnia, and anxiety were the most common conditions for which evaluating physicians recommended medical marijuana. Shifts in the medical marijuana patient population over time, the need for further research, and the issue of diversion are discussed.
Regulation of the sleep-wake cycle involves diverse brain circuits and molecules. Further complexity has been introduced by the recognition of sleep-promoting factors that accumulate in the brain naturally or during prolonged waking. The variety of sleep-inducing molecules includes peptides, cytokines, and lipids. With regard to the lipids, current evidence indicates the existence of endogenous lipids, called endocannabinoids, that mimic the pharmacological actions of the psychoactive ingredient of marijuana and that are likely to be essential factors in sleep promotion. This Mini-Review presents current knowledge concerning the role of endogenous compounds with sleep-promoting properties.
The major non-psychoactive component of Cannabis sativa, cannabidiol (CBD), displays a plethora of actions including wakefulness. In the present study, we addressed whether perfusing CBD via microdialysis into lateral hypothalamus (LH) during the lights-on period would modify the sleep-wake cycle of rats as well as the contents of dopamine (DA) collected from nucleus accumbens (AcbC). Additionally, we tested whether perfusion of CBD into LH would block the sleep rebound after a sleep deprivation period.
Electroencephalogram and electromyogram electrodes were implanted in rats as well as a guide-cannula aimed to LH or AcbC. CBD perfusion was carried out via cannulae placed into LH whereas contents of DA were collected from AcbC and analyzed using HPLC means.
We found that microdialysis perfusion of CBD (30, 60, or 90 nM) into LH of rat enhances alertness and suppresses sleep. This effect was accompanied with an increase in DA extracellular levels collected from the AcbC. Furthermore, perfusion of CBD into LH after total sleep deprivation prevented the sleep rebound.
These findings enhance the investigation about the neurobiological properties of CBD on sleep modulation.
Polysomnography studies are an essential tool for the sleep physician and aid in the diagnosis and treatment of sleep disorders. Polysomnography refers to the recording, analysis, and interpretation of multiple physiologic signals collected simultaneously. Rapid advancements in technology have transformed the field from a time when analog studies were collected on paper to computer-assisted collection of digitally transformed studies. Sleep clinicians, whether physicians, respiratory therapists, or sleep technologists, must therefore have an understanding of a broad array of principles underlying the collection of the various signals. In addition, an understanding of basic technical rules in the evaluation of polysomnography studies is necessary for both the scoring and interpretation of such studies. The American Academy of Sleep Medicine published a new manual for the scoring of sleep and associated events in 2007. These changes included modifications to the visual scoring of sleep, the scoring of sleep-disordered breathing events, and movement disorders during sleep. A few early studies have evaluated the effects of the changes in scoring guidelines to the previous Rechtschaffen and Kales (R&K) rules for sleep and the American Academy of Sleep Medicine rules for respiratory events. Some controversy regarding the scoring of respiratory events continues to exist and requires further studies to be performed.
Nabilone is a synthetic cannabinoid prescription drug approved in Canada since 1981 to treat chemotherapy-induced nausea and vomiting. In recent years, off-label use of nabilone for chronic pain management has increased, and physicians have begun to express concerns about nabilone becoming a drug of abuse. This study evaluates the evidence for abuse of nabilone, which is currently ill-defined.
Scientific literature, popular press and internet databases were searched extensively for evidence of nabilone abuse. Focused interviews with medical professionals and law enforcement agencies across Canada were also conducted.
The scientific literature and popular press reviews found very little reference to nabilone abuse. Nabilone is perceived to produce more undesirable side effects, to have a longer onset of action and to be more expensive than smoked cannabis. The internet review revealed rare and isolated instances of recreational use of nabilone. The database review yielded little evidence of nabilone abuse, although nabilone seizures and thefts have occurred in Canada in the past few years, especially in Ontario. Most law enforcement officers reported no instances of nabilone abuse or diversion, and the drug has no known street value. Medical professionals reported that nabilone is not perceived to be a matter of concern with respect to its abuse potential.
Reports of nabilone abuse are extremely rare. However, follow-up of patients using nabilone for therapeutic purposes is prudent and should include assessment of tolerance and dependence. Prospective studies are also needed to definitively address the issue of nabilone abuse.
Sleep disorders affect many patients with chronic pain conditions. Cannabis has been reported by several patient populations to help sleep. We evaluated the safety and efficacy of nabilone, a synthetic cannabinoid, on sleep disturbance in fibromyalgia (FM), a disease characterized by widespread chronic pain and insomnia.
We conducted a randomized, double-blind, active-control, equivalency crossover trial to compare nabilone (0.5-1.0 mg before bedtime) to amitriptyline (10-20 mg before bedtime) in patients with FM with chronic insomnia. Subjects received each drug for 2 wk with a 2-wk washout period. The primary outcome was sleep quality, measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Questionnaire. Secondary outcomes included pain, mood, quality of life, and adverse events (AEs).
Thirty-one subjects were enrolled and 29 completed the trial (26 women, mean age 49.5 yr). Although sleep was improved by both amitriptyline and nabilone, nabilone was superior to amitriptyline (Insomnia Severity Index difference = 3.2; 95% confidence interval = 1.2-5.3). Nabilone was marginally better on the restfulness (Leeds Sleep Evaluation Questionnaire difference = 0.5 [0.0-1.0]) but not on wakefulness (difference = 0.3 [-0.2 to 0.8]). No effects on pain, mood, or quality of life were observed. AEs were mostly mild to moderate and were more frequent with nabilone. The most common AEs for nabilone were dizziness, nausea, and dry mouth.
Nabilone is effective in improving sleep in patients with FM and is well tolerated. Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline. Longer trials are needed to determine the duration of effect and to characterize long-term safety.
Regulation of the sleep-waking cycle is complex, involving multiple neurological circuits and diverse endogenous molecules. Interplay among assorted neuroanatomical and neurochemical systems such as acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin maintain the waking (W) state. The sleep-onset is governed by the interacting forces of the sleep drive, which steadily increases with duration of W, and circadian fluctuations. Sleep-promoting neurons located in the anterior hypothalamus release GABA and inhibit wake-promoting regions in the hypothalamus and brainstem and participate in the generation of slow wave sleep (SWS). During rapid eye movement (REM) sleep, brainstem regions typically inhibited during W and SWS become active. In this regard, ascending projections from cholinergic neurons in the brainstem activate the thalamus which in turn increases the firing of the neurons in the cortex. Finally, sleep-promoting substances that accumulate in the brain during natural or prolonged W implicate a further complexity in the mechanism of modulation of the sleep-wake cycle. This review provides a broad understanding of our present knowledge in the field of sleep research.
Excessive daytime sleepiness is one of the most common sleep-related patient symptoms, and it affects an estimated 20 percent of the population. Persons with excessive daytime sleepiness are at risk of motor vehicle and work-related incidents, and have poorer health than comparable adults. The most common causes of excessive daytime sleepiness are sleep deprivation, obstructive sleep apnea, and sedating medications. Other potential causes of excessive daytime sleepiness include certain medical and psychiatric conditions and sleep disorders, such as narcolepsy. Obstructive sleep apnea is a particularly significant cause of excessive daytime sleepiness. An estimated 26 to 32 percent of adults are at risk of or have obstructive sleep apnea, and the prevalence is expected to increase. The evaluation and management of excessive daytime sleepiness is based on the identification and treatment of underlying conditions (particularly obstructive sleep apnea), and the appropriate use of activating medications.
Unlabelled:
This is the report of an open label clinical trial to evaluate the effects of nabilone, an endocannabinoid receptor agonist, on treatment-resistant nightmares in patients diagnosed with posttraumatic stress disorder (PTSD).
Methods:
Charts of 47 patients diagnosed with PTSD and having continuing nightmares in spite of conventional antidepressants and hypnotics were reviewed after adjunctive treatment with nabilone was initiated. These patients had been referred to a psychiatric specialist outpatient clinic between 2004 and 2006. The majority of patients (72%) receiving nabilone experienced either cessation of nightmares or a significant reduction in nightmare intensity. Subjective improvement in sleep time, the quality of sleep, and the reduction of daytime flashbacks and nightsweats were also noted by some patients. The results of this study indicate the potential benefits of nabilone, a synthetic cannabinoid, in patients with PTSD experiencing poor control of nightmares with standard pharmacotherapy. This is the first report of the use of nabilone (Cesamet; Valeant Canada, Ltd., Montreal, Canada) for the management of treatment-resistant nightmares in PTSD.
The present review provides an assessment of the efficacy and safety of benzodiazepine receptor agonists (BZRAs) and psychological and behavioral interventions for insomnia. These methods include relaxation techniques, sleep hygiene rules, stimulus control, sleep restriction and cognitive techniques, often also referred to as cognitive-behavioral therapy (CBT) when encompassing cognitive strategies and at least one kind of behavioral intervention. In order to provide a comprehensive assessment of the literature regarding the efficacy and safety of these standard treatments for insomnia, an integrative synthesis of the existing meta-analytic studies for each of the various treatment modalities was conducted. Where meta-analytic studies were not available, data from double-blind placebo-controlled randomized controlled trials (RCTs) were included. The summary findings from this review are (1) BZRAs and psychological and behavioral methods are effective to treat insomnia in the short-term and the latter have significantly more durable effects when active treatment is discontinued; and (2) there is only very limited evidence that BZRAs retain their efficacy during long-term treatment. The present review underscores the need for further research regarding the comparative efficacy and safety of these treatments for insomnia, how this varies with age and comorbidity, and how the various treatment modalities impact (1) daytime functioning, (2) quality of life, (3) health care utilization; and (4) pharmacoeconomics. Finally, it is particularly important that studies be conducted to determine if successful insomnia treatment influences the clinical course of the diseases that often occur co-morbidly with sleep continuity disturbance.
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.
The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats.
During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.
A model for control of the desynchronized phase of the sleep cycle postulates reciprocal interaction between cells in the
pontine gigantocellular tegmental field (FTG cells) and cells in the nucleus locus coeruleus and nucleus subcoeruleus (LC
cells). This physiological model leads to equations of the Lotka-Volterra type; the time course of activity predicted by the
model is in good agreement with actual long-term recordings of FTG cells and single-cycle data for LC cells.
Marijuana seems firmly established as another social drug in Western countries, regardless of its current legal status. Patterns of use vary widely. As with other social drugs, the pattern of use is critical in determining adverse effects on health. Perhaps the major area of concern about marijuana use is among the very young. Using any drug on a regular basis that alters reality may be detrimental to the psychosocial maturation of young persons. Chronic use of marijuana may stunt the emotional growth of youngsters. Evidence for an amotivational syndrome is largely based on clinical reports; whether marijuana use is a cause or effect is uncertain. A marijuana psychosis, long rumored, has been difficult to prove. No one doubts that marijuana use may aggravate existing psychoses or other severe emotional disorders. Brain damage has not been proved. Physical dependence is rarely encountered in the usual patterns of social use, despite some degree of tolerance that may develop. The endocrine effects of the drug might be expected to delay puberty in prepubertal boys, but actual instances have been rare. As with any material that is smoked, chronic smoking of marijuana will produce bronchitis; emphysema or lung cancer have not yet been documented. Cardiovascular effects of the drug are harmful to those with preexisting heart disease; fortunately the number of users with such conditions is minimal. Fears that the drug might accumulate in the body to the point of toxicity have been groundless. The potential deleterious effects of marijuana use on driving ability seem to be self-evident; proof of such impairment has been more difficult. The drug is probably harmful when taken during pregnancy, but the risk is uncertain. One would be prudent to avoid marijuana during pregnancy, just as one would do with most other drugs not essential to life or well-being. No clinical consequences have been noted from the effects of the drug on immune response, chromosomes, or cell metabolites. Contamination of marijuana by spraying with defoliants has created the clearest danger to health; such attempts to control production should be abandoned. Therapeutic uses for marijuana, THC, or cannabinoid homologs are being actively explored. Only the synthetic homolog, nabilone, has been approved for use to control nausea and vomiting associated with cancer chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
This study was designed to determine the acute effects of delta 9-THC on the cortical EEG with the spectral analysis technique. Adult female Sprague-Dawley rats were implanted with chronic cortical and temporalis muscle electrodes. Intraperitoneally administered delta 9-THC (5 and 10 mg/kg) produced a reduction in peak-to-peak voltage of the desynchronized cortical EEG during wakefulness. Associated spectral power was reduced to about 50% of control during the first hour after injection of delta 9-THC and gradually returned toward the control value over an 8-hr period. Occurrences of delta 9-THC-induced high-voltage EEG bursts, overriding the reduced EEG tracing, were associated with an EEG spectral peak at 6 Hz. The first few slow-wave sleep (SWS) episodes appearing after delta 9-THC administration were associated with more slow-frequency waveforms and more slow-frequency spectral power than with control slow-wave sleep episodes. During control rapid eye movement (REM) sleep episodes, an EEG theta wave pattern, with an associated spectral peak at about 8 Hz, was characteristic. Conversely, the first few REM sleep episodes emerging after delta 9-THC administration contained overriding high-voltage bursts, the related power spectra of which had two peaks at about 7 and 11 Hz.
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.
Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic patients conducted in the authors' laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.
Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum. The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana. Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system.
Review commissioned in 1996 by the Department of Health (DOH).
Assess therapeutic profile of cannabis and cannabinoids.
Medline search, references supplied by DOH and others, and personal communications.
Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.
The EEG and behavior of twelve adult cats were observed during lengthy intervals of normal sleep. All animals showed many periods of a low voltage, fast (activated) EEG in the face of continued behavioral sleep as indicated by absence of muscle potentials, relaxed posture, unresponsiveness, and elevated auditory threshold. These periods alternated regularly with periods during which the recordings were dominated by slow waves and spindles. The former EEG phase was concomitant with many twitching movements of the limbs, vibrissae, and ears, while the latter was generally associated with complete stillness on the part of the animals.
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.
Adherence to antiretroviral therapy (ART) is essential to successful treatment of HIV infection. Two recent studies reported a negative correlation between marijuana use and adherence to ART. Some patients, however, report that smoking marijuana improves adherence to ART. This study therefore sought to identify which subgroups of patients may have differential adherence to ART in association with recent marijuana use.
Cross-sectional survey design within a public health care system for HIV/AIDS.
With a 5% refusal rate, 252 patients completed the interview, 175 (69%) were on ART, and 168 (67%) provided ART adherence data. Forty-one subjects (24%), predominantly whites, used marijuana. In bivariate analysis, no association between ART adherence and marijuana use was found (odds ratio [OR] = 0.92, 95% CI = 0.4-1.9). Adherence was positively associated with undetectable plasma virus and negatively associated with alcohol and other illicit drug use. Examining subgroups of patients, among those with nausea, marijuana users were more likely to show an association with adherence than nonusers (OR = 3.3), while among those without nausea, marijuana use was lower associated with adherence (OR = 0.52, P for homogeneity 0.02). This relationship was confirmed in multivariate analyses controlling for the interactions between nausea and marijuana use, in which other illicit drug use remained a factor related to nonadherence.
These data suggest that medicinal use of marijuana may facilitate, rather than impede, ART adherence for patients with nausea, in contrast to the use of other illicit substances, which were associated with lower rates of ART adherence. To demonstrate any causal relationship between marijuana and adherence would require a longitudinal or controlled study.