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More evidence of cannabis efficacy in restless legs syndrome
Abstract
Restless legs syndrome (RLS) is one of the most disabling and sometimes painful sensorimotor ailment of the nervous system that has only in recent years become more widely accepted as a clinical disorder with its own distinct features. Usually, symptoms respond well to dopamine agonists, anticonvulsants, or opiates, but still a subset of patients remains refractory to medical therapy and/or reports serious side effects. Recently, patients’ statement of a remarkable and total remission of RLS symptoms following cannabis use has been reported. Here, we confirm and extend these findings to more patients with RLS. The antinociceptive effect of marijuana has been documented in many painful neurological conditions, and the potential benefit of cannabis use in patients with refractory RLS should therefore be questioned by robust clinical trials.
... Reasons for further exclusion were described in Figure 1. This study cohort had 40 articles, where 28 examined the effects of cannabis on sleep 33-60 , four evaluated on both sleep and chronic pain 61-64 , three described the effects of cannabis on sleep and post-traumatic stress disorders 65-67 , three examined the effects of cannabis solely on OSA [68][69][70] and two studies described cannabis for RLS [71][72] . ...
... Cannabis has been explored as an option for treating patients with OSA ( Table 6) and used in patients with RLS to improve their sleep quality [71][72] . In clinical practice, patients with OSA frequently ask if there is an "oral pill" to treat their apnea instead of continuous positive airway pressure (CPAP). ...
... Cannabis use has been reported associated to the treatment of refractory RLS [71][72] . All patients (n=6) in the first publication 71 complained of poor efficacy and/or poor tolerance to their current RLS medication and self-reported that the use of cannabis (e.g., recreational cannabis smoking or sublingual administration of CBD) improved RLS symptoms and sleep quality. ...
Study objectives:
To perform a qualitative scoping literature review for studies involving the effects of cannabis on sleep and sleep disorders.
Methods:
Two electronic databases MEDLINE and EMBASE searched for comprehensive published abstracted studies that involved human participants. Inclusion criteria were article of any type, published in English, a target population of cannabis users and reported data on cannabis effect on sleep and sleep disorders. The Joanna Briggs Institute's (JBI) approach was elected as the methodology framework guidance in the scoping review process.
Results:
A total of 40 unique publications were found. The majority (82.5%) were from the Americas with 60% published in the last decade. Of the 40 studies, only 25% were randomized control trials and the sleep outcome measurements were similar and comparable in only 20%. Cannabis users studied were reported either 73% frequent users or 27% sporadic users. The utilization of cannabis showed improved sleep (21%), worse sleep (48%), mixed results (14%) or no impact at all (17%) in the studies published in the last five decades.
Conclusions:
Our findings summarize the lack of robust evidence to support the use of cannabis for sleep disorders. The varied cannabis user-related characteristics may account for the inconsistent results identified. Further studies assessing cannabis and sleep are needed discerning what works in what context, how it works and for whom.
... In two case series combining 18 patients with treatmentresistant RLS, smoked cannabis (ie, THC-dominant products) was self-rated as more efficacious in improving RLS symptoms than sublingual CBD. 27,28 The evidence base for the use of cannabinoids in the treatment of other sleep disorders has been further reviewed elsewhere. 29 Since the introduction of legal (prescribed) medical cannabis in Australia in 2016, 10 consumer behaviours and patterns of use of prescribed and/or illicit medical cannabis for sleep disorders remain unclear. ...
Introduction:
Sleep disorders are the third most common indication for the prescription of medical cannabis products in Australia, after pain and anxiety. While the use of cannabis for medical purposes is growing in Australia, underlying consumer behaviours and patterns of use, particularly around sleep disorders, are poorly understood.
Methods:
We conducted a subanalysis of the cross-sectional "Cannabis as Medicine Survey" 2020-2021 (CAMS-20) (N = 1600), to explore the characteristics of a sample of Australians who were using prescribed and/or illicit medical cannabis to treat a self-reported sleep disorder.
Results:
When asked to specify up to seven different conditions they were treating with medical cannabis, a total of 1030 (64%) respondents [mean (SD) 44.9 (13.6) years] selected a sleep disorder, with "insomnia disorder" (85.5%), 'sleep-related movement disorders' (26%) and 'sleep-related breathing disorders' (11.1%) the most common subtypes. Only 165 (16.8%) respondents selected a self-reported sleep disorder as the main health condition being treated. Relative to other health conditions, use of medical cannabis for a self-reported sleep disorder was associated with younger age, increased likelihood of using both prescribed and illicit forms of medical cannabis, inhaled routes of administration, and THC-dominant products. Most respondents reported a reduction in the use of benzodiazepines and alcohol since starting medical cannabis. Binary logistic regression showed that respondents who predominantly used inhaled routes of administration, and concomitant use of medical cannabis for pain, mental health and/or substance use disorder, or a gastrointestinal disorder, were significantly more likely to also use medical cannabis to treat a self-reported sleep disorder.
Conclusion:
Overall, these results suggest that self-reported sleep disorders are often being treated with medical cannabis alongside other health conditions (often pain or a mental health disorder) and that use of inhaled methods, THC-dominant products, and illicit sources of medical cannabis are common among people with self-reported sleep disorders in Australia.
... W badaniu tym opisano całkowite ustąpienie objawów u tych pacjentów. W drugim przypadku badano dwunastu pacjentów, gdzie całkowita remisja wystąpiła u ośmiu z nich, a pozostali zgłaszali znaczne złagodzenie objawów [1,3,21,22]. ...
Proper and healthy sleep is an element of everyday life necessary for the proper functioning of the body. Unfortunately, a large part of humanity cannot experience proper rest, due to sleep disorders such as insomnia, restless leg syndrome, obturative sleep apnea and other diseases that complicate sleep. There are not many ways to treat sleep disorders and their use is often associated with difficulties in everyday life and side effects of the used methods. Work on this subject is still ongoing, with time there are more and more new possibilities and different, unconventional applications of substances discovered long ago. Plants containing cannabinoids have been known to mankind since ancient times. And this cannabinoids can have huge importance and contribute to the treatment and prevention of sleep disorders. Studies on the impact of these substances on sleep and sleep disorders are limited, which leads to the fact that in many countries their use is still prohibited. And therefore undertaking research on this topic requires a lot of effort. However, the data that has been collected so far on the subject of the influence of cannabinoids on sleep disorders carry optimistic information. Cannabinoids in the correct doses and ratio as to the content of individual subgroups can bring relief to people suffering from lack of proper sleep. However, the negative effects of these substances should not be forgotten. Chronic use, too high doses or improper application can have a negative impact on the quality of sleep.
... It is also interesting that of those who experienced complete symptom relief with smoked cannabis two also reported good symptom improvement with CBD alone, while one patient reported CBD to have no benefit. 54 It should be noted that there is strong risk of bias in these unblinded, uncontrolled case series with no baseline comparator. Furthermore, objective measures of RLS are lacking. ...
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.
... 55,56 Cannabis No controlled clinical trials have evaluated the use of cannabis for RLS. A case series from a single center and patient anecdotes suggest the possibility of some benefit, 57 but the formulation, dosage, and mode of administration that might be beneficial are unclear. Anecdotal experience suggests that ingested cannabis (brownies, cookies, or other edibles) is ineffective, whereas inhaled cannabis (cannabis cigarette or vaporizer) may, in some patients, provide rapid but short-lived relief of RLS symptoms. ...
Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.
... However, there has been limited evidence for their use to date. Two case series, one including 6 patients and another with 12 patients have shown near total remission in RLS with recreational marijuana smoking [72,73]. Patients in both series continued previously prescribed medications for RLS while adding marijuana. ...
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.
... However, the AASM recently recommended against the use of cannabis for the treatment of OSA due to insufficient evidence of effectiveness, tolerability, and safety [94]. Cannabis could be beneficial in RLS [95], though more robust trials are necessary. There is also evidence suggesting that palmitoylethanolamide (PEA), a cannabimimetic compound and lipid messenger, may be safe and effective in reducing chronic pain across a variety of conditions due to its analgesic, antiinflammatory and neuroprotective properties [96e99]. ...
The multimorbidity formed by sleep disturbances and pain conditions is highly prevalent and has a significant impact in global health and in the socioeconomic system. Although different approaches have been directed toward its management, evidence regarding an optimal treatment is lacking, and pharmacological options are often preferred. Health professionals (e.g., pain and sleep clinicians) tend to focus on their respective expertise, targeting a single symptom with a single drug. This may increase polypharmacy and the risk of drug interactions, adverse events, and mortality. Hence, the use of medications that can directly or indirectly improve sleep, pain, and other possible accompanying conditions without exacerbating them becomes especially relevant. The objectives of this comprehensive review are to: a) describe the beneficial or deleterious effects that some commonly used medications to manage pain have on sleep and sleep disorders; and b) describe the beneficial or deleterious effects that frequently prescribed medications for sleep may have on pain. Moreover, medications targeting some specific sleep-pain interactions will be suggested and future directions for improving sleep and alleviating pain of these patients will be provided with clinical and research perspectives.
Introduction
On the basis of both scientific progress and popular lore, there is growing optimism in the therapeutic potential of cannabis (marijuana) and cannabinoid-based chemicals for movement disorders. There is also notable skepticism regarding the scientific basis for this therapeutic optimism and significant concerns regarding the safety and regulation of cannabinoid products, particularly those available without prescription.
Methods
In recognition of the high interest and controversial nature of this subject, the meeting committee of the International Parkinson and Movement Disorders Society arranged for a talk on cannabis at the 2019 annual meeting's Controversies in Movement Disorders plenary session. This paper summarizes the highlights of this session.
Results
The endocannabinoid system is strongly tied to motor function and dysfunction, with basic research suggesting several promising therapeutic targets related to cannabinoids for movement disorders. Clinical research on cannabinoids for motor and nonmotor symptoms in Parkinson's disease, Huntington's disease, Tourette's syndrome, dystonia, and other movement disorders to date are promising at best and inconclusive or negative at worst. Research in other populations suggest efficacy for common symptoms like pain. While social campaigns against recreational cannabinoid use focus on cognitive changes in adolescents, the long-term sequelae of regulated medical use in older adults with movement disorders is unknown. The overall risks of cannabinoids may be similar to other commonly used medications and include falls and apathy.
Conclusion
Further research is greatly needed to better understand the actual clinical benefits and long-term side effects of medical cannabis products for movement disorders indications and populations.
Sleep disturbances are often cited as a primary reason for medicinal cannabis use and there is increasing clinical interest in the therapeutic potential of cannabinoids in treating sleep disorders. Burgeoning evidence suggests a role of the endocannabinoid system in regulating the circadian sleep-wake cycle, highlighting a potential avenue for developing novel therapeutics. Despite widespread use of cannabis products as sleep aids globally, robustly designed studies verifying efficacy in sleep-disordered populations are limited. While some study outcomes have suggested cannabinoid utility in insomnia disorder and sleep apnea, most studies to date are limited by small sample sizes, lack of rigorously controlled study designs, and high risk of bias. This critical review summarises the current evidence for the use of cannabinoids as a treatment for sleep disorders, and provides an overview of endocannabinoid modulation of sleep-wake cycles, and the sleep-modulating effects of plant-derived cannabinoids such as Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The review also discusses practical considerations for clinicians regarding cannabinoid formulations, routes of administration, respiratory concerns, dosing, potential side effects, drug interactions, and effects relevant to driving, tolerance, and withdrawal. While current interest in, and uptake of, medicinal cannabis use for sleep disorders may have surpassed the evidence-base, there is a strong rationale for continued investigation into the therapeutic potential of cannabinoids.
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.
People with kidney failure can experience a range of symptoms that lead to suffering and poor quality of life. Available therapies are limited, and evidence for new treatment options is sparse, often resulting in incomplete relief of symptoms. There is growing interest in the potential for cannabinoids, including cannabidiol and tetrahydrocannabinol, to treat symptoms across a wide range of chronic diseases. As legal prohibitions are withdrawn or minimized in many jurisdictions, patients are increasingly able to access these agents. Cannabinoid receptors, CB1 and CB2, are widely expressed in the body, including within the nervous and immune systems, and exogenous cannabinoids can have anxiolytic, anti-emetic, analgesic and anti-inflammatory effects. Considering their known physiological actions and successful studies in other patient populations, cannabinoids may be viewed as potential therapies for a variety of common symptoms affecting those with kidney failure, including pruritus, nausea, insomnia, chronic neuropathic pain, anorexia, and restless legs syndrome. In this review, we summarize the pharmacology and pharmacokinetics of cannabinoids, along with what is known about the use of cannabinoids for symptom relief in those with kidney disease, and the evidence available concerning their role in management of common symptoms. Presently, while these agents show varying efficacy with a reasonable safety profile in other patient populations, evidence-based prescribing of cannabinoids for people with symptomatic kidney failure is not possible. Given the symptom burden experienced by individuals with kidney failure, there is an urgent need to understand the tolerability and safety of these agents in this population, which must ultimately be followed by robust, randomized controlled trials to determine if they are effective for symptom relief.
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)
Autism spectrum disorder (ASD) is a common neurobehavioral disorder with considerable complexity and without clearly defined etiologic underpinnings. A variety of factors are intertwined in this condition including genetic, biochemical, and cellular characteristics. A major aspect of ASD management is behavioral therapy, though pharmacologic agents produce major benefits as well. This work considers current pharmacologic principles in treatment of ASD in children, adolescents, and adults. Pharmacologic intervention is particularly helpful for treatment of the conditions that are frequently co-morbid with ASD—including anxiety, depression, aggressive/violent behaviors, repetitive behaviors, inattention with hyperactivity, and sleep disorders.
Purpose of Review
The growing availability, legality, and use of marijuana products in the USA has contributed to increased patient and clinician interest in the treatment of sleep disorders, especially insomnia and restless legs. What should clinicians know about these drugs and what should they tell patients that inquire about using them?
Recent Findings
Increasing numbers of studies are being published revealing clear subjective improvement of sleep-onset latency, subjective improvement of sleep disruptions, and subjective improvement of restless legs symptoms. However, objective findings are most often mixed, with some studies demonstrating improvement of sleep characteristics, and some demonstrating worsening. There is a trend for improvement in sleep with short-term use of marijuana products and a longer-term attenuation of effect, or possibly worsening.
Summary
Evidence for their effectiveness in these disorders is robust from subjective patient reports but limited or mixed in objective measures. Discussions with patients should be individualized and risks and benefits weighed. Future large, randomized, placebo-controlled studies are needed to help clarify the discrepancy between subjective and objective measures.
The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2AR) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2AR and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2AR-CB1R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically-modified animal models, together with biochemical and pharmacological approaches, we provide a high resolution expression map and a detailed functional characterization of A2AR-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A2AR-CB1R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington’s disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases.
The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electrophysiological, neurochemical and behavioural evidences for modulation of the NA/5-HT systems by cannabinoids and the CB1 receptor. Cannabinoids regulate the neuronal activity of NA and 5-HT cells and the release of NA and 5-HT by direct and indirect mechanisms. The interaction between cannabinoid and NA/5-HT systems may underlie several behavioural changes induced by cannabis such as anxiolytic and antidepressant effects or side effects (e.g. disruption of attention). Further research is needed to better understand different aspects of NA and 5-HT systems regulation by cannabinoids, which would be relevant for their use in therapeutics.
Cannabis is the most widely used illicit drug globally, and users are at increased risk of mental illnesses including psychotic disorders such as schizophrenia. Substance dependence and schizophrenia are both associated with dopaminergic dysfunction. It has been proposed, although never directly tested, that the link between cannabis use and schizophrenia is mediated by altered dopaminergic function.
We compared dopamine synthesis capacity in 19 regular cannabis users who experienced psychotic-like symptoms when they consumed cannabis with 19 nonuser sex- and age-matched control subjects. Dopamine synthesis capacity (indexed as the influx rate constant [Formula: see text] ) was measured with positron emission tomography and 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine ([(18)F]-DOPA).
Cannabis users had reduced dopamine synthesis capacity in the striatum (effect size: .85; t36 = 2.54, p = .016) and its associative (effect size: .85; t36 = 2.54, p = .015) and limbic subdivisions (effect size: .74; t36 = 2.23, p = .032) compared with control subjects. The group difference in dopamine synthesis capacity in cannabis users compared with control subjects was driven by those users meeting cannabis abuse or dependence criteria. Dopamine synthesis capacity was negatively associated with higher levels of cannabis use (r = -.77, p < .001) and positively associated with age of onset of cannabis use (r = .51, p = .027) but was not associated with cannabis-induced psychotic-like symptoms (r = .32, p = .19).
These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.