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Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: A case series
Journal of Clinical Pharmacy and Therapeutics
Abstract
What is known and objective:
Cannabidiol (CBD) is the main non-psychotropic component of the Cannabis sativa plant. REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during REM sleep associated with nightmares and active behaviour during dreaming. We have described the effects of CBD in RBD symptoms in patients with Parkinson's disease.
Cases summary:
Four patients treated with CBD had prompt and substantial reduction in the frequency of RBD-related events without side effects.
What is new and conclusion:
This case series indicates that CBD is able to control the symptoms of RBD.
... CB1R activation in the midbrain has also been shown to increase acetylcholine release, thereby ameliorating the local cholinergic deficit observed in PD [60]. Furthermore, cannabis interactions with the serotonergic system may have an impact on LID; denervation of striatal dopamine neurons causes a shift in the conversion of levodopa to dopamine from dopamine to serotonin neurons, resulting in non-physiological pulsatile dopamine release (false messengers) [61]. ...
... Human investigations on the effects of CBD on sleep disorders are limited and modest in number [60,88,114,115]. Sleep problems, such as poor sleep quality, insomnia, restless legs syndrome, and rapid eye movement sleep behavior disorder, are more common in PD patients [116]. ...
... Sleep problems, such as poor sleep quality, insomnia, restless legs syndrome, and rapid eye movement sleep behavior disorder, are more common in PD patients [116]. Sleep problems in PD patients, similar to other non-motor symptoms, appear to be related to dopaminergic neurotoxicity and subsequent neurochemical abnormalities in areas of the brain involved in the regulation of the sleep-wake cycle [86] mediated by cholinergic, GABAergic, and serotonergic neurons [60]. The use of benzodiazepines and, less commonly, melatonin and cholinesterase inhibitors to treat sleep disorders in this population is limited because of side effects. ...
Background
Parkinson’s disease (PD) is primarily known as a motor disorder; however, its debilitating non-motor symptoms have a significant impact on patients’ quality of life. The current standard treatment, l-DOPA, is used to relieve motor symptoms, but prolonged use is often associated with severe side effects. This creates an urgent need for effective alternatives targeting both motor and non-motor symptoms.
Objectives
Over the past decade, Cannabis sativa and its cannabinoids have been widely studied across various health conditions. Among these compounds, cannabidiol (CBD), a non-psychoactive component, is garnering growing interest due to its multi-targeted pleiotropic properties. This work aims to provide a comprehensive overview of CBD’s efficacy in PD.
Methods
This review compiles data on both motor and non-motor symptoms of PD, integrating results from preclinical animal studies and available clinical trials.
Results
Preclinical research has demonstrated promising results regarding CBD’s potential benefits in PD; however, the total number of clinical trials is limited (with only seven studies to date), making it difficult to draw definitive conclusions on its efficacy.
Conclusions
While preclinical findings suggest that CBD may have therapeutic potential in PD, the limited number of clinical trials highlights the need for further research. This review emphasizes the gaps that need to be addressed in future studies to fully understand CBD’s role in treating both motor and non-motor symptoms of PD.
... Motor impairment includes resting tremor, rigidity, postural imbalance, slowness of movement, shuffling gate, and lack of facial expression (Schilder et al., 2017;Wei et al., 2017), while non-motor impairment includes constipation, dysphagia, hallucination, behavioral and cognitive problems in the disease late stages including sleep disturbances, anxiety and dementia (Titova and Chaudhuri, 2017;Muhammad et al., 2022). There are numerous theories explaining how Parkinson's disease manifests or the progression of its symptoms even though the exact cause is unknown (Chagas et al., 2014). ...
... The etiology of PD advancements is due to a complex interaction of both sporadic (90% of cases) and genetic (5-10%) aspects (Blauwendraat et al., 2020). It is possible to develop sporadic Parkinson's disease due to exposure to toxicants, free radicals, head trauma and inflammation of the nervous system (Singleton and Hardy, 2019;Ullah et al., 2021). ...
Parkinson’s disease resultant in the degeneration of Dopaminergic neurons and accumulation of α-synuclein in the substantia nigra pars compacta. The synthetic therapeutics for Parkinson’s disease have moderate symptomatic benefits but cannot prevent or delay disease progression. In this study, nicotine was employed by using transgenic Caenorhabditis elegans Parkinson’s disease models to minimize the Parkinson’s disease symptoms. The results showed that the nicotine at 100, 150, and 200 μM doses reduced degeneration of Dopaminergic neurons caused by 6-hydroxydopamine (14, 33, and 40%), lowered the aggregative toxicity of α-synuclein by 53, 56, and 78%, respectively. The reduction in food-sensing behavioral disabilities of BZ555 was observed to be 18, 49, and 86%, respectively, with nicotine concentrations of 100 μM, 150 μM, and 200 μM. Additionally, nicotine was found to enhance Daf-16 nuclear translocation by 14, 31, and 49%, and dose-dependently increased SOD-3 expression by 10, 19, and 23%. In summary, the nicotine might a promising therapy option for Parkinson’s disease.
... The NMS-Nab study was the first to assess the efficacy and safety of cannabinoids for the treatment of NMS in PD, making it a unique pilot trial. Prior uncontrolled studies evaluated the use of different cannabinoid applications in PD patients to find efficacy on problems with sleep, pain, anxiety, depression, or PD-associated psychosis [10][11][12][13] . Comparison is limited, however, due to the different routes of administration and substances (i.e., THC, cannabidiol). ...
... The ECS is known to be involved in the regulation of the circadian sleep-wake cycle and promotion as well as maintenance of sleep 9,22 . Cannabidiol has been used in PD patients before with inconsistent results 13,23,24 . Nabilone however has not been thoroughly assessed for sleep in PD patients before the NMS-Nab trials. ...
The synthetic tetrahydrocannabinol-analog nabilone improved non-motor symptoms (NMS) in Parkinson’s disease (PD) patients in a placebo-controlled, double-blind, parallel-group, randomized withdrawal trial with enriched enrollment (NMS-Nab-study). This was a single-center open-label extension study to assess the long-term safety and efficacy of nabilone for NMS in PD. To be eligible for this study, patients had to be treatment responders during the previous NMS-Nab-trial and complete its double-blind phase without experiencing a drug-related serious/severe/moderate adverse event (AE). Patients were re-introduced to nabilone during an up-titration phase until their overall NMS burden improved. Nabilone was continued for six months with clinic visits every 3 months. Evaluation of AEs was based on self-report and clinical assessment. Twenty-two patients participated in the NMS-Nab2-study (age-median 68.33 y, 52% females, disease duration-median 7.42 y). Nabilone was well tolerated with concentration difficulties as the most common treatment-related AE (possibly/not related n = 1 each). One in two drop-outs discontinued because of an AE for which a prohibited concomitant medication needed to be introduced (night-time sleep problems). Efficacy evaluation showed a significant and lasting improvement in NMS burden according to the CGI-I (79% at V3). Nabilone improved overall sleep (NMSS Domain-2: –8.26 points; 95%CI –13.82 to –2.71; p = 0.004; ES = –0.72), night-time sleep problems (MDS-UPDRS-1.7: –1.42 points; 95 CI –2.16 to –0.68; p = 0.002; ES = –0.92), and overall pain (KPPS Total Score: –8.00 points; 95%CI –15.05 to –0.95; p = 0.046; ES –0.55 and MDS-UPDRS-1.9: –0.74 points; 95%CI –1.21 to –0.26; p = 0.008; ES = –0.74). This study demonstrates continuous long-term safety and efficacy in PD patients responding early to nabilone without intolerable side effects.
... It is a psychoactive drug that finds its usage in the treatment of many medical conditions [41]. It is used as a hypnotic, antipsychotic, anxiolytic and neuroprotective agent [70]. About 100 different cannabinoids can be obtained from cannabis flowers [69]. ...
... The lipidbased formulation of 9-tetrahydrocannabinol is administered orally in humans, while intraperitoneal injections of the water-based solutions are administered in animals [73]. Dream recall is decreased using 3 doses of CBD is 40, 80,160 mg per day [70]. ...
Sleep is considered as one of the most important aspect for maintaining a healthy life. For a person to function normally at least 6-8 hours of sleep daily is necessary. Sleep not only affects our mood, but also regulates the efficiency of work done. Many complications arise due to inadequacy of sleep. The unhealthy food and lifestyle choices have made us more prone to sleep disorders. The medications which are used for the treatment of sleep disorders are mainly habit forming and have tendencies of withdrawal symptoms. This inadequacy in medication has lead to search for newer, better options. The field of nutraceuticals fits apt for treating such disorders. The quality of being non-toxic, non-habit forming, and being practically more efficient has had made it an excellent option. Nutraceuticals make use of food or part of food for the treatment or to prevent any disease. Remarkable positive effects of nutraceuticals like Caffeine, Chamomile, Kava kava, Cherries and Cherry juice, L tryptophan, Valerian, Vitamin D, Marijuana, melatonin, Lemon balmhad been mentioned in the treatment of sleep disorders. The present review gives a general overview of nutraceuticals and discusses their use in sleep disorders.
... Regarding the effect of CBD on sleep disorders in PD, some discrepancies are present in the existing results. A case study of 4 PD patients suffering from rapid eye movement (REM) sleep behavior disorder (RBD) showed a reduction in the frequency of RBD events, including nightmares and active behavior during dreaming in all 4 patients after treatment with CBD (75 or 300 mg/d for 6 weeks) (Chagas et al., 2014b). However, these results were not confirmed in a placebo-controlled randomized trial in PD patients with Restless Legs Syndrome and RBD. ...
... However, the calming effect of CBD on the CNS might reduce anxiety and promote relaxation (Shannon et al., 2019), via which CBD can indirectly improve sleep in people suffering from anxiety. In addition, some patient populations might also benefit from CBD use, since CBD increases sleeping time in insomnia patients (Carlini and Cunha, 1981) and improves REM sleep in Parkinson's disease patients (Chagas et al., 2014b). It should be noted that some reports showed that CBD increased the wakefulness during sleep in young adults (Nicholson et al., 2004), and even decreased the REM sleep in rats (Murillo-Rodríguez et al., 2006;Murillo-Rodríguez et al., 2008). ...
Cannabidiol (CBD) is a naturally occurring non-psychoactive cannabinoid found in Cannabis sativa, commonly known as cannabis or hemp. Although currently available CBD products do not meet the safety standards of most food safety authorities to be approved as a dietary supplement or food additive, CBD has been gaining widespread attention in recent years due to its various potential health benefits. While primarily known for its therapeutic effects in managing epileptic seizures, psychosis, anxiety, (neuropathic) pain, and inflammation, CBD’s influence on brain function has also piqued the interest of researchers and individuals seeking to enhance cognitive performance. The primary objective of this review is to gather, synthesize, and consolidate scientifically proven evidence on the impact of CBD on brain function and its therapeutic significance in treating neurological and mental disorders. First, basic background information on CBD, including its biomolecular properties and mechanisms of action is presented. Next, evidence for CBD effects in the human brain is provided followed by a discussion on the potential implications of CBD as a neurotherapeutic agent. The potential effectiveness of CBD in reducing chronic pain is considered but also in reducing the symptoms of various brain disorders such as epilepsy, Alzheimer’s, Huntington’s and Parkinson’s disease. Additionally, the implications of using CBD to manage psychiatric conditions such as psychosis, anxiety and fear, depression, and substance use disorders are explored. An overview of the beneficial effects of CBD on aspects of human behavior, such as sleep, motor control, cognition and memory, is then provided. As CBD products remain largely unregulated, it is crucial to address the ethical concerns associated with their use, including product quality, consistency, and safety. Therefore, this review discusses the need for responsible research and regulation of CBD to ensure its safety and efficacy as a therapeutic agent for brain disorders or to stimulate behavioral and cognitive abilities of healthy individuals.
... Another open-label study in 28 epilepsy patients found a 33% improvement in sleep duration recorded by the children's sleep habit questionnaire after 12 months treatment with CBD [79]. Increased sleep quality has also been noted in a case report of a child with PTSD (25 mg at bedtime for 5 months [80]), in an adult with cannabis addiction (24 then 18 mg for 5 month [81]) and in 4 patients with Parkinson's disease (75 or 300 mg/day for 6 weeks [82]). An audit [56] and a case series [57] similarly found 12% and 67% of CBD prescribed patients reported an improvement in sleep. ...
... Small, uncontrolled pilot studies in patients with Parkinson's have demonstrated improvements in dystonia over 6 weeks with oral CBD capsules (100-600 mg/day) [94] and in psychosis symptoms (Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire) over 4 weeks with oral CBD (n = 6, starting at 150 mg/ day [95]). A small (n = 4), uncontrolled study by Chagas and colleagues also showed improvements in REM sleep behaviour disorder (RBD) in patients with Parkinson's disease over 6 weeks (with individualised dosing in the 75-300 mg/day range) [82]. ...
The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial. The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson’s (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington’s or type 2 diabetes. In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.
... Current management includes sleep environment safety measures to protect the patient and bed partner from injury, and in select cases, pharmacological treatment. The evidence for cannabinoids for RBD treatment is currently restricted to a single case series of six weeks of CBD (75 or 300 mg/day) prescribed to four patients with Parkinson's Disease with comorbid psychosis and definite or probable RBD [90]. During treatment, RBD-related events were rapidly and substantially reduced. ...
Purpose of Review
Changes in the legislative landscape have stimulated an increase in research into therapeutic benefits of cannabinoids, including for management of sleep disturbances and disorders. This topical review brings together evidence from systematic reviews and recent clinical trials to assess the efficacy and safety of different exogenous cannabinoid-based pharmacotherapies for human sleep disturbances and disorders.
Recent Findings
Most clinical research has focused on symptoms of insomnia, with indication that cannabinoids may be an efficacious treatment option. However, samples have rarely been comprised of people with a clinical diagnosis, and variable cannabinoid formulations and doses across studies prevent unequivocal recommendations. The evidence for other sleep disorders (e.g., sleep apnea, Restless Leg Syndrome, REM sleep behavior disorder) is even more scant.
Summary
Reflecting on research conducted to date, there is an opportunity for active researchers in this field to consider developing common data collection protocols and core outcome sets to facilitate future standardization and pooling of data from high-quality trials.
... Due to the ability of CBD to modulate the endogenous cannabinoid system, there has been an increasing interest in CBD as a potential alternative treatment for several brain disorders defined by neuronal loss and/or damage. As such, the literature search on neuroprotective effects of CBD mostly provided results regarding animal models of neurodegenerative diseases, such as Alzheimer's (reviewed by [171]), Huntington's [172,173], and Parkinson's disease ( [174,175]; reviewed by [171,176]) as well as in experimental animal models of hypoxic-ischemia [177] and encephalopathy [178,179] or studies with patients with the above-mentioned diseases [110,[180][181][182] reviewed in [183,184]. In addition, various in vitro studies assessed CBD effects after induction of damage mimicking various neurological diseases, some of them suggesting that CBD is able to prevent a number of the cellular and molecular alterations associated with neurological damage [185,186]. ...
Background: Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5–40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. Methods: The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. Results: Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3–4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. Conclusions: The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers.
... Os efeitos positivos nos SNM da DP decorrem do potencial neuroprotetor que os canabinoides possuem, devido à sua ação nos receptores CB1, CB2 e outros (Costa el al., 2022). Tal Dessa forma, ainda que estes efeitos neuroprotetores provenientes da Cannabis já tenham sido relatados em modelos animais, sua comprovação em humanos não é facilmente medida (Chagas et al., 2014b). Portanto, esta revisão optou por basear-se no alívio sintomático dos SNM apresentados pelos artigos aqui compilados como medida de predizer a efetividade da Cannabis sativa. ...
Objetivo: Mapear e analisar as evidências disponíveis na literatura existente acerca da efetividade e segurança do uso da Cannabis sativa no tratamento dos Sintomas Não-Motores (SNM) da Doença de Parkinson (DP). Metodologia: Trata-se de uma revisão de escopo, com busca realizada nas bases de dados BVS Direct, EBSCO, Embase, PubMed e Scopus, sem limite temporal ou de idioma. Este processo foi norteado pela pergunta de pesquisa “Quais são as evidências da efetividade e segurança do uso terapêutico de Cannabis sativa no tratamento dos sintomas não-motores em pacientes com Doença de Parkinson?”. Resultados: Dos 2193 artigos encontrados, 90 estudos foram considerados elegíveis. Os estudos indicaram que a Cannabis sativa possui potencial para tratar diversos SNM, com melhora significativa da dor e distúrbios do sono, bem como melhora em manifestações neuropsiquiátricas e da qualidade de vida. As taxas de efeitos colaterais tendem a ser baixas e geralmente são classificados como leves e bem tolerados. No entanto, os resultados variam dependendo da dose utilizada, forma de administração do produto e composto canabinoide utilizado, sendo necessário mais estudos para avaliar a sua efetividade e segurança. Conclusão: O uso da Cannabis sativa pode melhorar os SNM, com potencial para impactar positivamente a qualidade de vida dos portadores de DP. Entretanto, mais estudos são necessários para garantir a efetividade e segurança dessa terapia complementar.
... Prior research on the impact of medicinal cannabis with REM sleep behaviour disorder (RBD) is limited. A 2014 case series of 4 patients found 75 -150 mg of CBD improved RBD symptoms at 6 weeks [85]. This review identified one (phase II/III) RCT study in RBD, evaluating the impact of 300 mg of CBD on RBD frequency in patients with established Parkinson's disease [59]. ...
Purpose of review
Cannabis sativa and constituent cannabinoids are in widespread use for the treatment of sleep disorders where many patients desire pharmacotherapy. Previous reviews highlight a lack of high-quality evidence to support the efficacy and long-term safety of cannabinoids in various conditions. We aim to provide an update of recent original research evaluating cannabinoid-based therapeutics in sleep disorders.
Recent findings
We identified twenty-one recent studies of cannabinoids for insomnia, subjective sleep impairment, obstructive sleep apnoea, rapid eye movement sleep behaviour disorder, and restless legs syndrome. We note trends towards the use of minor cannabinoids, studies using decentralised approaches and increased utilisation of objective measures in clinical trials.
Summary
The evidence-base does not match widespread use of cannabinoids for the treatment of sleep disorders. There is a growing need for adequately funded well-designed clinical trials with longer treatment durations and decent sample sizes to inform both the clinician and patient.
... Patients were given CBD orally for 6 weeks. The results showed that CBD improved the overall quality of life in these patients, as well as having a positive effect on the quality of sleep in PD patients with REM sleep behavior disorder [72,74]. ...
This review provides an overview of cannabis-based phytocannabinoids, focusing on their mechanisms of action, therapeutic applications, and production processes, along with the environmental factors that affect their quality and efficacy. Phytocannabinoids such as THC (∆⁹-tetrahydrocannabinol), CBD (cannabidiol), CBG (cannabigerol), CBN (cannabinol), and CBC (cannabichromene) exhibit significant therapeutic potential in treating various physical and mental health conditions, including chronic pain, epilepsy, neurodegenerative diseases, skin disorders, and anxiety. The cultivation of cannabis plays a crucial role in determining cannabinoid profiles, with indoor cultivation offering more control and consistency than outdoor methods. Environmental factors such as light, water, temperature, humidity, nutrient management, CO2, and the drying method used are key to optimizing cannabinoid content in inflorescences. This review outlines the need for broader data transfer between the health industry and technological production, especially in terms of what concentration and cannabinoid ratios are effective in treatment. Such data transfer would provide cultivators with information on what environmental parameters should be manipulated to obtain the required final product.
... In another double-blind randomized clinical trial involving 21 patients, CBD improved quality of life indicators over 6 weeks of treatment due to its effect on non-motor symptoms of the disease, while the motor functions of patients did not change [83]. Similarly, a pilot study involving four PD patients with a rapid eye movement sleep behavior disorder showed a decrease in the frequency of agitation, kicks, and nightmares after the treatment course based on 99.9% purified CBD [84]. ...
The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson’s disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.
... Reduction of psychotic symptoms [88] All components on ECS afected and many other targets Whole cannabis smoked Improvement on reducing tremors, rigidity, and bradykinesia, as well as sleep and pain [89] CB1 and CB2 agonism, FAAH inhibition, and PPARand TRPV-modulated activities CBD 75 and 300 mg oral Reduction of disorder related REM sleep behavior [90] CB1 and CB2 agonism, FAAH inhibition, and PPARand TRPV-modulated activities CBD 75 and 300 mg oral No improved motor but improved in quality of life on highest dosage [91] All components on ECS afected and many other targets Cannabis diferent dosage (patient survey) Improvement of mood and sleep and of motor symptoms [25,92] CB1 and CB2 agonism Nabilone 0.25 mg to 1 mg oral Benefcial efects on sleep disorders associated with PD [93] CB1 and CB2 agonism, FAAH inhibition, and PPARand TRPV-modulated activities CBD 300 mg oral Decrement in anxiety and tremor amplitude on PD patients [94] CB1 and CB2 agonism Nabilone 0.25 mg to 2 mg oral Benefcial efects on sleep outcomes in PD patients [95] 8 ...
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alterations in motor capacity resulting from a decrease in the neurotransmitter dopamine due to the selective death of dopaminergic neurons of the nigrostriatal pathway. Unfortunately, conventional pharmacological treatments fail to halt disease progression; therefore, new therapeutic strategies are needed, and currently, some are being investigated. The endocannabinoid system (ECS), highly expressed in the basal ganglia (BG) circuit, undergoes alterations in response to dopaminergic depletion, potentially contributing to motor symptoms and the etiopathogenesis of PD. Substantial evidence supports the neuroprotective role of the ECS through various mechanisms, including anti-inflammatory, antioxidative, and antiapoptotic effects. Therefore, the ECS emerges as a promising target for PD treatment. This review provides a comprehensive summary of current clinical and preclinical evidence concerning ECS alterations in PD, along with potential pharmacological targets that may exert the protection of dopaminergic neurons.
... In another double-blind randomized clinical trial involving 21 patients, CBD improved quality of life indicators over 6 weeks of treatment due to its effect on non-motor symptoms of the disease, although the motor functions of patients did not change [62]. Similarly, a pilot study involving 4 PD patients with a sleep disorder with rapid eye movements showed a decrease in the frequency of agitation, kicks and nightmares after treatment based on 99.9% purified CBD [63]. ...
Recent studies have shown that the endogenous cannabinoid system (ECS) of the brain is essentially involved in the pathogenesis of Parkinson's disease (PD), influencing its symptoms by regulating the level of endogenous cannabinoids and altering the activation of cannabinoid receptors (CBR). Therefore, modulation of ECS with new drugs developed for this purpose may prove to be a promising strategy in the treatment of PD. However, fine regulation of ECS is quite a challenge due to the functional diversity of CBR in the basal ganglia. Our review analyses the effects of ECS modulators on experimental PD models and in patients with PD, as well as presents the outlooks for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD.
... Its non-addictive nature makes it an appealing choice for patients seeking effective treatments without the risk of dependency. Clinical studies have indicated that CBD holds promise for potential applications in treating various chronic diseases and neurological conditions, with possible positive effects for managing conditions such as epilepsy, 2,3 Alzheimer's disease, 4 Parkinson's disease, 5,6 sleep disorders, 7,8 depression and psychotic disorders, 9 anxiety, 9 schizophrenia, 10 and post-traumatic stress disorder. 11 However, CBD has faced certain challenges affecting its administration and efficacy. ...
Purpose
Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes.
Methods
A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications.
Results
In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application.
Conclusion
CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form.
... Animal models have been used to support this finding. The synthetic cannabinoid drug WIN55,212-2 effectively binds CB1R and leads to allodynia inhibition and to hyperalgesia caused by constriction damage of the infraorbital branch of the trigeminal nerve (Chagas et al., 2014). Another preclinical research has pointed out this synthetic cannabinoid's ability to modulate signaling through N-type calcium channels, 5-HT 3 receptor activated ion channels and GABA receptor ion channels. ...
Chronic pain has been managed for decades, mainly by therapies based on a wide spectrum of analgesic drugs, surgical protocols and complex interventions aimed at interfering with pain outcomes or to, at least, modulate it. Unfortunately, all these techniques lead to several pharmacological hazards, besides their lack of efficacy and safety to treat chronic pain. This scenario justified the need of research focused on finding alternative treatments. Cannabinoids are naturally occurring substances deriving from Cannabis sativa L. The use of cannabinoids and their metabolites, mainly cannabidiol (CBD), emerged as option to manage different chronic pain conditions. The present review focuses on the CBD mechanism acting in chronic pain conditions, mostly on its specific use to treat trigeminal neuralgia. This review also discusses CBD’s safety and interaction with drugs prescribed for neuropathic orofacial pain, mainly Gabapentin/CBD interactions.
... 13 A recent meta-analysis criticized that rigorous, controlled evidence for the therapeutic efficacy of CBD is lacking for many health conditions, but they also found that the utility of CBD to treat epilepsy is well supported 69 while additional controlled trials are needed to elucidate the efficacy of CBD as a sleep aid given that findings in this area appear to be mixed. 11,[69][70][71] However, in one study 11 participants received oral placebo or CBD capsules (40, 80, iScience Article Oscillation-coupling for memory consolidation At this point we do know that ripples, spindles, and delta waves in sleep are important for memory consolidation. Further, for some of their functions these oscillations are coupled to each other, as reported by many researchers. ...
Cannabidiol (CBD) is on the rise as over-the-counter medication to treat sleep disturbances, anxiety, pain, and epilepsy due to its action on the excitatory/inhibitory balance in the brain. However, it remains unclear if CBD also leads to adverse effects on memory via changes of sleep macro- and microarchitecture. To investigate the effect of CBD on sleep and memory consolidation, we performed two experiments using the object space task testing for both simple and cumulative memory in rats. We show that oral CBD administration extended the sleep period but changed the properties of rest and non-REM sleep oscillations (delta, spindle, ripples). Specifically, CBD also led to less long (>100 ms) ripples and, consequently, worse cumulative memory consolidation. In contrast, simple memories were not affected. In sum, we can confirm the beneficial effect of CBD on sleep; however, this comes with changes in oscillations that negatively impact memory consolidation.
... The subclasses of flavonoids and the diverse chemicals identified within them can result from a variety of additional alterations. Flavonoids can also be found as aglycones or glycosides, which are sugars [227], stopped the development of the hippocampus neurons caused by hypobaric hypoxia [228], and protected against diabetic neuropathy. The drug prevented aggravations, stress, and initiating harm in mice treated with 3 NP [229]. ...
A neurodegenerative disorder (ND) refers to Huntington's disease (HD) which affects memory loss, weight loss, and movement dysfunctions such as chorea and dystonia. In the striatum and brain, HD most typically impacts medium-spiny neurons. Molecular genetics, excitotoxicity, oxidative stress (OS), mitochondrial, and metabolic dysfunction are a few of the theories advanced to explicit the pathophysiology of neuronal damage and cell death. Numerous in-depth studies of the literature have supported the therapeutic advantages of natural products in HD experimental models and other treatment approaches. This article briefly discusses the neuroprotective impacts of natural compounds against HD models. The ability of the discovered natural compounds to suppress HD was tested using either in vitro or in vivo models. Many bioactive compounds considerably lessened the memory loss and motor coordination brought on by 3-nitropropionic acid (3-NP). Reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and enhanced mitochondrial energy generation have profoundly decreased the biochemical change. It is significant since histology showed that therapy with particular natural compounds lessened damage to the striatum caused by 3-NP. Moreover, natural products displayed varying degrees of neuroprotection in preclinical HD studies because of their antioxidant and anti-inflammatory properties, maintenance of mitochondrial function, activation of autophagy, and inhibition of apoptosis. This study highlighted about the importance of bioactive compounds and their semi-synthetic molecules in the treatment and prevention of HD.
... 153 In a pilot study the use of cannabidiol (CBD) in PDRBD patients at doses ranging from 75 to 300 mg for six weeks, caused a reduction of up to 80% in the frequency of the nocturnal behaviors assessed through the sleep diary. 154 Other drugs such as zopiclone (doses ranging from 3.75 to 7.5 mg) and sodium oxybate (doses ranging from 3 to 9 g) are also effective in RBD therapy, but their effectiveness has not been demonstrated in PD. 155 Some case reports indicate that 10 mg daily of temazepam may be effective in treating RBD symptoms. 155 There are also cases or small series that show the possible effectiveness of carbamazepine 156 and gabapentin 157 on RBD symptoms. ...
Rapid eye movement (REM) sleep behavior disorder (RBD) is the result of the loss of physiological inhibition of muscle tone during REM sleep, characterized by dream-enacting behavior and widely recognized as a prodromal manifestation of alpha-synucleinopathies. Indeed, patients with isolated RBD (iRBD) have an extremely high estimated risk to develop a neurodegenerative disease after a long follow up. Nevertheless, in comparison with PD patients without RBD (PDnoRBD), the occurrence of RBD in the context of PD (PDRBD) seems to identify a unique, more malignant phenotype, characterized by a more severe burden of disease in terms of both motor and non-motor symptoms and increased risk for cognitive decline. However, while some medications (eg, melatonin, clonazepam, etc.) and non-pharmacological options have been found to have some therapeutic benefits on RBD there is no available treatment able to modify the disease course or, at least, slow down the neurodegenerative process underlying phenoconversion. In this scenario, the long prodromal phase may allow an early therapeutic window and, therefore, the identification of multimodal biomarkers of disease onset and progression is becoming increasingly crucial. To date, several clinical (motor, cognitive, olfactory, visual, and autonomic features) neurophysiological, neuroimaging, biological (biofluids or tissue biopsy), and genetic biomarkers have been identified and proposed, also in combination, as possible diagnostic or prognostic markers, along with a potential role for some of them as outcome measures and index of treatment response. In this review, we provide an insight into the present knowledge on both existing and future biomarkers of iRBD and highlight the difference with PDRBD and PDnoRBD, including currently available treatment options.
... An improvement in sleep quality scores was noticed initially, and a fluctuation of scores was reported afterward . A case series of CBD on four patients diagnosed with Parkinson's disease found that CBD reduced REM sleep behavior disorder (RBD) (Chagas et al. 2014). However, a recent double-blind, placebo-controlled clinical trial in 33 patients found that CBD did not reduce RBD manifestations, its primary outcome, although a transient improvement in sleep satisfaction as a secondary outcome was observed with a dose of 300 mg (de Almeida et al. 2021). ...
Among individuals with alcohol use disorder (AUD), it is estimated that the majority suffer from persistent sleep disturbances for which few candidate medications are available. Our aim wass to critically review the potential for cannabidiol (CBD) as a treatment for AUD-induced sleep disturbance. As context, notable side effects and abuse liability for existing medications for AUD-induced sleep disturbance reduce their clinical utility. CBD modulation of the endocannabinoid system and favorable safety profile have generated substantial interest in its potential therapeutic use for various medical conditions. A number of preclinical and clinical studies suggest promise for CBD in restoring the normal sleep-wake cycle and in enhancing sleep quality in patients diagnosed with AUD. Based on its pharmacology and the existing literature, albeit primarily preclinical and indirect, CBD is a credible candidate to address alcohol-induced sleep disturbance. Well-designed RCTs will be necessary to test its potential in managing this challenging feature of AUD.
... Cannabidiol (CBD) is the major non-psychomimetic compound in Cannabis sativa and studies have demonstrated several effects such as anxiolytic [1], anticonvulsant [2], cardiovascular and anti-inflammatory [3], and neuroprotective [4] in different models of degenerative disorders. For instance, CBD administration presents neuroprotective effects in newborn piglet model after hypoxic-ischemic encephalopathy [5], attenuates damage against 6-hydroxydopamine (6-OHDA) by increasing the tyrosine hydroxylase expression and activity in vitro and in vivo models [6], and reduces REM sleep behavior disorder in clinic [7]. ...
Progressive neurodegenerative disorders such as Parkinson Disease (PD) lack curative or long-term treatments. At the same time, the increase of the worldwide elderly population and, consequently, the extension in the prevalence of age-related diseases have promoted research interest in neurodegenerative disorders. Caenorhabditis elegans is a free-living nematode widely used as an animal model in studies of human diseases. Here we evaluated cannabidiol (CBD) as a possible neuroprotective compound in PD using the C. elegans models exposed to reserpine. Our results demonstrated that CBD reversed the reserpine-induced locomotor alterations and this response was independent of the NPR-19 receptors, an orthologous receptor for central cannabinoid receptor type 1. Morphological alterations of cephalic sensilla (CEP) dopaminergic neurons indicated that CBD also protects neurons from reserpine-induced degeneration. That is, CBD attenuates the reserpine-induced increase of worms with shrunken soma and dendrites loss, increasing the number of worms with intact CEP neurons. Finally, we found that CBD also reduced ROS formation and α-syn protein accumulation in mutant worms. Our findings collectively provide new evidence that CBD acts as neuroprotector in dopaminergic neurons, reducing neurotoxicity and α-syn accumulation highlighting its potential in the treatment of PD.
... CBD has already been proposed as a symptomatic treatment, which is usually prescribed when classical dopaminergic drugs fail to achieve adequate symptom control [18,196]. Although different immune-modulating approaches have already been tested, with some success in animal models, results of similar trials in human patients have so far proven less promising, with no disease-modifying treatment yet available for these patients [180]. ...
Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox–Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD’s effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases.
Cannabidiol (CBD), the major non-psychotropic compound of Cannabis sp., is an effective treatment for inflammatory and autoimmune diseases and produces various anti-tumor effects but the mechanisms of its long-term actions in vivo remain unclear. We have previously shown that CBD administration (5 mg/kg) in healthy rats significantly decreased lymphocyte numbers in peripheral blood, involving B, T CD4+ and T CD8+ lymphocyte subsets, but not natural killer (NK) cells. To examine the effects of CBD on lymphocyte subsets in the spleen and NK cellular cytotoxicity (NKCC), adult male Wistar rats (n = 63) were administered intraperitoneal injections of CBD (2.5 or 5 mg/kg/day) for 14 consecutive days and lymphocyte counts were obtained using flow cytometry. NKCC in the peripheral blood and spleen was quantified using a Chromium-51 release assay. Furthermore, CB2 receptors were blocked using selective receptor antagonist AM630 (1 mg/kg). The results indicate that repeated administration of CBD at a dose of 5 mg/kg/day resulted in a decrease in splenic lymphocyte number, involving T and B lymphocytes but not NK cells. The decrease in lymphocyte number was partially blocked by pretreatment with CB2 receptor antagonist while no changes in NKCC were observed following CBD administration. These results reveal that in healthy rats, CBD produces similar lymphopenic effects in the spleen as it does in peripheral blood and that the effects of CBD on lymphocyte numbers in vivo are at least partially mediated by CB2 receptors.
Background
Cannabidiol (CBD) has numerous therapeutic properties, and is used to treat neurological conditions, such as neuroinflammation. However, the optimal dose of CBD to penetrate the brain requires further investigation. The primary aim of this study was to use a mouse model and the intrabuccal route for CBD administration to determine the optimal dose at which CBD can penetrate the brain. The secondary aim was to determine whether sex is a confounding factor.
Methods
Thirty adult Kramnik mice, divided equally into three groups, were administered CBD oil intrabuccally at three doses—10, 20, and 30 mg/kg, euthanized 6 h later, and whole brain, urine, and blood samples were collected. Liquid chromatography with tandem mass spectrometry was used to analyze the collected samples.
Results
CBD and its three metabolites—7‐carboxy cannabidiol (7‐COOH‐CBD), 7‐hydroxy cannabidiol (7‐OH‐CBD) and 6‐hydroxy cannabidiol (6‐OH‐CBD), were identified and quantified in all samples. The 10 and 20 mg/kg doses of CBD produced similar results in the brain, but the group given the 10 mg/kg dose had the least variation. The 30 mg/kg dose yielded the highest abundance of CBD and its metabolites in all samples, but also the greatest variation. Sex only became a confounding factor at 30 mg/kg.
Conclusions
This study shows that the intrabuccal route of CBD administration is reliable and the 10 mg/kg dose of CBD is recommended in mice because there were good CBD metabolite concentrations in all samples, with the least variation among the doses, and sex was not a confounder at 10 mg/kg.
Cannabis-based medicine (CBM) is used in a wide variety of different neurological disorders. While the use of CBM in the treatment of pain, AIDS wasting, loss of appetite, and spasticity is well established, CBM application in movement disorders and neurodegenerative disorders is still an emerging topic. The purpose of this chapter is to summarize current evidence behind the use of CBM in selected neurological diseases, mainly movement and neurodegenerative disorders. The best evidence for efficacy of CBM is for Tourette syndrome resulting in an improvement of tics and psychiatric comorbidities. In this indication, delta-9-tetrahydrocannabinol (THC)-containing CBMs are recommended. There is limited evidence that CBMs are also effective in Parkinson’s disease in which they may improve tremor, but also non-motor symptoms such as pain and sleeping problems. With respect to other neurodegenerative diseases, there is limited evidence that CBMs may improve behavioral symptoms in Huntington’s disease. In addition, it has been speculated that CBMs may have neuroprotective effects, but this has not yet been confirmed in the clinical setting.
Identification and development of pharmaceuticals for neurological disorders is associated with several unique challenges. The primary weakness of candidate neurological compounds is the poor penetration efficacy across the blood-brain barrier (BBB). The BBB is the bottleneck in nervous system drug development and is the paramount factor that limits success in neurotherapeutics. Findings suggest cannabinoids might overcome the limiting effects of the BBB and play a key role in improving neurological dysfunctions. This supports the therapeutic potential of cannabidiol for the treatment of ischemic and inflammatory diseases of the central nervous system (CNS). The potential application of cannabinoids for Parkinson’s disease, Autism, and childhood Epilepsy is explored in this chapter.
Background
Cannabidiol (CBD) is a non-psychoactive phyto-cannabinoid derived from the Cannabis sativa plant. CBD exhibits various interactions at receptor sites, prompting the research of its potential anti-inflammatory, immunomodulatory, psychological, and pain-relieving effects. This study aimed to investigate the physiological, biochemical, and psychometric effects of a brand-specific, hemp-derived CBD product in healthy adults over a 12-week observation period.
Methods
54 healthy males and females (age = 25 ± 7y; BMI = 24.82 ± 3.25 kg/m²) recruited from a large Southeastern University completed the study. Participants arrived at the laboratory after > 8 h of fasting, and > 48 h without alcohol consumption and vigorous exercise. Following baseline measurements (height, weight, blood pressure, electrocardiogram (ECG), and blood work), participants were stratified by sex and randomized to either CBD or placebo groups. Products were administered double-blinded, with both given in liquid form containing medium-chain triglyceride oil, while the CBD product specifically contained 50 mg/mL of CBD. Participants were instructed to consume 1 mL of their product twice daily and were given enough product to last until their next laboratory visit. Data were collected at baseline and on days 30 ± 3, 60 ± 3, and 90 ± 3. Blood was drawn for analysis of immune and inflammatory biomarkers. Chronic pain among participants was calculated using urine samples according to the foundational pain index (FPI). Self-reported psychometric questionnaires were utilized (Cohen’s Perceived Stress Scale, Pittsburgh Sleep Quality Index, Profile of Mood States,10-item Likert scale for perceived pain) to assess stress, sleep quality, mood state, and body discomfort. To determine overall wellbeing, participants completed a daily survey indicating if they missed work or school due to illness. Change from baseline was calculated for each measure, and mixed effects models were used to determine differences between groups over time while adjusting for baseline values (α = 0.05). Data are presented as mean ± standard deviation.
Results
There were no Group-by-Time interactions or Group or Time main effects for immune or inflammatory biomarkers (p > 0.05). Analyses revealed no Group-by-Time interactions or main effects observed for perceived stress, sleep quality, overall mood disturbance, and all the profile of mood state subscales (p > 0.05), except “vigor-activity.” A Time main effect was found for the sub-score for “vigor-activity” (p = 0.007; Pre CBD = 19.5 ± 5.2, Post CBD = 17.3 ± 5.3; Pre PL = 19.0 ± 5.7, Post PL = 17.9 ± 7.1), which decreased from Visit 3 to Visit 4 (p = 0.025) and from Visit 3 to Visit 5 (p = 0.014). There was a Group main effect for FPI (p = 0.028; Pre CBD = 11.9 ± 14.4, Post CBD = 8.8 ± 10.9; Pre PL = 9.0 ± 14.2, Post PL = 12.9 ± 11.5), indicating that the placebo group had greater increases in pain over the intervention compared to the CBD group. No significant differences were found between groups in the incidence and prevalence of “colds or flus” (p > 0.05).
Discussion
CBD was safe and well tolerated in healthy adults. These findings show pain was lower in the CBD group, suggesting a potentially positive effect for consumption of CBD. “Vigor-activity” decreased across the intervention, which may be a confounding effect of the academic semester. While the dosage chosen was safe, more research may be warranted using higher doses as these may be needed to observe further therapeutic effects in healthy populations.
Cannabinoids are compounds with increasing scientific interest, particularly due to their interaction with the endocannabinoid system via CBR1 and CBR2 receptors. They can interfere with appetite, pain, and sleep or develop mood changes in the individual. Cannabidiol (CBD) is a well-known cannabinoid with potential benefits, including reducing epilepsy seizures, alleviating anxiety and obsessive-compulsive disorder (OCD) symptoms, aiding in Tourette Syndrome (a neurodevelopmental disorder), depression, sleep disorders, and promising in the treatment of cancer, pain relief, and heart health. Although generally safe, CBD can have side effects, including drug metabolism interference, fertility, and liver function. In addition, it can be administered by oral, sublingual, transdermal, or inhalation via each one with different bioavailability. The application of nanotechnology, specifically through colloidal carrier systems, holds promising potential for maximizing CBD's efficacy and pharmacological profile. There are reported CBD extraction methods using ethanol, carbon dioxide, deionised water, and non-polar oils like olive or coconut oil. Green extraction methods have gained popularity due to their higher yields, shorter extraction time, and reduced costs. A specific dose with the desired effects is challenging due to individual factors, with most studies suggesting a range between less than 1 and 50 mg/kg/d. This review aims to explore the principles of CBD-based products development, focusing on extraction methods and purification processes of this cannabinoid for tinctures, topicals, and other pharmaceutical forms, as well as further research to attain the objectives.
Background
The treatment of diverse diseases using plant-derived products is actively encouraged. In the past few years, cannabidiol (CBD) has emerged as a potent cannabis-derived drug capable of managing various debilitating neurological infections, diseases, and their associated complications. CBD has demonstrated anti-inflammatory and curative effects in neuropathological conditions, and it exhibits therapeutic, apoptotic, anxiolytic, and neuroprotective properties. However, more information on the reactions and ability of CBD to alleviate brain-related disorders and the neuroinflammation that accompanies them is needed.
Main body
This narrative review deliberates on the therapeutic and remedial prospects of CBD with an emphasis on neurological and neuropsychiatric disorders. An extensive literature search followed several scoping searches on available online databases such as PubMed, Web of Science, and Scopus with the main keywords: CBD, pro-inflammatory cytokines, and cannabinoids. After a purposive screening of the retrieved papers, 170 (41%) of the articles (published in English) aligned with the objective of this study and retained for inclusion.
Conclusion
CBD is an antagonist against pro-inflammatory cytokines and the cytokine storm associated with neurological infections/disorders. CBD regulates adenosine/oxidative stress and aids the downregulation of TNF-α, restoration of BDNF mRNA expression, and recovery of serotonin levels. Thus, CBD is involved in immune suppression and anti-inflammation. Understanding the metabolites associated with response to CBD is imperative to understand the phenotype. We propose that metabolomics will be the next scientific frontier that will reveal novel information on CBD’s therapeutic tendencies in neurological/neuropsychiatric disorders.
Background
Cannabis use is frequent in Parkinson's disease (PD), despite inadequate evidence of benefits and risks.
Objective
The aim is to study short‐term efficacy and tolerability of relatively high cannabidiol (CBD)/low Δ‐9‐tetrahydrocannabinol (THC) to provide preliminary data for a longer trial.
Methods
Persons with PD with ≥20 on motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) who had negative cannabis testing took cannabis extract (National Institute of Drug Abuse) oral sesame oil solution for 2 weeks, increasing to final dose of 2.5 mg/kg/day. Primary outcome was change in motor MDS‐UPDRS from baseline to final dose.
Results
Participants were randomized to CBD/THC (n = 31) or placebo (n = 30). Mean final dose (CBD/THC group) was 191.8 ± 48.9 mg CBD and 6.4 ± 1.6 mg THC daily. Motor MDS‐UPDRS was reduced by 4.57 (95% CI, −8.11 to −1.03; P = 0.013) in CBD/THC group, and 2.77 (−4.92 to −0.61; P = 0.014) in placebo; the difference between groups was non‐significant: −1.80 (−5.88 to 2.27; P = 0.379). Several assessments had a strong placebo response. Sleep, cognition, and activities of daily living showed a treatment effect, favoring placebo. Overall adverse events were mild and reported more in CBD/THC than placebo group. On 2.5 mg/kg/day CBD plasma level was 54.0 ± 33.8 ng/mL; THC 1.06 ± 0.91 ng/mL.
Conclusions
The brief duration and strong placebo response limits interpretation of effects, but there was no benefit, perhaps worsened cognition and sleep, and there was many mild adverse events. Longer duration high quality trials that monitor cannabinoid concentrations are essential and would require improved availability of research cannabinoid products in the United States. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system‐related receptors and other molecular targets, such as the 5‐HT 1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5‐HT 1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5‐HT 1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.
Background
Seborrheic dermatitis (SD) affects 18.6%-59% of persons with Parkinson disease (PD), and recent studies provide evidence that oral cannabidiol (CBD) therapy could reduce sebum production in addition to improving motor and psychiatric symptoms in PD. Therefore, oral CBD could be useful for improving symptoms of both commonly co-occurring conditions.
Objective
This study investigates whether oral CBD therapy is associated with a decrease in SD severity in PD.
Methods
Facial photographs were collected as a component of a randomized (1:1 CBD vs placebo), parallel, double-blind, placebo-controlled trial assessing the efficacy of a short-term 2.5 mg per kg per day oral sesame solution CBD-rich cannabis extract (formulated to 100 mg/mL CBD and 3.3 mg/mL THC) for reducing motor symptoms in PD. Participants took 1.25 mg per kg per day each morning for 4 ±1 days and then twice daily for 10 ±4 days. Reviewers analyzed the photographs independently and provided a severity ranking based on the Seborrheic Dermatitis Area and Severity Index (SEDASI) scale. Baseline demographic and disease characteristics, as well as posttreatment SEDASI averages and the presence of SD, were analyzed with 2-tailed t tests and Pearson χ2 tests. SEDASI was analyzed with longitudinal regression, and SD was analyzed with generalized estimating equations.
Results
A total of 27 participants received a placebo and 26 received CBD for 16 days. SD severity was low in both groups at baseline, and there was no treatment effect. The risk ratio for patients receiving CBD, post versus pre, was 0.69 (95% CI 0.41-1.18; P=.15), compared to 1.20 (95% CI 0.88-1.65; P=.26) for the patients receiving the placebo. The within-group pre-post change was not statistically significant for either group, but they differed from each other (P=.07) because there was an estimated improvement for the CBD group and an estimated worsening for the placebo group.
Conclusions
This study does not provide solid evidence that oral CBD therapy reduces the presence of SD among patients with PD. While this study was sufficiently powered to detect the primary outcome (efficacy of CBD on PD motor symptoms), it was underpowered for the secondary outcomes of detecting changes in the presence and severity of SD. Multiple mechanisms exist through which CBD can exert beneficial effects on SD pathogenesis. Larger studies, including participants with increased disease severity and longer treatment periods, may better elucidate treatment effects and are needed to determine CBD’s true efficacy for affecting SD severity.
Trial Registration
ClinicalTrials.gov NCT03582137; https://clinicaltrials.gov/ct2/show/NCT03582137
Parkinson's disease (PD) is a neurodegenerative pathology on the rise worldwide. There is a demand for new therapeutic options that contribute to more quality of life and autonomy for people with PD. Recent studies suggest the therapeutic potential of medicinal cannabinoids for neurological pathologies. This manuscript aimed to review the use of medicinal cannabinoids in PD to provide an updated overview and verify new demands. A scoping review was conducted with the search of references in Databases, grey literature, and manual search. Articles in Portuguese, Spanish, or English with no date restriction were included. Ninety-five articles published between 1990 and 2022 were eligible for the final sample, originating mainly in the USA and Brazil. As for the administration, the oral route was the most common and several symptoms showed improvement after the use of cannabinoids, highlighting: rest tremor, muscle rigidity, bradykinesia, dyskinesia, pain, insomnia, and anxiety. The most common undesirable effects were: dizziness, drowsiness, hallucinations, and xerostomia. It was observed studies with sample bias, recall bias, information bias and non-response bias, and low quality of evidence. To produce the evidence desired by all actors interested in the use of medicinal cannabinoids and their products, double-blind, multicentre randomized clinical trials are necessary with experimental, control and placebo, and follow-up groups, to evaluate the neurological potential of the cannabinoids in PD and elaborate systematic review protocols without language restriction, with a larger number of Databases and grey literature.
There are over 40 countries that have legalised the use of Cannabis sativa for medical purposes. The objective of this review is to discuss the benefits of C. sativa usage for medical purposes and the conflicts that may arise from its usage. In terms of neurological disorders, medical C. sativa is effective in reducing the symptoms of neuropathic and peripheral pain, Tic disorder, Parkinson’s Disease, and Alzheimer’s Disease. Besides, C. sativa has been proven to reduce the symptoms of post-traumatic stress disorder, insomnia, anxiety, and schizophrenia. With the legalization of C. sativa for medical purposes, there are conflicts that arise, including public attitudes and social acceptability. In conclusion, medical C. sativa showed significant medical benefits in managing neurological, mental, and other pain-related illnesses. However, C. sativa can also cause conflicts in the legalization process due to adverse effects shown to users after consuming it for a period of time.
Background:
The endocannabinoid system is active in nervous and immune cells and involves the expression of two cannabinoid receptor genes (CB1 and CB2), along with endogenous endocannabinoid ligands, 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide), and their synthetic enzymes. Cannabidiol (CBD) is a non-intoxicating exogenous cannabinoid agonist derived from plants that, at high doses, has received FDA approval as an anticonvulsant for epileptic seizures, and at low doses is marketed as a food-grade supplement for improved mental health, sleep quality, and immunological function. At present, the predominance of published CBD clinical research has focused on ameliorative or disease-specific intervention, with few trials investigating CBD effects in healthy populations.
Methods:
This clinical study aimed to investigate the effects of 8 weeks of 50 mg oral CBD on mental health, sleep quantity and quality, and immune cell function in healthy, college-aged individuals. Twenty-eight participants (average age 25.9 ± 6.1 y) were randomized to receive either daily oral capsules of 50 mg of CBD (CB, n = 14) or a calorie-matched placebo (CN, n = 14). Participants completed pre- and post-intervention assessments, including anthropometric measurements, mental health surveys, sleep analysis, and immunological function assessments.
Results:
After completing the 8-week intervention, there were no significant changes in body weight and BMI (CN: 1.09 ± 0.89%: CB: 1.41 ± 1.07%), or body fat percentage (CN: 9.01 ± 7.51%: CB: 8.57 ± 7.81%), respectively (values are % change pre to post, p > 0.05). There were also no significant differences between CB and CN groups with respect to mental health measures, sleep quantity, or circulating immunophenotype as a result of the intervention. However, the CB group experienced significant improvements in sleep quality measured objectively using a sleep questionnaire (p = 0.0023) and enhanced Natural Killer (NK) immune cell function assessed in situ (p = 0.0125).
Conclusions:
Eight weeks of daily 50 mg CBD may improve sleep quality, and NK immunosurveillance in healthy, younger adults.
Introduction: This review aims to provide an overview of the advancements and status of clinical studies and potential permeation-enhancing strategies in the transdermal delivery of cannabinoids. Methods: A systematic and comprehensive literature search across academic databases, search engines, and online sources to identify relevant literature on the transdermal administration of cannabinoids. Results: Cannabinoids have proven beneficial in the treatment of wide-ranging physical and psychological disorders. A shift toward legalized cannabinoid products has increased both interests in cannabinoid research and the development of novel medicinal exploitations of cannabinoids in recent years. Oral and pulmonary delivery of cannabinoids has several limitations, including poor bioavailability, low solubility, and potential side effects. This has diverted scientific attention toward the transdermal route, successfully overcoming these hurdles by providing higher bioavailability, safety, and patient compliance. Yet, due to the barrier properties of the skin and the lipophilic nature of cannabinoids, there is a need to increase the permeation of the drugs to the underneath layers of skin to reach desired therapeutic plasma levels. Literature describing detailed clinical trials on cannabinoid transdermal delivery, either with or without permeation-enhancing strategies, is limited. Conclusion: The limited number of reports indicates that increased attention is needed on developing and examining efficient transdermal delivery systems for cannabinoids, including patch design and composition, drug-patch interaction, clinical effectiveness and safety in vivo, and permeation-enhancing strategies.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by elevated motor behaviors and dream enactments in REM sleep, often preceding the diagnosis of Parkinson's disease (PD). As RBD could serve as a biomarker for early PD developments, pharmacological interventions targeting α-synuclein aggregation triggered RBD could be applied toward early PD progression. However, robust therapeutic guidelines toward PD-induced RBD are lacking, owing in part to a historical paucity of effective treatments and trials. We reviewed the bidirectional links between α-synuclein neurodegeneration, progressive sleep disorders, and RBD. We highlighted the correlation between RBD development, α-synuclein aggregation, and neuronal apoptosis in key brainstem regions involved in REM sleep atonia maintenance. The current pharmacological intervention strategies targeting RBD and their effects on progressive PD are discussed, as well as current treatments for progressive neurodegeneration and their effects on RBD are discussed. We also evaluated emerging and potential pharmacological solutions to sleep disorders and developing synucleinopathies. This review provides insights into the mechanisms and therapeutic targets underlying RBD and PD, and explores bidirectional treatment effects for both diseases, underscoring the need for further research in this area.
Aging is usually considered a key risk factor associated with multiple diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Furthermore, the burden of age-related diseases has become a global challenge. It is of great significance to search for drugs to extend lifespan and healthspan. Cannabidiol (CBD), a natural nontoxic phytocannabinoid, has been regarded as a potential candidate drug for antiaging. An increasing number of studies have suggested that CBD could benefit healthy longevity. Herein, we summarized the effect of CBD on aging and analyzed the possible mechanism. All these conclusions may provide a perspective for further study of CBD on aging.
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
Unlabelled:
Cannabidiol (CBD) is one of the main components of Cannabis sativa and has a wide spectrum of action, including effects in the sleep-wake cycle.
Objective:
The objective of this paper is to assess the effects on sleep of acute systemic administration of CBD.
Method:
Adult male Wistar rats were randomly distributed into four groups that received intraperitoneal injections of CBD 2.5 mg/kg, CBD 10 mg/kg, CBD 40 mg/kg or vehicle (n=seven animals/group). Sleep recordings were made during light and dark periods for four days: two days of baseline recording, one day of drug administration (test), and one day after drug (post-test).
Results:
During the light period of the test day, the total percentage of sleep significantly increased in the groups treated with 10 and 40 mg/kg of CBD compared to placebo. REM sleep latency increased in the group injected with CBD 40 mg/kg and was significantly decreased with the dose of 10 mg/kg on the post-test day. There was an increase in the time of SWS in the group treated with CBD 40 mg/kg, although this result did not reach statistical significance.
Conclusion:
The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency in the light period of the day of administration.
Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.
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.
The aim of this review is to describe the historical development of research on cannabidiol.
This review was carried out on reports drawn from Medline, Web of Science and SciELO.
After the elucidation of the chemical structure of cannabidiol in 1963, the initial studies showed that cannabidiol was unable to mimic the effects of Cannabis. In the 1970's the number of publications on cannabidiol reached a first peak, having the research focused mainly on the interaction with delta9-THC and its antiepileptic and sedative effects. The following two decades showed lower degree of interest, and the potential therapeutic properties of cannabidiol investigated were mainly the anxiolytic, antipsychotic and on motor diseases effects. The last five years have shown a remarkable increase in publications on cannabidiol mainly stimulated by the discovery of its anti-inflammatory, anti-oxidative and neuroprotective effects. These studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson's disease, Alzheimer's disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer.
In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials.
The management of psychosis in Parkinson's disease (PD) has been considered a great challenge for clinicians and there is a need for new pharmacological intervention. Previously an antipsychotic and neuroprotective effect of Cannabidiol (CBD) has been suggested. Therefore, the aim of the present study was to directly evaluate for the first time, the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms. This was an open-label pilot study. Six consecutive outpatients (four men and two women) with the diagnosis of PD and who had psychosis for at least 3 months were selected for the study. All patients received CBD in flexible dose (started with an oral dose of 150 mg/day) for 4 weeks, in addition to their usual therapy. The psychotic symptoms evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire showed a significant decrease under CBD treatment. CBD did not worsen the motor function and decreased the total scores of the Unified Parkinson's Disease Rating Scale. No adverse effect was observed during the treatment. These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
To describe the treatment response with melatonin for rapid eye movement (REM) sleep behavior disorder (RBD) associated with other neurologic disorders.
Clonazepam has been considered the treatment of choice for RBD. However, an alternative treatment is desirable for those with RBD refractory to clonazepam, for those who experience intolerable side-effects with clonazepam, and for those in whom clonazepam precipitates or aggravates obstructive sleep apnea (OSA). To date, there is minimal published data and limited follow-up regarding the use of melatonin for patients with RBD associated with other neurologic syndromes and disorders.
The response to melatonin treatment for RBD was reviewed on consecutive patients the investigators treated with this agent at Mayo Clinic Rochester from January 2000 to June 2001. The coexisting neurologic disorders, reasons for using melatonin, effective doses, side-effects, and duration of follow-up were also reviewed on all patients.
Fourteen patients were commenced on melatonin over the specified time period (13 male, median RBD onset age 56 years, range 20-77 years). The coexisting neurologic findings/disorders were dementia with Lewy bodies (n=7), mild cognitive impairment with mild parkinsonism (n=2), multiple system atrophy (n=2), narcolepsy (n=2), and Parkinson's disease (n=1). The reasons for using melatonin in these cases were incomplete response of RBD to clonazepam in six patients, existing cognitive impairment in five, intolerable side-effects with clonazepam in two, and presence of severe obstructive sleep apnea and narcolepsy in one. With seven patients continuing to use clonazepam at 0.5-1.0 mg/night, RBD was controlled in six patients, significantly improved in four, and initially improved but subsequently returned in two; no improvement occurred in one patient and increased RBD frequency/severity occurred in one patient. The effective melatonin doses were 3 mg in two cases, 6 mg in seven cases, 9 mg in one case, and 12 mg in two cases. Five patients reported side-effects, which included morning headaches (2), morning sleepiness (2), and delusions/hallucinations (1); these symptoms resolved with decreased dosage. The mean duration of follow-up was 14 months (range 9-25 months), with eight patients experiencing continued benefit with melatonin beyond 12 months of therapy.
In this series, persistent benefit with melatonin beyond 1 year of therapy occurred in most but not all patients. Melatonin can be considered as a possible sole or add-on therapy in select patients with RBD. Prospective, long-term, controlled trials with melatonin are warranted in a larger number of patients with RBD associated with a variety of neurologic symptoms and disorders.
Objective:
REM sleep behavior disorder (RBD) is usually characterized by potentially injurious dream enactment behaviors (DEB). RBD treatment aims to reduce DEBs and prevent injury, but outcomes require further elucidation. We surveyed RBD patients to describe longitudinal treatment outcomes with melatonin and clonazepam.
Methods:
We surveyed and reviewed records of consecutive RBD patients seen at Mayo Clinic between 2008-2010 to describe RBD-related injury frequency-severity as well as RBD visual analog scale (VAS) ratings, medication dosage, and side effects. Statistical analyses were performed with appropriate non-parametric matched pairs tests before and after treatment, and with comparative group analyses for continuous and categorical variables between treatment groups. The primary outcome variables were RBD VAS ratings and injury frequency.
Results:
Forty-five (84.9%) of 53 respondent surveys were analyzed. Mean age was 65.8 years and 35 (77.8%) patients were men. Neurodegenerative disorders were seen in 24 (53%) patients and 25 (56%) received antidepressants. Twenty-five patients received melatonin, 18 received clonazepam, and two received both as initial treatment. Before treatment, 27 patients (60%) reported an RBD associated injury. Median dosages were melatonin 6 mg and clonazepam 0.5 mg. RBD VAS ratings were significantly improved following both treatments (p(m) = 0.0001, p(c) = 0.0005). Melatonin-treated patients reported significantly reduced injuries (p(m) = 0.001, p(c) = 0.06) and fewer adverse effects (p = 0.07). Mean durations of treatment were no different between groups (for clonazepam 53.9 ± 29.5 months, and for melatonin 27.4 ± 24 months, p = 0.13) and there were no differences in treatment retention, with 28% of melatonin and 22% of clonazepam-treated patients discontinuing treatment (p = 0.43).
Conclusions:
Melatonin and clonazepam were each reported to reduce RBD behaviors and injuries and appeared comparably effective in our naturalistic practice experience. Melatonin-treated patients reported less frequent adverse effects than those treated with clonazepam. More effective treatments that would eliminate injury potential and evidence-based treatment outcomes from prospective clinical trials for RBD are needed.
The presence of central cannabinoid receptor (CB1), involving the N-terminal 14 amino acid peptide, was demonstrated in the rat brain by immunohistochemistry. Intensely stained neurons were observed in the principal neurons of the hippocampus, striatum, substantia nigra, cerebellar cortex, including the Purkinje cells. Moderate CB1-IR cell bodies and fibers were present in the olfactory bulb, cingulate, entorhinal and piriform cortical areas, amygdala and nucleus accumbens. The perivascular glial fibers have shown moderate to high density CB1-IR in olfactoric and limbic structures. Low density was detected in the thalamus and hypothalamus and area postrema. The CB1 receptor was widely distributed in the forebrain and sparsely in the hindbrain.These new data support the view that the endogenous cannabinoids play an important role in different neuronal functions as neuromodulators or neurotransmitters.
Neurology 2010;75;494-499 Background: Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]). Methods: We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome. Results: Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients. Conclusions: These cases illustrate that the-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.
Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]).
We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome.
Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients.
These cases illustrate that the alpha-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.
Parkinson's disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non-selective cannabinoid receptor agonist WIN55,212-2 (WIN) protects mouse nigrostriatal neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP-induced loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP-treated mice. At 3 days post-MPTP, we found significant microglial activation and up-regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP-induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP-associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP-induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.
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.
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.
The effects of the central (CB1) cannabinoid receptor antagonist SR 141716A on the sleep-waking cycle were investigated in freely-moving rats using time scoring and power spectral analysis of the electroencephalogram (EEG). Over a 4-hour recording period, SR 141716A (0.1, 0.3, 1, 3, and 10 mg/kg I.P.) dose-dependently increased the time spent in wakefulness at the expense of slow-wave sleep (SWS) and rapid eye movement sleep (REMS), delayed the occurrence of REMS but did not change the mean duration of REMS episodes. Moreover, the compound induced no change in motor behavior. At the efficient dose of 3 mg/kg I.P., SR 141716A reduced the spectral power of the EEG signals typical of SWS but did not affect those of wakefulness. Taken together, these results demonstrate that the EEG effects of SR 141716A reflect arousal-enhancing properties. In addition, the present study suggests that an endogenous cannabinoid-like system is involved in the control of the sleep-waking cycle.
We report longitudinal data on a group of 29 male patients 50 years of age or older who were initially diagnosed as having idiopathic REM sleep behavior disorder (RBD) after extensive polysomnographic and neurologic evaluations. Thirty-eight percent (11/29) were eventually diagnosed as having a parkinsonian disorder (presumably Parkinson's disease) at a mean interval of 3.7 +/- 1.4 (SD) years after the diagnosis of RBD+, and at a mean interval of 12.7 +/- 7.3 years after the onset of RBD. To date, only 7% (2/29) of patients have developed any other neurologic disorder. At the time of RBD diagnosis, data from the RBD group with eventual Parkinson's disease (n = 11) and the current idiopathic RBD group (n = 16) were indistinguishable, with two exceptions: the RBD-Parkinson's disease group had a significantly elevated hourly index of periodic limb movements of non-REM sleep and an elevated REM sleep percentage. RBD was fully or substantially controlled with nightly clonazepam treatment in 89% (24/27) of patients in both groups. Thus, RBD can be the heralding manifestation of Parkinson's disease in a substantial subgroup of older male RBD patients. However, a number of presumed Parkinson's disease patients may eventually be diagnosed with multiple system atrophy (striatonigral degeneration subtype). Our findings indicate the importance of serial neurologic evaluations after RBD is diagnosed and implicate the pedunculopontine nucleus as a likely site of pathology in combined RBD-Parkinson's disease, based on experimental and theoretical considerations rather than on autopsy data.
In this study we have assessed the effect of the intracerebroventricular administration of anandamide (ANA) as well as its precursor metabolite arachidonic acid (AA), on the sleep-wakefulness cycle, memory formation, locomotor activity and pain perception. Our results have indicated that ANA strikingly increases slow-wave sleep (SWS)2 and rapid-eye movement (REM) sleep at the expense of wakefulness (W); while deteriorating memory consolidation. ANA also increases locomotor activity but does not modify pain perception threshold. In contrast, AA increases W and reduces SWS2, while deteriorating memory consolidation and increasing locomotor activity. AA has no effect on pain perception. These results suggest that the brain cannabinoid system participates in the modulation of the vigilance states and mnemonic processes. Additionally, they suggest that the effect on pain perception may be a peripheral rather than a central effect.
Intravenous administration of the cannabinoid CB(1) receptor agonists (R-(+)-[2, 3-Dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1, 4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), WIN 55,212-2 (10, 37.5, 75 and 150 microg/kg), and ((6aR)-trans-3-(1, 1-Dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol), HU 210 (1 and 4 microg/kg) dose-dependently increased acetylcholine release in dialysates from the prefrontal cortex and the hippocampus of freely moving rats. Administration of the cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide]HCl, SR 141716A, at a dose that per se did not affect basal acetylcholine release (2. 5 microg/kg), prevented the increase of acetylcholine release by WIN 55,212-2 (150 microg/kg i.v.) or by HU 210 (4 microg/kg i.v.) in both areas. These data demonstrate that, at low i.v. doses, the synthetic cannabinoid CB(1) receptor agonists, WIN 55,212-2 and HU 210 stimulate cortical and hippocampal acetylcholine release.
Three patients with REM behavior disorder whose nocturnal symptoms were markedly improved by treatment with the acetylcholinesterase inhibitor donepezil are reported. Donepezil may have a role in the treatment of REM behavior disorder, possibly through its actions on cholinergic pathways in the brainstem.
The authors immunocytochemically identified mesopontine cholinergic and rostral raphe serotonergic neurons in brains obtained at autopsy from four patients with multiple system atrophy (MSA) and four matched controls. There was a severe depletion of cholinergic neurons in the pedunculopontine (20 +/- 2 vs 81 +/- 10 cells/section, p< 0.001) and laterodorsal tegmental nucleus (18 +/- 3 vs 47 +/- 4 cells/section, p < 0.001) in MSA. Whereas there was also depletion of locus ceruleus neurons, there was a striking preservation of rostral raphe neurons in MSA.
Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by 6-hydroxydopamine, both in vivo and in vitro, which may be relevant to Parkinson's disease (PD). First, we evaluated whether the administration of cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of dopamine contents and a reduction of tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of delta9-tetrahydrocannabinol (delta9-THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of delta9-THC appeared to be irreversible since interruption of the daily administration of this cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same neuroprotective effect was also produced by cannabidiol (CBD), another plant-derived cannabinoid with negligible affinity for cannabinoid CB1 receptors, suggests that the antioxidant properties of both compounds, which are cannabinoid receptor-independent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether cannabinoids also provide neuroprotection against the in vitro toxicity of 6-hydroxydopamine. We found that the non-selective cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the cannabinoid was directly added to neuronal cultures than when these cultures were exposed to conditioned medium obtained from mixed glial cell cultures treated with HU-210, suggesting that the cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of cannabinoids against the in vivo and in vitro toxicity of 6-hydroxydopamine, which might be relevant for PD. Our data indicated that these neuroprotective effects might be due, among others, to the antioxidant properties of certain plant-derived cannabinoids, or exerted through the capability of cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms.
Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol (CBD) are two major constituents of Cannabis sativa. Delta(9)-THC modulates sleep, but no clear evidence on the role of CBD is available. In order to determine the effects of CBD on sleep, it was administered intracerebroventricular (icv) in a dose of 10 microg/5 microl at the beginning of either the lights-on or the lights-off period. We found that CBD administered during the lights-on period increased wakefulness (W) and decreased rapid eye movement sleep (REMS). No changes on sleep were observed during the dark phase. Icv injections of CBD (10 microg/5microl) induced an enhancement of c-Fos expression in waking-related brain areas such as hypothalamus and dorsal raphe nucleus (DRD). Microdialysis in unanesthetized rats was carried out to characterize the effects of icv administration of CBD (10 microg/5 microl) on extracellular levels of dopamine (DA) within the nucleus accumbens. CBD induced an increase in DA release. Finally, in order to test if the waking properties of CBD could be blocked by the sleep-inducing endocannabinoid anandamide (ANA), animals received ANA (10 microg/2.5 microl, icv) followed 15 min later by CBD (10 microg/2.5 microl). Results showed that the waking properties of CBD were not blocked by ANA. In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD. Both regions are apparently involved in the generation of alertness. Also, CBD increases DA levels as measured by microdialysis and HPLC procedures. Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence.
We have recently demonstrated that two plant-derived cannabinoids, Delta9-tetrahydrocannabinol and cannabidiol (CBD), are neuroprotective in an animal model of Parkinson's disease (PD), presumably because of their antioxidant properties. To further explore this issue, we examined the neuroprotective effects of a series of cannabinoid-based compounds, with more selectivity for different elements of the cannabinoid signalling system, in rats with unilateral lesions of nigrostriatal dopaminergic neurons caused by local application of 6-hydroxydopamine. We used the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 receptor agonist HU-308, the non-selective agonist WIN55,212-2, and the inhibitors of the endocannabinoid inactivation AM404 and UCM707, all of them administered i.p. Daily administration of ACEA or WIN55,212-2 did not reverse 6-hydroxydopamine-induced dopamine (DA) depletion in the lesioned side, whereas HU-308 produced a small recovery that supports a possible involvement of CB2 but not CB1 receptors. AM404 produced a marked recovery of 6-hydroxydopamine-induced DA depletion and tyrosine hydroxylase deficit in the lesioned side. Possibly, this is caused by the antioxidant properties of AM404, which are derived from the presence of a phenolic group in its structure, rather than by the capability of AM404 to block the endocannabinoid transporter, because UCM707, another transporter inhibitor devoid of antioxidant properties, did not produce the same effect. None of these effects were observed in non-lesioned contralateral structures. We also examined the timing for the effect of CBD to provide neuroprotection in this rat model of PD. We found that CBD, as expected, was able to recover 6-hydroxydopamine-induced DA depletion when it was administered immediately after the lesion, but it failed to do that when the treatment started 1 week later. In addition, the effect of CBD implied an upregulation of mRNA levels for Cu,Zn-superoxide dismutase, a key enzyme in endogenous defenses against oxidative stress. In summary, our results indicate that those cannabinoids having antioxidant cannabinoid receptor-independent properties provide neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons occurring in PD. In addition, the activation of CB2 (but not CB1) receptors, or other additional mechanisms, might also contribute to some extent to the potential of cannabinoids in this disease.