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Abstract

Over recent years, the interest in the endocannabinoid system (eCBs) as a new target for the treatment of schizophrenia has evolved. The eCBs represents one of the most relevant neurotransmitter systems in the brain and mainly fulfills a homeostatic role in terms of neurotransmission but also with respect to inflammatory processes. Two main approaches to the modulation of endocannabinoid functioning have been chosen so far. First, the selective blockade or inverse agonism of the cannabinoid CB1-receptor has been tested for the improvement of acute psychotic symptoms as well as for the improvement of cognitive functions in schizophrenia. This was not effective in either case. Second, the modulation of endocannabinoid levels by use of the phytocannabinoid cannabidiol and selective fatty acid amide hydrolase (FAAH) inhibitors has been proposed and the antipsychotic properties of cannabidiol are currently investigated in humans. Unfortunately, for most these trials that focused on psychopathological and cognitive effects of cannabidiol no published data is available. However, there is first evidence that cannabidiol may ameliorate psychotic symptoms with a superior side-effect profile compared to established antipsychotics. In conclusion, several clinical trials targeting the eCBs in acute schizophrenia have either been completed or are under way. Although publicly available results are limited by now, preliminary data indicate that selected compounds modulating the eCBs may be effective in acute schizophrenia. Nevertheless, sample sizes of patients investigated are not sufficient to come to a final judgment so far and no maintenance studies are available to ensure long-term efficacy and safety.

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... So far, there are two main approaches to the modulation of endocannabinoid functioning. The function of ECS might be modulated in a direct way, by ligands of CB (CB1 or/and CB2) receptors, or indirectly by FAAH or MAGL inhibitors [15]. Following that, this plasticity of ECS signaling opened the way to the development of drugs that counteract the action of endocannabinoids, by inhibiting their inactivation or their binding to the receptor, respectively. ...
... Naturally, the third component of the ECS system, i.e., endocannabinoids and enzymes responsible for the metabolism of endocannabinoids (FAAH and MAGL), is also important in the context of schizophrenia-like effects [15,22]. ...
... In clinical studies, this assumption was supported by several observations showing that cannabis use is associated with an increased risk of developing schizophrenia or that schizophrenia-like symptoms may develop in nonschizophrenic cannabis users [82,83]. In addition, schizophrenic patients showed both positive and negative symptoms and cognitive deficits after administration of delta-9-THC [15,84]. ...
Article
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The connection between the endocannabinoid system (ECS) and schizophrenia is supported by a large body of research. The ECS is composed of two types cannabinoid (CB: CB1 and CB2) receptors and their endogenous ligands, endocannabinoids. The best-known endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are intracellularly degraded by fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Thus, the function of ECS might be modulated in a direct way, through CB receptor ligands or indirectly by FAAH and MAGL inhibitors. We evaluated that the direct influence of ECS, using FAAH (URB 597) and MAGL (JZL 184) inhibitors, on the schizophrenia-like effects in mice. The behavioral schizophrenia-like symptoms were obtained in animals by using N-methyl D-aspartate (NMDA) receptor antagonists, MK-801. An acute administration of MK-801 (0.3 and 0.6 mg/kg) induced psychotic symptoms in rodents, manifested as the increase in locomotor activity, measured in actimeters, as well as the memory impairment, assessed in the passive avoidance (PA) task. We revealed that an acute administration of URB 597, at the dose of 0.3 mg/kg, attenuated MK-801 (0.6 mg/kg)-induced memory impairment. In turn, an acute administration of URB 597 at a higher dose (1 mg/kg) potentiated MK-801 (0.3 mg/kg)-induced memory impairment. Similarly, an acute administration of JZL 184 (20 and 40 mg/kg) intensified an amnestic effect of MK-801 (0.3 mg/kg). Moreover, an acute injection of JZL 184 (1 mg/kg) potentiated hyperlocomotion is provoked by MK-801 (0.3 and 0.6 mg/kg) administration. The present findings clearly indicate that ECS, through an indirect manner, modulates a variety of schizophrenia-like responses in mice.
... Future studies should use consistent outcome variables (e.g., assessment of abstinence) and treatments (manualized CBT/relapse prevention) in order to provide comparable findings. Psychoses/Schizophrenia (F20 ICD-10) Two systematic reviews [45,90] of 6 RCTs [13,15,46,55,74,81] and two new RCTs [16,51] were found (n = 887 participants). In the studies of Leweke and colleagues individuals with psychosis received CBD (800 mg/day, 4 weeks) [46] or CBD (600 mg/day, 2 weeks) [81]. ...
... Overall, CBD was well tolerated with no worsening of mood, suicidality or movement side effects. Leweke et al. [45] (LoE: 2; ROBIS: high) included 3 further published double-blind RCTs (of unclear risk of bias). The interventions were Rimonabant [15,55] and drinabant (AVE1625) [74] compared to placebo (n = 3). ...
... The two CB1R antagonists/inverse agonists tested in schizophrenia had no significant effects on psychopathology and cognition. Rimonabant and drinabant (AVE1625) were withdrawn from worldwide marketing due to psychiatric side effects [45]. Altogether, cannabidiol plus existing antipsychotic medication showed beneficial effects. ...
Article
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We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006—August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.
... In recent years there have been many publications on the efficacy of medical cannabis in treating mental disorders. These include Tourette's syndrome [69,70], anorexia nervosa [71], dementia [72][73][74], PTSD [75], opioid [76][77][78] and cannabinoid [79,80] dependence syndromes, trichotillomania [81], social phobia [82], psychosis/schizophrenia [83][84][85] and ADHD [86]. wywołują mniej działań niepożądanych w porównaniu z (S)-ketaminą i ketaminą racemiczną [63]. ...
... fobia społeczna [82], psychoza/schizofrenia [83][84][85] i ADHD [86]. Leki stosowane w badaniach klinicznych podzielono na cztery grupy ze względu na mechanizm działania -agoniści receptora CB1: dronabinol, nabilon, nabiksimol, THC; antagoniści receptora CB1 lub jego odwrotni agoniści: rimonabant, drinabant; modulator kannabinoidów: kannabidiol oraz pozostałe kannabinoidy [66]. ...
Article
Research on the use of psychoactive substances in mental disorder treatment has become increasingly important over the last 50 years. Numerous publications suggest their effectiveness in the treatment of many diseases, including depression and anxiety disorders, PTSD, psychoactive substance dependence, ADHD and Tourette’s Syndrome. Particularly noteworthy is the use of psychedelics such as psilocybin and LSD in the treatment of anxiety and depression associated with terminal diseases as they do not have the adverse effects that often occur in the course of standard treatment with classical antidepressants and antipsychotics. These may include extrapyramidal syndrome, dyskinesia and sexual, endocrine or metabolic disorders. Their significant advantage is the immediate therapeutic effect of, for example, esketamine or LSD. During standard treatment with antidepressants, the expected effect is usually achieved after many weeks of use, which may reduce therapeutic adherence and discourage continuation of the treatment. This article provides a review of the literature on the treatment of mental disorders with psychoactive substances. The publication discusses aspects like the mechanism of action, potential uses and side effects of substances from the groups of classic psychedelics, empathogens, cannabinoids, stimulants and dissociants. Some of the psychoactive substances in question have gained hard evidence of their effectiveness in the treatment of mental disorders. Ketamine is a substance whose scientifically proven effectiveness in the treatment of depressive disorders has resulted in its introduction to the market as a new form of depression treatment.
... THC can cause intoxication [4,5] and has antiemetic, analgesic, and potentially neuroprotective and anti-inflammatory effects. On the other hand, CBD is nonintoxicating [5,6] with antiepileptic and potentially also anti-inflammatory, neuroprotective, antioxidant, and antipsychotic effects [7][8][9]. While several trials have used these cannabinoids for a wide range of diseases and indications, a majority of these have investigated younger people [10,11]. ...
... Existing meta-analytic investigations [16,17] have generally considered all CBMs together, irrespective of whether they included THC, CBD, or THC:CBD in combination. However, THC can cause intoxication and may induce anxiety and transient psychotomimetic effects [5], especially at higher doses and in vulnerable individuals, while CBD does not cause intoxication when directly compared in the same individuals [5] and may potentially ameliorate anxiety and psychosis [9,[22][23][24]. FurtherAU : PleaseconfirmwhethertheeditstothesentenceFurther; thereisgr , there is growing evidence that THC and CBD may have opposing acute effects on autonomic arousal and brain [15] and cardiovascular function [25,26], and CBD may mitigate some of the harmful effects of THC on cognition and behaviour [15,27,28], consistent with their opposing effects on some of their molecular targets [4]. ...
Article
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Background Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years. Methods and findings A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those <50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies. Conclusions This pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.
... Early case series [20,21] highlighted the potential antipsychotic effects of CBD. More recently, preliminary data provided initial evidence that CBD may improve psychotic symptoms, while also possibly being better tolerated than standard antipsychotic medications [22,23]. It seems that, as compared with THC, CBD may have antipsychotic and anxiolytic properties, without detrimental effects on cognition [24]. ...
... It has been hypothe-sized that cannabis use might have an impact on mental health, altering endocannabinoid signaling in the central nervous systems of individuals suffering from schizophrenia [48]. On the other hand, CBD, inhibiting the enzyme fatty acid amide hydrolase, may in turn enhance anandamide signaling [22]. Consistently, an association between the increase in anandamide blood levels and the decrease in psychotic symptoms in subjects treated with CBD has been reported [38]. ...
Article
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Although cannabis’ major psychoactive component, Δ-9-tetrahydrocannabinol (THC), has been linked to both earlier onset and poorer outcomes of psychotic disorders, Cannabidiol (CBD) seems to have different pharmacological mechanisms and potential therapeutic properties. However, no clinical study has investigated CBD for the treatment of co-occurring psychotic and cannabis use disorders so far, even though its utility seems grounded in a plausible biological basis. The aim of this work is thus to provide an overview of available clinical studies evaluating the efficacy of CBD for psychotic symptoms induced by THC, schizophrenia, and cannabis use disorders. After searching for relevant studies in PubMed, Cochrane Library, and ClinicalTrials.gov, we included 10 clinical studies. Available evidence suggests that CBD may attenuate both psychotic-like symptoms induced by THC in healthy volunteers and positive symptoms in individuals with schizophrenia. In addition, preliminary data on the efficacy of CBD for cannabis use disorders show mixed findings. Evidence from ongoing clinical studies will provide insight into the possible role of CBD for treating psychotic and cannabis use disorders.
... In some of the trials evaluated, the use of cannabinoids was found, in addition to alleviating the symptoms of the diseases being targeted, to also improve the quality of sleep in clinical subjects by reducing sleep disturbance episodes and reducing the onset of sleep latency [47]. Preliminary data from some of the clinical trials have indicated that the use of CBD can alleviate the symptoms of acute schizophrenia [48], and the use of THC and/or CBD is thought to potentially reduce chronic pain in some patients and may require further trials for confirmation [49]. For example, THC/CBD extracts have been shown to provide pain relief in some patients with advanced cancer whose pains had not been successfully relieved by opioid pain killers [50]. ...
... A number of studies support the notion that cannabinoids could potentially enhance the immune response, thereby preventing growth and spread of tumors. An in vivo melanoma xenograft model showed that the activity of WIN 55,212-2 promotes tumor regression efficiently in the immunocompetent mice against immunodeficiency [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58]. Another study showed that CBD, THC, and R(+)-methanandamide make lung cancer cell susceptible to lysis by lymphokine killer cells [59]. ...
Article
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Melanoma is the fourth most common type of cancer diagnosed in Australians after breast, prostate, and colorectal cancers. While there has been substantial progress in the treatment of cancer in general, malignant melanoma, in particular, is resistant to existing medical therapies requiring an urgent need to develop effective treatments with lesser side effects. Several studies have shown that “cannabinoids”, the major compounds of the Cannabis sativaL. plant, can reduce cell proliferation and induce apoptosis in melanoma cells. Despite prohibited use of Cannabis in most parts of the world, in recent years there have been renewed interests in exploiting the beneficial health effects of the Cannabis plant-derived compounds. Therefore, the aim of this study was in the first instance to review the evidence from in vivo studies on the effects of cannabinoids on melanoma. Systematic searches were carried out in PubMed, Embase, Scopus, and ProQuest Central databases for relevant articles published from inception. From a total of 622 potential studies, six in vivo studies assessing the use of cannabinoids for treatment of melanoma were deemed eligible for the final analysis. The findings revealed cannabinoids, individually or combined, reduced tumor growth and promoted apoptosis and autophagy in melanoma cells. Further preclinical and animal studies are required to determine the underlying mechanisms of cannabinoids-mediated inhibition of cancer-signaling pathways. Well-structured, randomized clinical studies on cannabinoid use in melanoma patients would also be required prior to cannabinoids becoming a viable and recognized therapeutic option for melanoma treatment in patients.
... In addition, among other known benefits, CBD also acts as an anti-psychotic, anti-nausea, neuroprotective, anti-cancer and anti-diabetic agent, all without causing overly strong side effects (Aizpurua-olaizola et al., 2016;Rock et al., 2011). There is evidence that CBD has the potential to be exploited in the treatment and relief of various symptoms associated with neurological disorders such as epilepsy and seizures (Hofmann dan Frazier, 2013;Jones et al., 2010), psychosis (Leweke et al., 2016), anxiety (Bergamaschi et al., 2011) and movement disorders (for example, Huntington's disease and amyotrophic lateral sclerosis) (De Lago and Fernandez-Ruiz, 2007;Luvone et al., 2009). Meanwhile migraine, gastritis, allergies, back pain and asthma are common diseases/symptoms that are commonly treated with hemp (Ware et al., 2005). ...
Article
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Hemp is considered a cannabis species with significant health benefits. There is growing evidence that hemp (Cannabis Sativa L.) can be used as a therapy for neurological disorders, autism, depression, Parkinson's disease, and cancer. The Dangerous Drugs Act 1952, however, prohibits cannabis cultivation, production, distribution, import, export, possession, and abuse in Malaysia. The purpose of this study is to examine the Islamic legal perspective surrounding cannabis cultivation, which has been extensively discussed in recent years, particularly in terms of benefits to health and medical conditions. It will then examine the basics of the need for planting the tree in the context of the Maqasid Shari’ah perspective with special concentration on the principle of maslahah (benefits) and mafsadah(harmful). Based on qualitative research, content analysis is adopted to obtain the views of fuqaha regarding the law of cultivation of hasyish (marijuana), khasykhasy (poppy), tabgh (tobacco), as well as relevant current fatwas from several legal institutions. This study recommends that it is extremely pertinent to consider the provisions of National Law when determining the law at present along with the reflection derived from the maslahah and mafsadah devine principles. These findings indicate that hemp species are pure and clean, and are not considered impurities. To make cultivation permissible, however, specific and comprehensive guidelines are needed to ensure the consumption and use of hemp is not abusive and to prevent the consumption of harmful effects for society at large. Researchers believe this is the first academic study on the hem position since it has never been discussed before. Further research could be conducted in the future regarding the specific requirements to be included in the proposed guideline for hemp cultivation and consumption. Taking into account Islamic rulings while simultaneously taking into consideration of technical and legal aspects is crucial to achieving a holistic approach to dealing with the legality of hemp. Keywords: Hemp Cultivation, Cannabis, Islamic Perspective, Maqasid Shari’ah, Medical Needs.
... Responses toward molecular SSD targets of interest derived from these phospholipid precursors (Figure 1) were also observed. These included regulators of the ECS-a promising pathway for therapeutic intervention (104), as well as AA and AAderived eicosanoids whose effects on inflammatory response are well-established in SSD, with evidence to suggest that decreasing these inflammatory biomarkers may improve clinical outcome (105). ...
Article
Full-text available
Schizophrenia spectrum disorders (SSD) are traditionally diagnosed and categorized through clinical assessment, owing to their complex heterogeneity and an insufficient understanding of their underlying pathology. However, disease progression and accurate clinical diagnosis become problematic when differentiating shared aspects amongst mental health conditions. Hence, there is a need for widely accessible biomarkers to identify and track the neurobiological and pathophysiological development of mental health conditions, including SSD. High-throughput omics applications involving the use of liquid chromatography-mass spectrometry (LC-MS) are driving a surge in biological data generation, providing systems-level insight into physiological and pathogenic conditions. Lipidomics is an emerging subset of metabolomics, largely underexplored amongst the omics systems. Lipid profiles in the brain are highly enriched with well-established functions, including maintenance, support, and signal transduction of neuronal signaling pathways, making them a prospective and exciting source of biological material for neuropsychiatric research. Importantly, changes in the lipid composition of the brain appear to extend into the periphery, as there is evidence that circulating lipid alterations correlate with alterations of psychiatric condition(s). The relative accessibility of fluid lipids offers a unique source to acquire a lipidomic “footprint” of molecular changes, which may support reliable diagnostics even at early disease stages, prediction of treatment response and monitoring of treatment success (theranostics). Here, we summarize the latest fluid lipidomics discoveries in SSD-related research, examining the latest strategies to integrate information into multi-systems overviews that generate new perspectives of SSD-related psychosis identification, development, and treatment.
... 30,31 The lipophilic nature of these eCBs and NAEs also allows them to modulate and readily cross the blood-brain barrier, 32-34 making them promising biomarker candidates and therapeutic targets. 35,36 Quantification of eCBs and NAEs relies on mass spectrometry as their concentrations are often found at trace levels under physiological conditions, making their detection difficult. 37 Liquid chromatographytandem mass spectrometry (LC-MS/MS) with collisioninduced dissociation (CID) is conventional for their analysis, as the additional structural information obtained from CID fragment ions can be used for selective reaction monitoring and multiple reaction monitoring (MRM) to improve sensitivity and reduce background interference. ...
Article
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Introduction: The primary compounds of Cannabis sativa, delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), inflict a direct influence on the endocannabinoid system-a complex lipid signaling network with a central role in neurotransmission and control of inhibitory and excitatory synapses. These phytocannabinoids often interact with endogenously produced endocannabinoids (eCBs), as well as their structurally related N-acylethanolamines (NAEs), to drive neurobiological, nociceptive, and inflammatory responses. Identifying and quantifying changes in these lipid neuromodulators can be challenging owing to their low abundance in complex matrices. Materials and Methods: This article describes a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the extraction and quantification of the eCBs anandamide and 2-arachidonoylglycerol, along with their congener NAEs oleoylethanolamine and palmitoylethanolamine, and phytocannabinoids CBD, Δ9-THC, and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol, a major metabolite of Δ9-THC. Our method was applied to explore pharmacokinetic and pharmacodynamic effects from intraperitoneal injections of Δ9-THC and CBD on circulating levels of eCBs and NAEs in rodent serum. Results: Detection limits ranged from low nanomolar to picomolar in concentration for eCBs (0.012-0.24 pmol/mL), NAEs (0.059 pmol/mL), and phytocannabinoids (0.24-0.73 pmol/mL). Our method displayed good linearity for calibration curves of all analytes (R2>0.99) as well as acceptable accuracy and precision, with quality controls not deviating >15% from their nominal value. Our LC-MS/MS method reliably identified changes to these endogenous lipid mediators that followed a causal relationship, which was dependent on both the type of phytocannabinoid administered and its pharmaceutical preparation. Conclusion: We present a rapid and reliable method for the simultaneous quantification of phytocannabinoids, eCBs, and NAEs in serum using LC-MS/MS. The accuracy and sensitivity of our assay infer it can routinely monitor endogenous levels of these lipid neuromodulators in serum and their response to external stimuli, including cannabimimetic agents.
... Cannabidiol (CBD), a cannabinoid that does not cause the euphoric "high" associated with THC, is a potential treatment for psychosis. [43][44][45] Preliminary data from RCTs suggest that CBD as monotherapy 46 or as an augmentation strategy to conventional antipsychotics 47 may decrease positive symptoms and improve cognition. However, other studies have not demonstrated any beneficial effect of adding CBD to an antipsychotic regimen. ...
Article
Amidst a rapidly changing legal landscape, cannabis use in the United States has become increasingly common in the past several years. There is strong evidence to suggest that chronic and early cannabis use increases the risk of developing a psychotic disorder, and there is at least moderate evidence that suggests ongoing cannabis use among individuals with a psychotic disorder worsens clinical outcomes (eg, decreased psychiatric medication adherence, more frequent psychiatric hospitalizations). In this Review Article, we provide a focused, clinically oriented overview of the epidemiology and characteristics of cannabis use among individuals with first-episode psychosis; evaluation of cannabis use; and treatment modalities, focusing on behavioral interventions suitable for outpatient primary care settings. We discuss the limited data supporting pharmacologic interventions for cannabis use disorder, specifically among individuals with first-episode psychosis, and the unique potential of cannabidiol to serve as a harm-reduction strategy for individuals who are not able or willing to achieve abstinence for cannabis.
... Some studies reported that CBD has a potentially beneficial, symptom-reducing effect on psychotic disorders [43,44], while others found CBD to have moderate-to-no reduction effects on psychotic experiences within acute psychosis [45][46][47]. ...
Article
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The rising popularity of medical marijuana and its potential therapeutic uses has resulted in passionate discussions that have mainly focused on its possible benefits and applications. Although the concept itself seems promising, the multitude of presented information has noticeable ramifications-terminological chaos being one. This work aimed to synthesize and critically analyze scientific evidence on the therapeutic uses of cannabinoids in the field of psychiatry. Emphasis was placed on the anxiolytic effects of cannabis constituents and their effects on post-traumatic stress disorder, anxiety disorders, schizophrenia spectrum, and other psychotic disorders. The review was carried out from an addictological perspective. A database search of interchangeably combined keywords resulted in the identification of subject-related records. The data were then analyzed in terms of relevance, contents, methodologies, and cited papers. The results were clear in supporting one common conclusion: while most findings provide support for beneficial applications of medical marijuana in psychiatry, no certain conclusions can be drawn until larger-scaled, more methodo-logically rigorous, and (preferably) controlled randomized trials verify these discoveries.
... 1 case in 2,800 heavy cannabis users ages 20-24 (the highest risk group), and 1 case in 10,000 light cannabis users in the same age group (Ksir & Hart, 2016). Furthermore, recent research has shown CBD can be very effective in treating the symptoms of schizophrenia: one RCT showed 1000 mg/d CBD improved symptoms of schizophrenia in 79% of patients using over 6 weeks, and other RCTs showed 200-800 mg/d CBD was more effective than amisulpride at reducing symptom severity with fewer extrapyramidal side effects (Gururajan & Malone, 2016;Leweke, Mueller, Lange, & Rohleder, 2016;McGuire et al., 2018). Again, this highlights how careful selection of dose and ratio are key to avoiding bidirectional effects with cannabis, especially in those with more severe mental health issues. ...
Article
Medical Cannabis is receiving renewed interest in clinical practice due to the gradual increase over the last few decades of cannabis legalization and high-quality research on the potential benefits of cannabis for treating a variety of conditions (NASEM, 2017; Nursing Care of the Patient, 2018). However, the pace of medical cannabis legalization and research are outpacing the training for medical providers, leaving gaps in their confidence and ability to safely guide patients using medical cannabis (NCSBN, 2018). Medical providers are increasingly fielding questions from patients regarding the use of medical cannabis for conditions commonly seen in clinical practice, but many are uncertain of if and how they should guide patients on this use. The aim of this research is two-fold: to assess current barriers to medical providers discussing medical cannabis with their patients; and to assess the impact a one-hour educational presentation can have on addressing these barriers and increasing the likelihood of providers engaging in discussions. Though the results of this research may be limited by the small sample size surveyed, they could highlight barriers present in clinical practice and indicate possible areas for future research in expanding cannabis education for medical providers.
... Clinical studies have shown that cannabidiol (CBD), a nonaddictive cannabis compound, ameliorates schizophrenia symptoms (Leweke et al., 2012;Leweke et al., 2016;Rohleder et al., 2016;McGuire et al., 2018). Several experimental studies support the anti-psychotic properties of CBD by investigating its potential to counteract/reverse behavioral and neurobiological abnormalities that mirror psychosis and schizophrenia (Long et al., 2012;Rohleder et al., 2016;Osborne et al., 2017;Hudson et al., 2019;Rodrigues da Silva et al., 2020). ...
Article
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Clinical evidence and experimental studies have shown the psychotomimetic properties induced by ketamine. Moreover, acute or chronic ketamine (KET) administration has been widely used for modeling schizophrenia-like symptomatology and pathophysiology. Several studies have reported the antipsychotic potential of cannabidiol (CBD), while there is limited information on the cannabidiol effect on KET-induced schizophrenia-like impairments. Therefore, the goal of the present study was to evaluate neuroplastic changes induced by repeated KET administration, which is used as an experimental model of schizophrenia—with a behavioral focus on positive-like symptomatology– and to assess the modulatory role of CBD treatment. The present findings have shown a robust increase in motor activity in KET-treated rats, following a 10-day period of chronic administration at the sub-anesthetic dose of 30 mg/kg (i.p), that was reversed to normal by subsequent chronic CBD treatment. Concerning the expression of glutamate receptors, the current findings have shown region-dependent KET-induced constitutional alterations in NMDA and AMPA receptors that were modified by subsequent CBD treatment. Additionally, repeated KET administration increased ERK1/2 phosphorylation state in all regions examined, apart from the ventral hippocampus that was modulated by subsequent CBD treatment. The present results show, for the first time, a stimulated motor output coupled with a specific glutamatergic-related status and ERK1/2 activation following chronic KET administration that were attenuated by CBD treatment, in a region-dependent manner. These findings provide novel information concerning the antipsychotic potential of CBD using a specific design of chronic KET administration, thus contributing to experimental approaches that mirror the symptomatology and pathophysiology of schizophrenia.
... The cannabinoid receptors are part of the endocannabinoid system, which is also comprised of endogenous cannabinoids and several enzymes which control synthesis and degradation of the endocannabinoids [11]. CBD indirectly affects the endocannabinoid system by impairing the degradation of anandamide (endogenous cannabinoid ligand), which modulates and stabilizes several neurotransmitter systems including the dopaminergic, glutamatergic and GABAergic system [15,16]. Due to this globally stabilizing effect, CBD theoretically has the potential to reduce craving for cannabis. ...
Article
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Background Cannabis use is an important risk factor for development of psychosis and further transition to schizophrenia. The prevalence of patients with psychosis and comorbid cannabis use (dual diagnosis) is rising with no approved specialized pharmacological treatment option. Cannabidiol, a constituent of the Cannabis sativa plant, has potential both as an antipsychotic and as a cannabis substituting agent. The aim of this study is to evaluate the efficacy of cannabidiol versus a first-choice second-generation antipsychotic (risperidone) in patients with early psychosis and comorbid cannabis use. Methods The study is a phase II randomized, double-blinded, parallel-group, active-comparator clinical trial. We plan to include 130 patients aged between 18 and 64 years with a recent diagnosis of psychosis, comorbid cannabis use, and currently not treated with antipsychotics. The participants will be randomized to seven weeks of treatment with either cannabidiol 600 mg (300 mg BID) or risperidone 4 mg (2 mg BID). Participants will undergo clinical assessment after 1, 3, 5 and 7 weeks, telephone assessment the weeks in between, and a safety visit two weeks after end of treatment. The primary outcomes are cessation of cannabis use (self-reported) and psychotic symptom severity. The secondary outcomes include frequency and quantity of cannabis use, global illness severity, psychosocial functioning, subjective well-being, cognition, sleep, circadian rhythmicity, and metabolomics. Discussion The results of this trial can potentially contribute with a new treatment paradigm for patients suffering from dual diagnosis. Trial registration ClinicalTrials.gov , NCT04105231 , registered April 23rd, 2021
... Neuroimaging studies measuring in vivo CB1 receptor availability in schizophrenia patients reported a widespread increase in levels of CB1 receptors, including the nucleus accumbens, insula, cingulate cortex, inferior frontal cortex, parietal cortex, mediotemporal lobe and pons (Ceccarini et al., 2013;Wong et al., 2010). The endocannabinoid system is also one of the most important neurotransmitter systems in the brain that mainly fulfils a homeostatic role by modulating other neurotransmitter systems and processes related to inflammation (Leweke et al., 2016). Specifically, the upregulation of anandamide (Leweke, 2012) and an increase in CB1 receptor availability (Ceccarini et al., 2013) may have a therapeutic and potentially even protective effect on positive psychotic symptoms. ...
Article
Background No biological treatment has been firmly established for the at-risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non-psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra-high risk (UHR) for psychosis group. Methods Three-arm randomized controlled trial of 405 patients (135 per arm) aged 12–25 years who meet UHR for psychosis criteria. The study includes a 6-week lead-in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At-Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained. Conclusion This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder.
... The results from basic and clinical studies suggested that CBD may present beneficial effects for the management of neurological disorders such as epilepsy (Carlini and Cunha, 1981;Devinsky et al., 2014;Devinsky et al., 2016), multiple sclerosis (Kozela et al., 2011;Giacoppo et al., 2015;Jones and Vlachou, 2020), Parkinson's (Zuardi et al., 2009;Chagas et al., 2014) or Alzheimer's diseases (Martín-Moreno et al., 2011;Cheng et al., 2014). Moreover, there is a growing body of evidence suggesting that CBD improves cognition (Osborne et al., 2016) and neurogenesis (Liput et al., 2013;Schiavon et al., 2016), and presents antipsychotic (Zuardi et al., 1991;Moreira and Guimarães, 2005;Long et al., 2006;Leweke et al., 2012;Leweke et al., 2016;Peres et al., 2016), anxiolytic (Guimarães et al., 1990;Moreira et al., 2006;Resstel et al., 2006;Blessing et al., 2015) and antidepressant-like effects (Zanelati et al., 2010;Linge et al., 2016;Sartim et al., 2016). All these potential therapeutic actions of CBD are due to its multiple pharmacological mechanisms. ...
Article
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Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson’s, or Alzheimer’s diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the ‘anti-addictive’ action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD endorse the relevance of this review.
... It is thought to play a critical role in regulating glutamatergic signalling, modulating NMDA receptor activity in order to prevent excitotoxicity (Sanchez-Blazquez et al., 2014). The endocannabinoid system has also been strongly implicated in the pathophysiology of psychosis in both clinical and pre-clinical studies (Appiah-Kusi et al., 2016;Bhattacharyya et al., 2012b;Bossong et al., 2014;Dalton et al., 2011;D'Souza et al., 2004;Leweke et al., 2016;Muguruza et al., 2013). It follows that aberrant activity of the endocannabinoid system resulting in NMDA receptor hypofunction could support the glutamatergic model of psychosis (Sanchez-Blazquez et al., 2014). ...
Article
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Background Emerging evidence supports the antipsychotic effect of cannabidiol, a non-intoxicating component of cannabis, in people with psychosis. Preclinical findings suggest that this antipsychotic effect may be related to cannabidiol modulating glutamatergic signalling in the brain. Aim The purpose of this study was to investigate the effects of cannabidiol on the neurochemical mechanisms underlying psychosis. Methods We investigated the effects of a single oral dose of cannabidiol (600 mg) in patients with psychosis, using a double-blind, randomised, placebo-controlled, repeated-measures, within-subject cross-over design. After drug administration, 13 patients were scanned using proton magnetic resonance spectroscopy to measure left hippocampal glutamate levels. Symptom severity was rated using the Positive and Negative Syndrome Scale 60 min before drug administration (pre-scan), and 270 min after drug administration (post-scan). Effects of cannabidiol on hippocampal glutamate levels, symptom severity, and correlations between hippocampal glutamate and symptoms were investigated. Results Compared to placebo, there was a significant increase in hippocampal glutamate ( p=0.035), and a significantly greater decrease in symptom severity ( p=0.032) in the psychosis patients under cannabidiol treatment. There was also a significant negative relationship between post-treatment total Positive and Negative Syndrome Scale score and hippocampal glutamate ( p=0.047), when baseline Positive and Negative Syndrome Scale score, treatment (cannabidiol vs placebo), and interaction between treatment and glutamate levels were controlled for. Conclusions These findings may suggest a link between the increase in glutamate levels and concomitant decrease in symptom severity under cannabidiol treatment observed in psychosis patients. Furthermore, the findings provide novel insight into the potential neurochemical mechanisms underlying the antipsychotic effects of cannabidiol.
... Several factors may have led to the disparate results obtained via the different methods, including condition of the protein, location of the receptor, or specificity of the antibody or radioligand for the receptor (Jenko et al. 2012). Nevertheless, existing evidence generally tends to suggest that endocannabinoid dysfunction may be linked to the pathophysiology of psychotic disorders such as schizophrenia (Leweke et al. 1999a;Leweke et al. 2016;Ranganathan et al. 2016). ...
Article
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Background Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. Aims We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. Methods This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis Results There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. Conclusions There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.
... As a result, it is described as an agonist-PAM (i.e., ago-PAM) of CB1R . Unlike orthosteric agonists that bind an identical site on their receptor to the endogenous ligand, PAMs binds to a separate site(s), which increases the receptor's affinity for orthosteric ligands as well as the potency and/ or efficacy of that receptor's signaling (Leweke et al. 2016;Laprairie et al. 2017). Thus, CB1R PAMs have significant advantages over CB1R agonists such as THC because they enhance endogenous cannabinoid tone rather than directly activating their receptors, thereby limiting potential for ontarget adverse effects associated with supraphysiological activation, and limiting desensitizing and tolerance-inducing effects associated with direct activation (Wootten et al. 2013). ...
Article
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Rationale Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. Objectives This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆⁹-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. Methods The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. Results GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3–3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. Conclusion Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.
... In contrast to THC, as mentioned in the introduction, CBD may in fact provide an opposing effect to THC albeit more research into this mechanism is required. Additional effects include the inhibition of anandamide breakdown via fatty acid amide hydrolase (FAAH) blocking effects, and anti-inflammatory effects [97,98]. ...
Article
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Background: Medicinal cannabis has received increased research attention over recent years due to loosening global regulatory changes. Medicinal cannabis has been reported to have potential efficacy in reducing pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and intractable childhood epilepsy. Yet its potential application in the field of psychiatry is lesser known. Methods: The first clinically-focused systematic review on the emerging medical application of cannabis across all major psychiatric disorders was conducted. Current evidence regarding whole plant formulations and plant-derived cannabinoid isolates in mood, anxiety, sleep, psychotic disorders and attention deficit/hyperactivity disorder (ADHD) is discussed; while also detailing clinical prescription considerations (including pharmacogenomics), occupational and public health elements, and future research recommendations. The systematic review of the literature was conducted during 2019, assessing the data from all case studies and clinical trials involving medicinal cannabis or plant-derived isolates for all major psychiatric disorders (neurological conditions and pain were omitted). Results: The present evidence in the emerging field of cannabinoid therapeutics in psychiatry is nascent, and thereby it is currently premature to recommend cannabinoid-based interventions. Isolated positive studies have, however, revealed tentative support for cannabinoids (namely cannabidiol; CBD) for reducing social anxiety; with mixed (mainly positive) evidence for adjunctive use in schizophrenia. Case studies suggest that medicinal cannabis may be beneficial for improving sleep and post-traumatic stress disorder, however evidence is currently weak. Preliminary research findings indicate no benefit for depression from high delta-9 tetrahydrocannabinol (THC) therapeutics, or for CBD in mania. One isolated study indicates some potential efficacy for an oral cannabinoid/terpene combination in ADHD. Clinical prescriptive consideration involves caution in the use of high-THC formulations (avoidance in youth, and in people with anxiety or psychotic disorders), gradual titration, regular assessment, and caution in cardiovascular and respiratory disorders, pregnancy and breast-feeding. Conclusions: There is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.
... Especially drug-drug interactions precipitated by CBD have gained interest as CBD is being employed in the treatment of refractory epilepsia [29,30]. There is further evidence for CBDs efficacy as an antipsychotic [31][32][33][34] and its usefulness in the treatment of non-motor symptoms in Parkinson's disease [35]. CYP3A4 inhibition by CBD may explain the increased buprenorphine levels observed. ...
Article
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Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug-drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring.
... Interestingly enough, the pharmaceutical version of delta 9-THC, dronabinol, was used in a small case-study of six patients with treatment-resistant schizophrenia. Of the six patients, four responded positively to a dose of 20mg dronabinol per day (Leweke et al., 2016). ...
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Implications for cannabis use and mental health treatments and potential negative effects.
... 5 It reduces anxiety levels in patients with social phobia, 6 and recent data indicate that modulation of the endocannabinoid system may have antipsychotic effects in schizophrenia. 4,7 Pharmacokinetics of CBD indicate that the most common adverse effects are pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior 8 ; still mostly, they show fewer adverse effects compared with standard treatments. 4 Interactions were most likely related to CBD inhibition of cytochrome P450 subtype 2C19. ...
... However, evidence from other PET and post-mortem studies has not always been consistent (Wong et al., 2010;Ceccarini et al., 2013), potentially due to methodological differences between studies. Nevertheless, existing evidence reviewed above suggests that eCB dysfunction may be linked to the pathophysiology of psychotic disorders such as schizophrenia (Leweke et al., 2016;Ranganathan et al., 2016). Therefore, the objective of the present study was to investigate whether established risk factors of psychosis are associated with evidence of eCB dysfunction as indexed by eCB levels in peripheral blood. ...
Article
Background Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis. Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder. We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels. Method We compared 33 CHR participants with 58 healthy controls (HC) and collected information about previous exposure to childhood trauma as well as plasma samples to analyse endocannabinoid levels. Results Individuals with both CHR and experience of childhood trauma had higher N- palmitoylethanolamine ( p < 0.001) and anandamide ( p < 0.001) levels in peripheral blood compared to HC and those with no childhood trauma. There was also a significant correlation between N- palmitoylethanolamine levels and symptoms as well as childhood trauma. Conclusions Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis.
... CBD may restore an imbalance in the eCB system, which may result in clinical improvement. Although previous excellent reviews (e.g., [37,48,49]) described the potential of CBD as a treatment for psychosis and SUD, this review provides a detailed and up-to-date systematic literature overview of clinical studies that investigated the efficacy of CBD treatment for schizophrenia and/or SUD. In addition, this review examined whether there are specific subgroup of patients with schizophrenia, SUD, or both that may benefit the most from CBD treatment. ...
Article
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The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the efficacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.
... The cannabinoid system involves two types of cannabinoid receptors (CB1 and CB2 receptors), and it acts a crucial neuromodulator in the central nervous system (CNS) (Colizzi et al., 2016;Curran et al., 2016;Leweke et al., 2016). Furthermore, synthetic cannabinoids have been related with psychosis and psychosis-like conditions (van Amsterdam et al., 2015), and exogenous cannabinoid agonists, administered during adolescence to rodents or nonhuman primates, produce a schizophrenia-like phenotype in adulthood (Rubino et al., 2009;Cass et al., 2014;Verrico et al., 2014;Aguilar et al., 2018). ...
... In recent years, clinical research has focused increasingly on cannabidiol (CBD), the second most significant plant-derived cannabinoid, after Δ 9 -tetrahydrocannabinol (Δ 9 -THC). The reason for this attention lies in the neuroprotective, antipsychotic, anti-inflammatory and anti-epileptic properties exhibited by this compound, both in animal models and human studies [1][2][3][4]. In fact, a 1:1 Δ 9 -THC/CBD combination (Sativex®/Nabiximols, GW Pharmaceuticals, UK) is currently approved in more than 20 countries for the treatment of spasticity in multiple sclerosis and is under clinical development for other applications. ...
Article
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At present, clinical interest in the plant-derived cannabinoid compound cannabidiol (CBD) is rising exponentially, since it displays multiple therapeutic properties. In addition, CBD can counteract the undesirable effects of the psychoactive cannabinoid Δ⁹-tetrahydrocannabinol (Δ⁹-THC) that hinder clinical development of cannabis-based therapies. Despite this attention, the mechanisms of CBD action and its interaction with Δ⁹-THC are still not completely elucidated. Here, by combining in vivo and complementary molecular techniques, we demonstrate for the first time that CBD blunts the Δ⁹-THC-induced cognitive impairment in an adenosine A2A receptor (A2AR)-dependent manner. Furthermore, we reveal the existence of A2AR and cannabinoid CB1 receptor (CB1R) heteromers at the presynaptic level in CA1 neurons in the hippocampus. Interestingly, our findings support a brain region-dependent A2AR-CB1R functional interplay; indeed, CBD was not capable of modifying motor functions presumably regulated by striatal A2AR/CB1R complexes, nor anxiety responses related to other brain regions. Overall, these data provide new evidence regarding the mechanisms of action of CBD and the nature of A2AR-CB1R interactions in the brain.
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Cannabis use disorder is frequent in schizophrenia patients, and it is associated with an earlier age of onset and poor schizophrenia prognosis. Serotonin 2A receptors (5-HT2AR) have been involved in psychosis and, like Akt kinase, are known to be modulated by THC. Likewise, endocannabinoid system dysregulation has been suggested in schizophrenia. The presence of these molecules in blood makes them interesting targets, as they can be evaluated in patients by a minimally invasive technique. The aim of the present study was to evaluate 5-HT2AR protein expression and the Akt functional status in platelet homogenates of subjects diagnosed with schizophrenia, cannabis use disorder, or both conditions, compared with age- and sex-matched control subjects. Additionally, endocannabinoids and pro-inflammatory interleukin-6 (IL-6) levels were also measured in the plasma of these subjects. Results showed that both platelet 5-HT2AR and the active phospho (Ser473)Akt protein expression were significantly increased in schizophrenia subjects, whereas patients with a dual diagnosis of schizophrenia and cannabis use disorder did not show significant changes. Similarly, plasma concentrations of anandamide and other lipid mediators such as PEA and DEA, as well as the pro-inflammatory IL-6, were significantly increased in schizophrenia, but not in dual subjects. Results demonstrate that schizophrenia subjects show different circulating markers pattern depending on the associated diagnosis of cannabis use disorder, supporting the hypothesis that there could be different underlying mechanisms that may explain clinical differences among these groups. Moreover, they provide the first preliminary evidence of peripherally measurable molecules of interest for bigger prospective studies in these subpopulations.
Article
Background While pharmacological treatments for positive symptoms of schizophrenia are widely used, their beneficial effect on negative symptoms, particularly social impairment, is insufficiently studied. Therefore, there is an increasing interest in preclinical research of potentially beneficial treatments, with mixed results. The current review aims to evaluate the efficacy of available treatments for social deficits in different animal models of schizophrenia. Study Design A systematic literature search generated 145 outcomes for the measures “total time” and “number” of social interactions. Standardized mean differences (SMD) and 95% confidence interval (CI) were calculated, and heterogeneity was tested using Q statistics in a random-effect meta-analytic model. Given the vast heterogeneity in effect sizes, the animal model, treatment group, and sample size were all examined as potential moderators. Study Results The results showed that in almost all models, treatment significantly improved social deficit (total time: SMD = 1.24; number: SMD = 1.1). The moderator analyses discovered significant subgroup differences across models and treatment subgroups. Perinatal and adult pharmacological models showed the most substantial influence of treatments on social deficits, reflecting relative pharmacological validity. Furthermore, atypical antipsychotic drugs had the highest SMD within each model subgroup. Conclusions Our findings indicate that the improvement in social interaction behaviors is dependent on the animal model and treatment family used. Implications for the preclinical and clinical fields are discussed.
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Authorizing and monitoring Cannabinoid-Based Medicines in advanced cancer and palliative care is not as difficult as it seems. Clinicians with a basic knowledge of the endocannabinoid system and cannabinoid pharmacology can surmise the appropriate settings where it can be introduced and, within a structured goal-setting environment, can safely initiate and monitor the use of Cannabinoid-Based Medicines, even in advanced cancer patients. Starting with a trial of approved pharmaceutical cannabinoids is recommended before attempting natural cannabis products. Cannabis comes in two main product types: dried flowers meant for inhalation and extracts meant for inhalation, oral ingestion, and other applications. The former is primarily inhaled through combustion or vaporization, while the latter is usually further transformed into other products, including edibles, oils, capsules, topical salves, suppositories, etc. Most patients will benefit from oral or oromucosal administration for baseline administration, while inhaled cannabis is reserved for breakthrough or episodic symptoms in specific clinical settings.The main active ingredients of cannabis are THC and CBD, which have their own indications, contraindications, drug interactions, and titration regimens. The three main types of cannabis product formulations include THC dominant, CBD dominant, and products with mixed THC/CBD ratios. Cannabinoid-Based Medicines is an individualized treatment, and slow titration is key in order to reduce adverse effects, particularly in frail or cannabis-naive patients. Risks of cannabis use disorder must always be kept in mind if long-term survival is expected.KeywordsDosing Microgram dosing Product Formulation Inhalation Edibles Cannabis concentrate Titration Monitoring Tolerance
Chapter
Cannabis use for cancer symptom management is increasing and is becoming part of polypharmacy that patients with advanced cancer are often subjected to. Drug-drug interactions depend in part on the schedule of administration, absorption, method of administration, the capacity of either the drug and cannabinoids to inhibit CYP enzymes (inhibitory constant) or the ability to upregulate CYP enzymes. Phytocannabinoids and endocannabinoids are both metabolized by CYP450 enzymes, though endocannabinoids also have their own specific metabolic pathways. In general, endocannabinoids influence responses to various drug classes such as antiseizure medications, antidepressants, and opioids. Both tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations in blood are dependent on dose, diet(fat), route of administration, vehicle, and disease state. The more important cannabis-induced drug interactions are largely inhibitory in nature and encountered through the CYP2C family. Other drug interactions via immunomodulatory mechanisms have been shown to reduce efficacy of check-point inhibitors and are a reminder that cannabis use should be closely monitored in cancer patients.KeywordsCytochromeCompetitiveInhibitionDrug interactionsEndocannabinoidsAnandamide2-AGFAAHMAGLCheckpoint inhibitor
Chapter
While research continues to determine the efficacy of lower-dose cannabis use for pain, nausea, and other symptoms, the therapeutic potential of higher-dose cannabis psychoactivity in cancer and palliative care remains unclear for most clinicians. However, non-ordinary states of consciousness, whether induced by meditative and religious practices or psychactive compounds, are beginning to be recognized as having therapeutic potential in multiple clinical settings, including end-of-life anxiety. With the resurgence of psychedelic-assisted psychotherapy (PAP) in medicine, it is now becoming clear that a thorough understanding of the neurocognitive effects of cannabis and other psychedelics are required if patients are to be counseled appropriately on their use. Although low-to-moderate doses of cannabis are not generally considered to produce psychedelic effects, reports dating back to the mid-nineteenth century suggest that cannabis-induced altered states of consciousness can be encountered at higher doses and are similar in nature to the effects produced by LSD or psilocybin. It has been hypothesized that traditional psychedelic compounds disrupt neural networks as a result of interactions with the 5HT2A receptor. With cannabis, this seems to also occur, likely by way of CB1-5HT2A receptor dimerization. The loosening of normal thinking processes which cannabis and psychedelics give rise to may explain why these experiences have been commonly associated with a reduction in rigid mental patterns encountered in mental health disorders such as refractory depression, PTSD, or death anxiety. Since high doses of THC-rich cannabis products are usually required to achieve these states, its use may be limited by dose-related psychiatric or cardiovascular side effects, such as hypotension and tachycardia. While proper knowledge of major cannabinoid pharmacology is required for dealing with low-dose cannabis dosage ranges, higher-dose cannabis use requires additional preparation with an appropriate set, setting, and effective integration for patients who wish to explore the possible benefits of these effects.KeywordsPsychoactivityPsychedelic5HT2A receptorNeuroplasticityDefault mode networkSalience networkCentral executive networkOceanic boundlessnessMystical experiencePeak experiencePsychedelic-assisted psychotherapy (PAP)
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The canonical endocannabinoid system (ECS) was originally considered to contain two receptors, CB1 and CB2, and two ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Five enzymes were then discovered to be responsible for the biosynthesis of these ligands: N-acyl phosphatidylethanolamine phospholipase D (NAPE-PD), diacylglycerol lipase-alpha and-beta (DAGLs) for the synthesis of endocannabinoids, and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for the catabolism of AEA and 2-AG, respectively. However, the original conception of the endocannabinoid system has turned out to be too simplistic. Heterodimers of CB1/CB2 and more recently identified non-canonical receptors are described as having distinctly different signaling compared with monomers. Certain cannabinoids are not direct agonists but act as allosteric modulators of receptors which may be positive or negative. There are now several orphan receptors which have been determined to interact with cannabinoids, including GPR3, GPR6, GPR12, GPR18, GPR55, and GPR119. It has been therefore proposed to name this expanded endocannabinoid system the endocannabinoidome, which would better reflect the multisystem influence of cannabinoids and endocannabinoid system modulators.KeywordsEndocannabinoid systemEndocannabinoidomeEndocannabinoid modulatorCannabinoid receptorLigands
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ZUSAMMENFASSUNG Hintergrund Bei Patienten mit Störungen aus dem schizophrenen Formenkreis ist der Konsum von Cannabis und anderen psychoaktiven Substanzen weit verbreitet. Es besteht eine wissenschaftliche Evidenz, dass der hochdosierte und regelmäßige Freizeitkonsum von Cannabis mit nachteiligen Langzeitfolgen assoziiert ist. Und dennoch könnte die physiologische Bedeutung des Endocannabinoidsystems (ECS) den Einsatz von Cannabispräparaten – womöglich mit einem hohen Gehalt an Cannabidiol (CBD) – zur Therapie neuropsychiatrischer Erkrankungen als nützlich erscheinen lassen. Ziel Darstellung der Grundlagen für die Wirksamkeit von medizinischem Cannabis bei neuropsychiatrischen Erkrankungen – insbesondere Störungen aus dem schizophrenen Formenkreis – und kritische Nutzen-Risiko-Bewertung. Ergebnisse und Diskussion Die beiden wichtigsten neuroaktiven Bestandteile von Cannabis sind CBD und Tetrahydrocannabinol (THC). THC scheint psychose- und angstfördernd zu wirken und die Kognition zu beeinträchtigen. Basierend auf einer Recherche aktueller Literatur ist anzunehmen, dass CBD im Gegensatz zu THC nicht euphorisierend, sondern antikonvulsiv, analgetisch, angstlösend und antipsychotisch wirken könnte und möglicherweise die kognitive Leistungsfähigkeit verbessern kann. Somit wäre CBD ein natürlicher Antagonist von THC. Während es eine hinreichende Evidenz gibt, dass der Freizeitkonsum von meist THC-lastigem Cannabis die psychische Gesundheit nachteilig beeinflusst und Psychosen fördert, gibt es Studien, die darauf hindeuten, dass CBD protektiv sein könnte. Allerdings mangelt es an hochwertigen kontrollierten klinischen Studien mit größeren Patientenzahlen und guter Methodik, um eine ausreichende Evidenz für den Einsatz von Cannabidiol in der klinischen Praxis zu begründen.
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The plant Cannabis sativa has been in use by humans for thousands of years, medicinally, for food and for various industrial uses. There are hundreds of different strains or cultivars of cannabis, and each has its own chemical profile which helps determine the therapeutic action. The key active constituents of cannabis, the phytocannabinoids and terpenes, are produced within glandular structures called trichomes which grow predominantly on the buds or flowers of the female plant. Two of the main phytocannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD); however, the plant has well over 500 chemical constituents. The ‘entourage effect’ describes the synergism between all active constituents which contributes to the overall therapeutic effect. When used medicinally, cannabis can take several forms including use as a raw or dried herb or in proprietary forms of medicines (e.g. oils or tinctures, oils in capsules and others). Proprietary forms of medicines include whole plant extracts as well as phytocannabinoid isolates, and there are also synthetic copies of THC which are clearly pharmaceuticals. This chapter presents an overview of medicinal cannabis, including its taxonomy, history of use, a little on regulations in the USA, different forms of medicinal cannabis, key active constituents and their therapeutic actions.KeywordsCannabisMarijuanaCannabidiolTetrahydrocannabinolTerpenesHistoryMental healthRegulations
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Background and objective: Although cannabinoid-based medications are increasingly used by older adults, their safety and tolerability in this age group remain unclear. The purpose of this systematic review was to examine the safety and tolerability of cannabinoid-based medications by conducting a meta-analysis of open-label observational studies of cannabinoid-based medications for all indications in individuals with a mean age of ≥50 years. Methods: A systematic search was conducted on PubMed, PsycINFO, MEDLINE, EMBASE and CINHAL. Study quality was assessed using an adapted version of the Grading of Recommendations Assessment, Development and Evaluation criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. We included studies that (a) were published from 1990 onwards; (b) included older adults (mean age ≥50 years); and (c) provided data on the safety and tolerability of medical cannabinoids. Data were pooled using a random-effects approach. Risk of adverse events, serious adverse events and withdrawals was computed as the incidence rate (IR). Separate analyses were conducted by the cannabinoid-based medication used, for delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and a combination of THC and CBD (THC:CBD). Results: Thirty-eight studies were identified (THC = 23; CBD = 6; THC:CBD = 9; N = 2341, mean age: 63.19 ± 8.08 years, men: 53.86%). THC had a very low incidence of all-cause and treatment-related adverse events (IR: 122.18, 95% confidence interval [CI] 38.23-253.56; IR: 84.76, 95% CI 0.13-326.01, respectively) and negligible serious adverse events (IR = 0). Similar IRs for CBD (all cause, IR: 111.91, 95% CI 1.24-495.93; treatment related, IR: 1.76, 95% CI 4.63-23.05) and no serious adverse events (IR = 0). CBD was not associated with a risk of treatment-related withdrawals. THC had a low risk of all-cause and treatment-related withdrawals (IR: 25.18, 95% CI 12.35-42.52; IR: 7.83, 95% CI 3.26-14.38, respectively). The THC:CBD treatment had a low risk of all-cause and treatment-related adverse events (IR: 100.72, 95% CI 0.25-383.00; IR: 55.38, 95% CI 8.61-142.80, respectively), but reported a risk of all-cause and treatment-related serious adverse events (IR: 21.32, 95% CI 0.18-93.26; IR: 3.71, 95% CI 0.21-11.56, respectively), and all-cause and treatment-related withdrawals (IR: 78.63, 95% CI 17.43-183.90; IR: 34.31, 95% CI 6.09-85.52, respectively). Significant heterogeneity (I2 >55%) was present in most analyses. Conclusions: Although cannabinoid-based medications were generally safe and acceptable to adults aged over 50 years, these estimates are limited by the lack of a control condition and considerable heterogeneity. Nevertheless, they complement and are consistent with comparable evidence from randomised controlled trials.
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The aim of this study was to develop a stable microemulsion (ME) for transdermal delivery of Tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA). The lipid-based vehicles were selected by screening cannabinoid solubility and the emulsifying ability of surfactants. Pseudo-ternary phase diagrams were constructed by formulation of cannabinoids with Capryol® 90 as oil phase, Tween® 80, Solutol® HS15, Procetyl® AWS, and Cremophor® RH40 as surfactants, ethanol as cosurfactant, and distilled water as the aqueous phase. A significant improvement in transmembrane flux (Jss), permeability coefficient (Kp), and enhancement ratio (ER) was found in one system compared to other formulations. This ME consisted of 1.0% (w/w) of cannabinoids, 5% (w/w) of Capryol® 90, 44% (w/w) Smix (2:1, Procetyl® AWS and Ethanol) and 50.0% (w/w) of distilled water. Additionally, the effects of pH on the permeation of the cannabinoids were investigated. Based on the pH value THCA and CBDA-loaded ME exhibited the highest permeation at pH 5.17 and pH 5.25. After storing the pH-adjusted P2 ME and the optimized P2 ME for 180 days at 4℃ and 25℃, the content of cannabinoids was over 95%. Consequently, the cannabinoids-loaded ME system is a promising option for solubilizing and stabilizing lipophilic drugs like cannabinoids and utilize them for transdermal delivery.
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Issues The Cannabis sativa L. plant contains hundreds of phytocannabinoids, but putatively of highest importance to public health risk is the psychoactive cannabinoid delta‐9‐tetrahydrocannabinol (THC), which is associated with risk for cannabis use disorder, affective disturbance, cognitive harm and psychomotor impairment. Recently, there has been an increase in the use and availability of concentrated cannabis products (or ‘concentrates’) that are made by extracting cannabinoids from the plant to form a product with THC concentrations as high as 90–95%. These products are increasingly popular nationwide. The literature on these widely available high potency concentrates is limited and there are many unknowns about their potential harms. Approach This review covers the state of the research on cannabis concentrates and behavioural health‐related outcomes and makes recommendations for advancing the science with studies focused on accurately testing the risks in relation to critical public and behavioural health questions. Key Findings Data point to unique behavioural health implications of concentrate use. However, causal, controlled and representative research on the effects of cannabis concentrates is currently limited. Implications Future research is needed to explore chronic, acute and developmental effects of concentrates, as well as effects on pulmonary function. We also highlight the need to explore these relationships in diverse populations. Conclusion While the literature hints at the potential for these highly potent products to increase cannabis‐related behavioural health harms, it is important to carefully design studies that more comprehensively evaluate the impact of concentrates on THC exposure and short‐ and long‐term effects across user groups.
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Nematode Caenorhabditis elegans (C. elegans) exhibited a vigorous swimming behavior in liquid medium. Addition of dopamine inhibited the swimming behavior, causing paralysis in 65% of wild-type nematodes. Interestingly, phytocannabinoids cannabidiol (CBD) or cannabidivarin (CBDV), caused paralysis in 40% of the animals. Knockout of DOP-3, the dopamine D2-like receptor critical for locomotor behavior, eliminated the paralysis induced by dopamine, CBD, and CBDV. In contrast, both CBD and CBDV caused paralysis in animals lacking CAT-2, an enzyme necessary for dopamine synthesis. Co-administration of dopamine with either CBD or CBDV caused paralysis similar to that of either phytocannabinoid treatment alone. These data support the notion that CBD and CBDV act as functional partial agonists on dopamine D2-like receptors in vivo. The discovery that dopamine receptor is involved in the actions of phytocannabinoids moves a significant step toward our understanding of the mechanisms for medical uses of cannabis in the treatment of neurological and psychiatric disorders.
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The endocannabinoid system is a complex neuronal system involved in a number of biological functions, like attention, anxiety, mood, memory, appetite, reward and immune responses. It is at the centre of scientific interest, which is driven by therapeutic promise of certain cannabinoid ligands and the changing legalization of herbal cannabis in many countries. The endocannabinoid system is a modulatory system, with endocannabinoids as retrograde neurotransmitters rather than direct neurotransmitters. Neuropharmacology of cannabinoid ligands in the brain can therefore be understood in terms of their modulatory actions through other neurotransmitter systems. The CB1 receptor is chiefly responsible for effects of endocannabinoids and analogous ligands in the brain. An overview of the neuropharmacology of several cannabinoid receptor ligands, including endocannabinoids, herbal cannabis and synthetic cannabinoid receptor ligands is given in this review. Their mechanism of action at the endocannabinoid system is described, mainly in the brain. In addition, effects of cannabinoid ligands on other neurotransmitter systems will also be described, such as dopamine, serotonin, glutamate, noradrenaline, opioid and GABA. In light of this, therapeutic potential and adverse effects of cannabinoid receptor ligands will also be discussed.
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Parkinson’s Disease (PD) is currently the most rapid growing neurodegenerative disease and over the past generation, its global burden has more than doubled. The onset of PD can arise due to environmental, sporadic or genetic factors. Nevertheless, most PD cases have an unknown etiology. Chemicals, such as the anthropogenic pollutant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amphetamine-type stimulants, have been associated with the onset of PD. Conversely, cannabinoids have been associated with the treatment of the symptoms’. PD and medical cannabis is currently under the spotlight, and research to find its benefits on PD is on-going worldwide. However, the described clinical applications and safety of pharmacotherapy with cannabis products are yet to be fully supported by scientific evidence. Furthermore, the novel psychoactive substances are currently a popular alternative to classical drugs of abuse, representing an unknown health hazard for young adults who may develop PD later in their lifetime. This review addresses the neurotoxic and neuroprotective impact of illicit substance consumption in PD, presenting clinical evidence and molecular and cellular mechanisms of this association. This research area is utterly important for contemporary society since illicit drugs’ legalization is under discussion which may have consequences both for the onset of PD and for the treatment of its symptoms.
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Medical cannabis, or cannabinoid-based products, continues to grow in popularity globally, driving the evolution of regulatory access frameworks; cancer patients and caregivers often rely on guidance from their physicians regarding cannabinoid-based treatments. But the majority of healthcare practitioners still feel unprepared and insufficiently informed to make reasonable, evidence-based recommendations about medical cannabis. More than 30 countries worldwide have now legalized access to medical cannabis; yet various nations still face arduous regulatory challenges to fulfill the needs of patients, healthcare practitioners, and other medical stakeholders. This has affected the deployment of comprehensive medical cannabis access programs adapted to cultural and social realities. With a 20-year history of legal medical cannabis access and nearly 400,000 registered patients under its federal access program, Canada serves as a model for countries which are developing their regulatory frameworks. The Canadian clinical experience in cannabinoid-based treatments is also a valuable source of lessons for healthcare professionals who wish to better understand the current evidence examining medical cannabis for oncology patients.
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Background: Medicinal cannabinoids, including medicinal cannabis and pharmaceutical cannabinoids and their synthetic derivatives, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been suggested to have a therapeutic role in certain mental disorders. We analysed the available evidence to ascertain the effectiveness and safety of all types of medicinal cannabinoids in treating symptoms of various mental disorders. Methods: For this systematic review and meta-analysis we searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for studies published between Jan 1, 1980, and April 30, 2018. We also searched for unpublished or ongoing studies on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry. We considered all studies examining any type and formulation of a medicinal cannabinoid in adults (≥18 years) for treating depression, anxiety, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder, or psychosis, either as the primary condition or secondary to other medical conditions. We placed no restrictions on language, publication status, or study type (ie, both experimental and observational study designs were included). Primary outcomes were remission from and changes in symptoms of these mental disorders. The safety of medicinal cannabinoids for these mental disorders was also examined. Evidence from randomised controlled trials was synthesised as odds ratios (ORs) for disorder remission, adverse events, and withdrawals and as standardised mean differences (SMDs) for change in symptoms, via random-effects meta-analyses. The quality of the evidence was assessed with the Cochrane risk of bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO (CRD42017059372, CRD42017059373, CRD42017059376, CRD42017064996, and CRD42018102977). Findings: 83 eligible studies (40 randomised controlled trials, n=3067) were included: 42 for depression (23 randomised controlled trials; n=2551), 31 for anxiety (17 randomised controlled trials; n=605), eight for Tourette syndrome (two randomised controlled trials; n=36), three for ADHD (one randomised controlled trial; n=30), 12 for post-traumatic stress disorder (one randomised controlled trial; n=10), and 11 for psychosis (six randomised controlled trials; n=281). Pharmaceutical THC (with or without CBD) improved anxiety symptoms among individuals with other medical conditions (primarily chronic non-cancer pain and multiple sclerosis; SMD -0·25 [95% CI -0·49 to -0·01]; seven studies; n=252), although the evidence GRADE was very low. Pharmaceutical THC (with or without CBD) worsened negative symptoms of psychosis in a single study (SMD 0·36 [95% CI 0·10 to 0·62]; n=24). Pharmaceutical THC (with or without CBD) did not significantly affect any other primary outcomes for the mental disorders examined but did increase the number of people who had adverse events (OR 1·99 [95% CI 1·20 to 3·29]; ten studies; n=1495) and withdrawals due to adverse events (2·78 [1·59 to 4·86]; 11 studies; n=1621) compared with placebo across all mental disorders examined. Few randomised controlled trials examined the role of pharmaceutical CBD or medicinal cannabis. Interpretation: There is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, or psychosis. There is very low quality evidence that pharmaceutical THC (with or without CBD) leads to a small improvement in symptoms of anxiety among individuals with other medical conditions. There remains insufficient evidence to provide guidance on the use of cannabinoids for treating mental disorders within a regulatory framework. Further high-quality studies directly examining the effect of cannabinoids on treating mental disorders are needed. Funding: Therapeutic Goods Administration, Australia; Commonwealth Department of Health, Australia; Australian National Health and Medical Research Council; and US National Institutes of Health.
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In den 1990er-Jahren wurde das endocannabinoide System als Teil der menschlichen Physiologie entdeckt. In der Folge nahm die systematischere Erforschung der medizinischen Anwendung von Cannabis zu. Um den aktuellen wissenschaftlichen Kenntnisstand zusammenzufassen, hat das Bundesministerium für Gesundheit eine Expertise in Auftrag gegeben.
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The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.
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Positron emission tomography with [(11)C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test-retest reliability of [(11)C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test-retest [(11)C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n=2 each). The composite parameter λk3 (an index of FAAH activity, λ=K1/k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [(11)C]CURB injection. Oral administration of PF-04457845 reduced [(11)C]CURB binding to a homogeneous level at all three doses, with λk3 values decreased by ⩾91%. Excellent reproducibility and good reliability (test-retest variability=9%; intraclass correlation coefficient=0.79) were observed across all regions of interest investigated. Our findings suggest that λk3/[(11)C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 June 2015; doi:10.1038/jcbfm.2015.133.
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Endocannabinoids are lipid-derived messengers, and both their synthesis and breakdown are under tight spatiotemporal regulation. As retrograde signalling molecules, endocannabinoids are synthesized postsynaptically but activate presynaptic cannabinoid receptor 1 (CB1) receptors to inhibit neurotransmitter release. In turn, CB1-expressing inhibitory and excitatory synapses act as strategically placed control points for activity-dependent regulation of dynamically changing normal and pathological oscillatory network activity. Here, we highlight emerging principles of cannabinoid circuit control and plasticity, and discuss their relevance for epilepsy and related comorbidities. New insights into cannabinoid signalling may facilitate the translation of the recent interest in cannabis-related substances as antiseizure medications to evidence-based treatment strategies.
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Based on evidence that the therapeutic properties of Cannabis preparations are not solely dependent on the presence of Δ9-tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid type-1 (CB1) receptors, thus behaving like first generation CB1 inverse agonists, such as rimonabant. Here we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent preclinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action, and thus appear very unlikely to produce unwanted central nervous system effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low affinity CB1 ligand which can nevertheless affect CB1 activity in vivo in an indirect manner, whilst THCV is a high affinity CB1 ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 antagonism. THCV also has high affinity for CB2 and signals as a partial agonist, a departure from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology, and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.
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The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.
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The discovery of the endocannabinoid system (ECS) has stimulated a growing body of psychiatric research focusing on the role of this system in major psychiatric disorders like schizophrenia. Epidemiological studies revealed that frequent and, in particular, early cannabis use at least doubles the risk for psychotic symptoms and schizophrenia. In parallel, research has focused on endocannabinoids, their synthesizing and metabolizing enzymatic apparatus, and the central nervous distribution of cannabinoid receptors and their relation to psychotic symptoms in schizophrenia. In addition, animal models related to aspects of schizophrenia have been developed that target the ECS. Based on these findings, a neurobiological role of the ECS involving the disruption of endogenous cannabinoid signaling and functioning in schizophrenia and a mechanism for the deleterious influence of cannabis use in schizophrenia have been suggested. The proposed model was the starting point for psychopharmacological studies raising evidence for further studies to explore this therapeutic potential.