ArticleLiterature Review

Therapeutic Potential of Cannabinoids in Psychosis

November 2015
Biological Psychiatry 79(7)

November 2015
79(7)

DOI:10.1016/j.biopsych.2015.11.018

Authors:

F. Markus Leweke

The University of Sydney

Juliane K Mueller

University Hospital Frankfurt

Bettina Lange

Central Institute of Mental Health

Cathrin Rohleder

Brain and Mind Centre, University of Sydney

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.

The use of psychoactive substances in the treatment of mental disorders

Article

Full-text available

Dec 2021

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.

Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis

Article

Full-text available

Mar 2021
PLOS MED

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.

Efficacy of Cannabidiol for Δ-9-Tetrahydrocannabinol-Induced Psychotic Symptoms, Schizophrenia, and Cannabis Use Disorders: A Narrative Review

Article

Full-text available

Mar 2021

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.

Roles of Cannabinoids in Melanoma: Evidence from In Vivo Studies

Article

Full-text available

Aug 2020
INT J MOL SCI

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.

The safety and efficacy of cannabinoids for the treatment of mental health and substance use disorders: protocol for a systematic review and meta-analysis

Preprint

Full-text available

Aug 2023

There has been a global increase in the use of cannabinoids as a treatment for mental health (MH) and substance use disorders (SUD). In 2016, an Australian government-funded review found that although medicinal cannabinoids accounted for a small reduction in MH symptoms, the results varied according to study design. There has since been a rise in randomised controlled trials (RCTs) aiming to examine the efficacy of cannabinoids for the treatment of MH and SUD. Therefore, the current systematic review will a) identify all RCTs examining the efficacy of cannabinoids in treating MH and SUD, b) provide a quantitative or qualitative synthesis of the evidence examining efficacy, and c) synthesise adverse event data to examine evidence of harm. Electronic databases (Ovid MEDLINE, PsychINFO, Cochrane Central Register of Controlled Clinical Trials, Cochrane Database of Systematic Reviews, and Embase) were searched from 1980 to 24 May 2023. The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Guidelines. Articles will be screened to capture peer-reviewed RCTs evaluating the efficacy of plant-based and pharmaceutical cannabinoids in reducing or treating MH and SUD among people of any age. The Cochrane risk of bias tool 2.0 will be used to assess bias, while the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) tool will be used to assess the quality of evidence for each outcome. Study findings will be disseminated through published manuscripts, conferences and health policy guidelines.

Keharusan Penggunaan Ganja Untuk Maslahah Perubatan Kesihatan: Satu Perbincangan Awal [The Necessity Of Using Cannabis For Medical Health Importance: A Preliminary Discussion]

Article

Nov 2023

Artikel ini menganalisis hukum penanaman kanabis atau ganja yang kerap diperbincangkan sejak kebelakangan ini khususnya dari segi manfaat terhadap keperluan perubatan kesihatan. Antara spesis kanabis yang dipercayai mengandungi manfaat kesihatan ialah hemp (Cannabis Sativa L.). Hemp dipercayai mampu bertindak sebagai terapi bagi pesakit gangguan saraf, autisme, kemurungan, parkinson dan kanser. Namun menurut undang-undang Malaysia, kanabis disenaraikan dalam Akta Dadah Berbahaya 1952 yang mengharamkan penanaman, pengeluaran, pengedaran, import, eskport, pemilikan dan penyalahgunaannya. Artikel ini juga bertujuan untuk meneliti asas-asas keharusan penanaman pokok tersebut daripada sudut pertimbangan maslahah dan mafsadah dalam konteks penjagaan maqasid syariah yang lebih luas. Sebagai sebuah kajian kualitatif, metod analisis kandungan akan digunakan bagi memperoleh pandangan fuqaha Islam mengenai hukum penanaman hasyish (ganja), khasykhasy (popi), tabg (tembakau) dan dan fatwa-fatwa semasa yang berkaitan daripada pelbagai institusi hukum yang berautoriti. Bagi menentukan hukumnya pada masa kini, aspek maslahah dan mafsadah perlu dipertimbangkan dengan mengambilkira ketetapan undang-undang negara. Seterusnya, kajian ini telah mendapati bahawa spesis hemp adalah suci dan tidak dianggap najis namun keharusan penanamannya tertakluk kepada beberapa garis panduan bagi mengelak timbulnya kesan kemudaratan kepada masyarakat. This article analyses the ruling regarding the cultivation of cannabis or ganja which has often been discussed in recent times, particularly in terms of its benefits for medical health needs. Hemp is one of the varieties of cannabis thought to have health advantages (Cannabis Sativa L.). Patients with cancer, Parkinson's disease, depression, anxiety disorders, and autism may benefit from using hemp as a therapy. However, as per the Dangerous Drugs Act 1952 in Malaysia, cannabis is prohibited from being cultivated, produced, distributed, imported, exported, possessed, or abused. This article also aims to examine the fundamentals of the necessity of planting cannabis from the point of view of maslahah and mafsadah in the context of taking care of the wider shariah maqasid. As a qualitative study, the content analysis method will be employed to obtain the views of Islamic jurists regarding the legality of cultivating hasyish (marijuana), khasykhasy (poppy), tabg (tobacco) as well as the pertinent current fatwas from multiple reputable legal institutions. Today, the maslahah and mafsadah aspects must be taken into consideration while determining the law, keeping in mind the provisions of national law. Next, this study has shown that although the hemp species is sacred and not regarded as impure, its cultivation needs to adhere to a number of rules in order to prevent negative effects on the community

Endocannabinoid Degradation Enzyme Inhibitors as Potential Antipsychotics: A Medicinal Chemistry Perspective

Article

Full-text available

Feb 2023

The endocannabinoid system (ECS) plays a very important role in numerous physiological and pharmacological processes, such as those related to the central nervous system (CNS), including learning, memory, emotional processing, as well pain control, inflammatory and immune response, and as a biomarker in certain psychiatric disorders. Unfortunately, the half-life of the natural ligands responsible for these effects is very short. This perspective describes the potential role of the inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), which are mainly responsible for the degradation of endogenous ligands in psychic disorders and related pathologies. The examination was carried out considering both the impact that the classical exogenous ligands such as Δ9-tetrahydrocannabinol (THC) and (−)-trans-cannabidiol (CBD) have on the ECS and through an analysis focused on the possibility of predicting the potential toxicity of the inhibitors before they are subjected to clinical studies. In particular, cardiotoxicity (hERG liability), probably the worst early adverse reaction studied during clinical studies focused on acute toxicity, was predicted, and some of the most used and robust metrics available were considered to select which of the analyzed compounds could be repositioned as possible oral antipsychotics.

Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance

Article

Full-text available

Feb 2023
INT J MOL SCI

Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox–Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD’s effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases.

Islamic Legal Perspective on Hemp Cultivation in Malaysia: Wonder or Evil?

Article

Full-text available

Dec 2022

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.

Treatments for Social Interaction Impairment in Animal Models of Schizophrenia: A Critical Review and Meta-analysis

Article

Aug 2022
SCHIZOPHRENIA BULL

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.

Current State of Fluid Lipid Biomarkers for Personalized Diagnostics and Therapeutics in Schizophrenia Spectrum Disorders and Related Psychoses: A Narrative Review

Article

Full-text available

May 2022

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.

Simultaneous Assessment of Serum Levels and Pharmacologic Effects of Cannabinoids on Endocannabinoids and N -Acylethanolamines by Liquid Chromatography–Tandem Mass Spectrometry

Article

Full-text available

May 2022

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.

Cannabis Use Among Patients With Psychotic Disorders

Article

Full-text available

May 2021

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.

The Construct of Medical and Non-Medical Marijuana - Critical Review

Article

Full-text available

Feb 2022
Int J Environ Res Publ Health

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.

The Use of Medical Cannabis in Clinical Practice

Article

Dec 2021

Arianne Kryskow

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.

CBD Effects on Motor Profile and Neurobiological Indices Related to Glutamatergic Function Induced by Repeated Ketamine Pre-Administration

Article

Full-text available

Oct 2021

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.

Cannabidiol versus risperidone for treatment of recent-onset psychosis with comorbid cannabis use: study protocol for a randomized controlled clinical trial

Article

Full-text available

Aug 2021
BMC PSYCHIATRY

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

Cannabidiol for at risk for psychosis youth: A randomized controlled trial

Article

Jul 2021

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.

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders

Article

Full-text available

May 2021

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.

Cannabidiol modulation of hippocampal glutamate in early psychosis

Article

Full-text available

Apr 2021
J PSYCHOPHARMACOL

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.

Advancing the science on cannabis concentrates and behavioural health

Article

Mar 2021

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.

Cannabinoids, reward processing, and psychosis

Article

Full-text available

May 2022
PSYCHOPHARMACOLOGY

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.

Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies

Article

Full-text available

Apr 2021
PSYCHOPHARMACOLOGY

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.

Medicinal cannabis for psychiatric disorders: A clinically-focused systematic review

Article

Full-text available

Jan 2020
BMC PSYCHIATRY

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.

Buprenorphine–cannabis interaction in patients undergoing opioid maintenance therapy

Article

Full-text available

Aug 2021
EUR ARCH PSY CLIN N

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.

Cannabis use and Psychosis

Preprint

Full-text available

Dec 2019

Alexandra Arnett

Implications for cannabis use and mental health treatments and potential negative effects.

A Case Report of Cannabidiol Treatment of a Crohn's Disease Patient With Anxiety Disorder

Article

Dec 2019

Childhood trauma and being at-risk for psychosis are associated with higher peripheral endocannabinoids

Article

Aug 2019

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.

The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review

Article

Full-text available

Jul 2019

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.

Alterations to sphingolipid metabolism from antipsychotic administration in healthy volunteers are restored following the use of cannabidiol

Article

Jun 2024
PSYCHIAT RES

Cannabidiol as a Potential Antipsychotic

Chapter

Jun 2023

An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.

Medizinisches Cannabis: Einsatzmöglichkeiten in der Psychiatrie

Article

Apr 2023

ZUSAMMENFASSUNG Es liegen Untersuchungen zur Wirksamkeit von Cannabinoiden bei psychischen Störungen vor, jedoch fehlen ausreichende große, randomisiert-kontrollierte Studien mit Replikation. Der genaue Effekt von Cannabinoiden auf die Psychopathologie der jeweiligen Störungen konnte ebenfalls nicht mit hinreichender Evidenz belegt werden. Es ergaben sich jedoch keine Hinweise auf schwerwiegende Nebenwirkungen. Allgemeine Empfehlungen zum Einsatz von Cannabinoiden bei psychischen Störungen sind nicht möglich, dennoch kann in Einzelfällen bei fehlender Neigung zu Substanzgebrauchsstörungen der Einsatz von Cannabinoiden durchaus sinnvoll sein, insbesondere bei Patienten mit komorbiden Schmerzstörungen.

Cannabis use selectively modulates circulating biomarkers in the blood of schizophrenia patients

Article

Full-text available

Sep 2022

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.

Choosing a Product, Route of Administration, Initial Dosage, Titration, Monitoring and Management of Adverse Effects

Chapter

Feb 2022

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

Cannabinoid-Based Medicine: Pharmacology and Drug Interactions

Chapter

Feb 2022

Mellar P. Davis

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

Psychoactive Effects of Cannabinoid-Based Medicines: Exploration and Inquiry

Chapter

Feb 2022

Claude Cyr

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)

Overview of the Endocannabinoid System and Endocannabinoidome

Chapter

Full-text available

Feb 2022

Mellar P. Davis

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

Therapeutischer Einsatz von Cannabis bei Störungen aus dem schizophrenen Formenkreis: Medizin oder Droge – eine kritische Nutzen-Risiko-Bewertung

Article

Feb 2022

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.

Overview of Medicinal Cannabis

Chapter

Oct 2021

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

Safety and Tolerability of Natural and Synthetic Cannabinoids in Older Adults: A Systematic Review and Meta-Analysis of Open-Label Trials and Observational Studies

Article

Jul 2021

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.

Development of a novel cannabinoid-loaded microemulsion towards an improved stability and transdermal delivery

Article

Jun 2021
INT J PHARMACEUT

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.

Treatment possibilities of pharmaco-resistant schizofrenie in common clinical practice

Article

Full-text available

Jun 2020

Novel treatment possibilities in depression and schizophrenia

Article

Jun 2018

Eva Ceskova

Involvement of dopamine receptor in the actions of non-psychoactive phytocannabinoids

Article

Oct 2020

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.

The neuropharmacology of cannabinoid receptor ligands in central signaling pathways

Article

Full-text available

Sep 2020
EUR J NEUROSCI

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.

Neuroprotection or Neurotoxicity of Illicit Drugs on Parkinson’s Disease

Article

Full-text available

Jun 2020

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.

Choice of pharmacotherapy in patient s with schizophrenia and co-occurring substance use

Article

May 2017

Medical cannabis in supportive cancer care: lessons from Canada

Article

Mar 2020

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.

Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis

Article

Oct 2019

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.

Improving brain plasticity in schizophrenia: possibility for therapeutic advancements?

Chapter

Aug 2019

Endocannabinoid Signaling in the Brain

Article

Full-text available

Apr 2002

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.

Blocking of Fatty Acid Amide Hydrolase Activity with PF-04457845 in Human Brain: A Positron Emission Tomography Study with the Novel Radioligand [ 11 C]CURB

Article

Full-text available

Jun 2015
J CEREBR BLOOD F MET

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.

Weeding out bad waves: Towards selective cannabinoid circuit control in epilepsy

Article

Full-text available

Apr 2015

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.

Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review

Article

Full-text available

Sep 2014
BRIT J PHARMACOL

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.

Cannabinoid 1 and Transient Receptor Potential Vanilloid 1 Receptors Discretely Modulate Evoked Glutamate Separately from Spontaneous Glutamate Transmission

Article

Full-text available

Jun 2014

Action potentials trigger synaptic terminals to synchronously release vesicles, but some vesicles release spontaneously. G-protein-coupled receptors (GPCRs) can modulate both of these processes. At cranial primary afferent terminals, the GPCR cannabinoid 1 (CB1) is often coexpressed with transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel present on most afferents. Here we tested whether CB1 activation modulates synchronous, action potential-evoked (eEPSCs) and/or spontaneous (sEPSCs) EPSCs at solitary tract nucleus neurons. In rat horizontal brainstem slices, activation of solitary tract (ST) primary afferents generated ST-eEPSCs that were rapidly and reversibly inhibited from most afferents by activation of CB1 with arachidonyl-2'-chloroethylamide (ACEA) or WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate]. The CB1 antagonist/inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] blocked these responses. Despite profound depression of ST-eEPSCs during CB1 activation, sEPSCs in these same neurons were unaltered. Changes in temperature changed sEPSC frequency only from TRPV1(+) afferents (i.e., thermal sEPSC responses only occurred in TRPV1(+) afferents). CB1 activation failed to alter these thermal sEPSC responses. However, the endogenous arachidonate metabolite N-arachidonyldopamine (NADA) promiscuously activated both CB1 and TRPV1 receptors. NADA inhibited ST-eEPSCs while simultaneously increasing sEPSC frequency, and thermally triggered sEPSC increases in neurons with TRPV1(+) afferents. We found no evidence for CB1/TRPV1 interactions suggesting independent regulation of two separate vesicle pools. Together, these data demonstrate that action potential-evoked synchronous glutamate release is modulated separately from TRPV1-mediated glutamate release despite coexistence in the same central terminations. This two-pool arrangement allows independent and opposite modulation of glutamate release by single lipid metabolites.

Δ9Tetrahydrocannabinol Induces Dopamine Release in the Human Striatum

Article

Full-text available

Feb 2009
NEUROPSYCHOPHARMACOL

The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D2/D3 receptor tracer [11C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [11C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.

Medical Needs in the Treatment of Psychotic Disorders

Article

Full-text available

Nov 2012
Handbook Exp Pharmacol

Schizophrenia and psychotic disorders represent psychiatric disease patterns characterized by remarkable impairment arising from alterations in cognition, perception, and mood. Although these severe illnesses have been known for more than 100 years, psychopharmacological treatment of their characteristically broad spectrum of symptoms as well as patients’ quality of life, compliance, and time to relapse still remain a challenge in everyday clinical practice. In the following, we will provide a brief synopsis of first-generation antipsychotics (FGAs) followed by a detailed description of current second-generation antipsychotics (SGAs) along with their effects and side effects to evaluate unmet needs in the treatment of schizophrenia and psychotic disorders. Overall, drug profiles differ concerning their efficacy, associated side effects, cost, and mechanism of action. Thus, a shared decision-making process taking all these factors into account is necessary to develop an effective treatment based on currently approved compounds. To date, however, the spectrum of options is limited and only serves a limited proportion of patients. In addition, certain symptoms do not respond well to currently available strategies or respond only at the price of considerable side effects leading to reduced compliance and adherence in a substantial number of cases. Unmet needs in the field of antipsychotic treatment are found in a wide range of areas starting from efficacy, safety and tolerability, compliance and adherence, and continuing to stage-dependent and more personalized approaches.

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.Transl. Psychiatry 2:e94

Article

Full-text available

Feb 2012

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

Corrigendum: A catalytically silent FAAH-1 variant drives anandamide transport in neurons

Article

Full-text available

Nov 2011
NAT NEUROSCI

The endocannabinoid anandamide is removed from the synaptic space by a selective transport system, expressed in neurons and astrocytes, that remains molecularly uncharacterized. Here we describe a partly cytosolic variant of the intracellular anandamide-degrading enzyme fatty acid amide hydrolase-1 (FAAH-1), termed FAAH-like anandamide transporter (FLAT), that lacked amidase activity but bound anandamide with low micromolar affinity and facilitated its translocation into cells. Known anandamide transport inhibitors, such as AM404 and OMDM-1, blocked these effects. We also identified a competitive antagonist of the interaction of anandamide with FLAT, the phthalazine derivative ARN272, that prevented anandamide internalization in vitro, interrupted anandamide deactivation in vivo and exerted profound analgesic effects in rodent models of nociceptive and inflammatory pain, which were mediated by CB(1) cannabinoid receptors. The results identify FLAT as a critical molecular component of anandamide transport in neural cells and a potential target for therapeutic drugs.

Comparative receptor binding analyses of cannabinoid agonists and antagonists

Article

Full-text available

Apr 1998

To further characterize neuronal cannabinoid receptors, we compared the ability of known and novel cannabinoid analogs to compete for receptor sites labeled with either [3H]SR141716A or [3H]CP-55,940. These efforts were also directed toward extending the structure-activity relationships for cannabinoid agonists and antagonists. A series of alternatively halogenated analogs of SR141716A were synthesized and tested in rat brain membrane binding assays along with the classical cannabinoids, Delta9-tetrahydrocannabinol, cannabinol, cannabidiol, the nonclassical cannabinoid CP-55,940, the aminoalkylindole WIN55212-2 and the endogenous fatty acid ethanolamide, anandamide. Saturation binding isotherms were performed with both radioligands, as were displacement studies, allowing an accurate comparison to be made between the binding of these various compounds. Competition studies demonstrated that all of the compounds were able to displace the binding of [3H]CP-55,940 with rank order potencies that agreed with previous studies. However, the rank order potencies of these compounds in competition studies with [3H]SR141716A differed significantly from those determined with [3H]CP-55,940. These results suggest that CP-55,940, WIN55212-2 and other agonists interact with cannabinoid binding sites within the brain which are distinguishable from the population of binding sites for SR141716A, its analogs and cannabidiol. Structural modification of SR141716A significantly altered the affinity of the compound and its relative ability to displace either [3H]CP-55,940 or [3H]SR141716A preferentially within the rat brain receptor membrane preparation.

Paranoid Schizophrenia is Characterized by Increased CB1 Receptor Binding in the Dorsolateral Prefrontal Cortex

Article

Full-text available

Apr 2011
NEUROPSYCHOPHARMACOL

A number of studies suggest a dysregulation of the endogenous cannabinoid system in schizophrenia (SCZ). In the present study, we examined cannabinoid CB(1) receptor (CB(1)R) binding and mRNA expression in the dorsolateral prefrontal cortex (DLPFC) (Brodmann's area 46) of SCZ patients and controls, post-mortem. Receptor density was investigated using autoradiography with the CB(1)R ligand [(3)H] CP 55,940 and CB(1)R mRNA expression was measured using quantitative RT-PCR in a cohort of 16 patients with paranoid SCZ, 21 patients with non-paranoid SCZ and 37 controls matched for age, post-mortem interval and pH. All cases were obtained from the University of Sydney Tissue Resource Centre. Results were analyzed using one-way analysis of variance (ANOVA) and post hoc Bonferroni tests and with analysis of covariance (ANCOVA) to control for demographic factors that would potentially influence CB(1)R expression. There was a main effect of diagnosis on [(3)H] CP 55,940 binding quantified across all layers of the DLPFC (F(2,71) = 3.740, p = 0.029). Post hoc tests indicated that this main effect was due to patients with paranoid SCZ having 22% higher levels of CB(1)R binding compared with the control group. When ANCOVA was employed, this effect was strengthened (F(2,67) = 6.048, p = 0.004) with paranoid SCZ patients differing significantly from the control (p = 0.004) and from the non-paranoid group (p = 0.016). In contrast, no significant differences were observed in mRNA expression between the different disease subtypes and the control group. Our findings confirm the existence of a CB(1)R dysregulation in SCZ and underline the need for further investigation of the role of this receptor particularly in those diagnosed with paranoid SCZ.

Effect of cannabidiol in a MK-801-rodent model of aspects of Schizophrenia

Article

Full-text available

Mar 2011

Cannabidiol is a non-psychoactive phytocannabinoid which, based on several previous preclinical and clinical reports, is purported to have antipsychotic potential. The purpose of this investigation was to further investigate if these effects would be seen using an MK-801-induced rat model of aspects of schizophrenia. MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviours which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. Following a 4-day acclimatisation to the holding room, rats were acclimatised to startle chambers on day 5 and their prepulse inhibition (PPI) determined on day 6 following treatment with cannabidiol or vehicle and MK-801 or vehicle. On day 9, rats were acclimatised to the social interaction testing arena and on day 10, were tested for social interaction and locomotor activity following the same treatments. Cannabidiol treatment alone disrupted PPI and produced hyperactivity but had no effect on social behaviour. Cannabidiol had no effect on MK-801-induced disruption of PPI or hyperactivity but showed potential towards inhibiting MK-801-induced social withdrawal. As a comparator, we also tested the effect of the atypical antipsychotic clozapine which only partially reversed MK-801-induced disruption of PPI but was able to reverse MK-801-induced hyperactivity and social withdrawal. In conclusion, cannabidiol showed both propsychotic activity and partial antipsychotic activity in an MK-801-induced model of aspects of schizophrenia. Further behavioural studies would be required using a range of species, strains, animal models and testing paradigms to conclusively establish the antipsychotic potential of cannabidiol.

Effects of the Cannabinoid-1 Receptor Antagonist Rimonabant on Psychiatric Symptoms in Overweight People With Schizophrenia A Randomized, Double-Blind, Pilot Study

Article

Full-text available

Feb 2011
J CLIN PSYCHOPHARM

Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m or higher with hyperlipidemia or body mass index of 30 kg/m or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, -1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (-1.4 ± 0.35, P = 0.0004) and hostility (-0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.

Cannabinoid CB1 Receptor Immunoreactivity in the Prefrontal Cortex: Comparison of Schizophrenia and Major Depressive Disorder

Article

Full-text available

Sep 2010
NEUROPSYCHOPHARMACOL

We recently showed that measures of cannabinoid 1 receptor (CB1R) mRNA and protein were significantly reduced in dorsolateral prefrontal cortex (DLPFC) area 9 in schizophrenia subjects relative to matched normal comparison subjects. However, other studies have reported unaltered or higher measures of CB1R levels in schizophrenia. To determine whether these discrepancies reflect differences across brain regions or across subject groups (eg, presence of depression, cannabis exposure, etc), we used immunocytochemical techniques to determine whether lower levels of CB1R immunoreactivity are (1) present in another DLPFC region, area 46, in the same subjects with schizophrenia, (2) present in area 46 in a new cohort of schizophrenia subjects, (3) present in major depressive disorder (MDD) subjects, or (4) attributable to factors other than a diagnosis of schizophrenia, including prior cannabis use. CB1R immunoreactivity levels in area 46 were significantly 19% lower in schizophrenia subjects relative to matched normal comparison subjects, a deficit similar to that observed in area 9 in the same subjects. In a new cohort of subjects, CB1R immunoreactivity levels were significantly 20 and 23% lower in schizophrenia subjects relative to matched comparison and MDD subjects, respectively. The lower levels of CB1R immunoreactivity in schizophrenia subjects were not explained by other factors such as cannabis use, suicide, or pharmacological treatment. In addition, CB1R immunoreactivity levels were not altered in monkeys chronically exposed to haloperidol. Thus, the lower levels of CB1R immunoreactivity may be common in schizophrenia, conserved across DLPFC regions, not present in MDD, and not attributable to other factors, and thus a reflection of the underlying disease process.

Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists

Article

Full-text available

Mar 2010
WORLD J BIOL PSYCHIA

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.

High-potency cannabis and the risk of psychosis

Article

Full-text available

Dec 2009
BRIT J PSYCHIAT

People who use cannabis have an increased risk of psychosis, an effect attributed to the active ingredient Delta 9-tetrahydrocannabinol (Delta 9-THC). There has recently been concern over an increase in the concentration of Delta 9-THC in the cannabis available in many countries. To investigate whether people with a first episode of psychosis were particularly likely to use high-potency cannabis. We collected information on cannabis use from 280 cases presenting with a first episode of psychosis to the South London & Maudsley National Health Service (NHS) Foundation Trust, and from 174 healthy controls recruited from the local population. There was no significant difference between cases and controls in whether they had ever taken cannabis, or age at first use. However, those in the cases group were more likely to be current daily users (OR = 6.4) and to have smoked cannabis for more than 5 years (OR = 2.1). Among those who used cannabis, 78% of the cases group used high-potency cannabis (sinsemilla, 'skunk') compared with 37% of the control group (OR 6.8). The finding that people with a first episode of psychosis had smoked higher-potency cannabis, for longer and with greater frequency, than a healthy control group is consistent with the hypothesis that Delta 9-THC is the active ingredient increasing risk of psychosis. This has important public health implications, given the increased availability and use of high-potency cannabis.

Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

Article

Full-text available

Nov 2009
P NATL ACAD SCI USA

Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana, and other direct cannabinoid receptor (CB1) agonists produce a number of neurobehavioral effects in mammals that range from the beneficial (analgesia) to the untoward (abuse potential). Why, however, this full spectrum of activities is not observed upon pharmacological inhibition or genetic deletion of either fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively, has remained unclear. Here, we describe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. Falling into this latter category was drug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were reversed by a CB1 antagonist. These data indicate that AEA and 2-AG signaling pathways interact to regulate specific behavioral processes in vivo, including those relevant to drug abuse, thus providing a potential mechanistic basis for the distinct pharmacological profiles of direct CB1 agonists and inhibitors of individual endocannabinoid degradative enzymes.

Cannabidiol Displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo

Article

Full-text available

Nov 2009
J PHARMACOL EXP THER

Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.

Immunodensity and mRNA expression of A2A adenosine, D 2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: Effect of antipsychotic treatment

Article

Full-text available

Aug 2009
PSYCHOPHARMACOLOGY

Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions. The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.

Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor

Article

Full-text available

Jan 1993

Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.

Structure of a Cannabinoid Receptor and Functional Expression of the Cloned Cdna

Article

Full-text available

Sep 1990

Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.

Pharmacological and molecular targets in the search for novel antipsychotics

Article

Jun 2000
BEHAV PHARMACOL

The recent enthusiasm among clinicians for the so-called 'atypical antipsychotics' has both improved treatment for schizophrenic patients and provided a welcome stimulus for basic research on antipsychotic mechanisms. Even the newer drugs have shortcomings, and research is underway aimed at identifying novel agents with greater efficacy and safety. Much of this effort is directed towards compounds which, in addition to blocking dopamine receptors, also act on other neurotransmitter receptors such as 5-HT(2), 5-HT(1A) and alpha(2)-adrenergic receptors. However, there is also a large amount of scientific activity seeking to discover and develop selective dopamine receptor subtype antagonists (including compounds which specifically block D(3) or D(4) receptors) or drugs that specifically target the dopamine autoreceptor. Finally, a number of drug development programmes are searching for non-dopaminergic antipsychotics. Drugs that do not have affinity for dopamine receptors but act through neurotensin, sigma or cannabinoid CB, receptors or glutamatergic mechanisms are currently being evaluated. If any of these agents prove to have clinical efficacy this may lead to a third generation of antipsychotics. It is likely, however, that the mechanisms of action of such drugs will nevertheless imply the intimate involvement of dopaminergic pathways. (C) 2000 Lippincott Williams & Wilkins.

Psychiatric aspects of marihuana intoxication

Article

Allosteric modulation of the cannabinoid CB1 receptor

Article

Jan 2005

Marijuana

Article

R. Adams

The endocannabinoid system in guarding against fear, anxiety and stress

Article

Nov 2015
NAT REV NEUROSCI

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.

Evidence that early intervention may impact on disease progression and outcome in schizoprenia

Article

Jan 2006
SCHIZOPHR RES

Cannabinoids and schizophrenia

Chapter

Dec 2015

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.

Reciprocal Alterations in Cortical Cannabinoid Receptor 1 Binding Relative to Protein Immunoreactivity and Transcript Levels in Schizophrenia

Article

Aug 2014

The deleterious effects of cannabis use in schizophrenia have been linked, in part, to underlying disturbances in endogenous cannabinoid signaling in the prefrontal cortex. However, while receptor autoradiography studies of the primary cannabinoid receptor (CB1R) have consistently found higher CB1R binding in the prefrontal cortex in schizophrenia, deficits in CB1R mRNA levels and protein immunoreactivity have also been reported in the illness. To investigate this apparent discrepancy, we quantified CB1R binding using receptor autoradiography with the selective CB1R ligand [(3)H]-OMAR in the prefrontal cortex of 21 subjects with schizophrenia who were previously found to have lower levels of both CB1R mRNA using in situ hybridization and CB1R protein using radioimmunocytochemistry relative to matched healthy comparison subjects. We observed higher levels of [(3)H]-OMAR binding in the prefrontal cortex of schizophrenia subjects that did not appear to be attributable to psychotropic medications or substance abuse. The combination of lower levels of CB1R mRNA and immunoreactivity with higher CB1R receptor binding may reflect 1) altered trafficking of the receptor resulting in higher levels of membrane-bound CB1R or 2) higher CB1R affinity. In either case, greater CB1R receptor availability may contribute to the increased susceptibility of schizophrenia subjects to the deleterious effects of cannabis use.

Capsazepine, a vanilloid receptor antagonist, inhibits nicotinic acetylcholine receptors in rat trigeminal ganglia

Article

May 1997
NEUROSCI LETT

Delta-9-Tetrahydrocannabinol induces dopamine release in the human striatum

Article

Nov 2008

The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Δ9- tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D2/D 3 receptor tracer [11C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [11C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.

Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia

Article

Apr 2013
NEUROIMAGE

Effects of the Cannabinoid-1 Receptor Antagonist/Inverse Agonist Rimonabant on Satiety Signaling in Overweight People with Schizophrenia A Randomized, Double-Blind, Pilot Study

Article

Dec 2012
J CLIN PSYCHOPHARM

Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp. I

Article

Jan 1940
J AM CHEM SOC

Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish

Article

Apr 1964

Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

Article

Oct 2001
BRIT J PHARMACOL

(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327

Anandamide Dysfunction in Prodromal and Established Psychosis

Article

Jun 2012
CURR PHARM DESIGN

F. Markus Leweke

There is epidemiological evidence that frequent cannabis use in general and during puberty in particular increases the risk to suffer psychosis and psychotic symptoms. Based on these observations, there is growing interest in the role of the endogenous cannabinoid system (eCB system) - the point of action for psychoactive cannabinoids - in psychiatric disorders and schizophrenia in particular. It has been hypothesized nearly two decades ago that the eCB system may play a pathophysiological role in schizophrenia either in terms of an endogenous malfunction of the system itself and/or of a secondary malfunction as a result of the use of exogenous cannabinoids like Δ 9-tetrahydrocannabinol, the major psychoactive phytocannabinoid in Cannabis sativa. To test this hypothesis, several studies have been performed investigating endogenous ligands to cannabinoid CB1-receptors such as anandamide both in cerebrospinal fluid and plasma of patients and controls. Here a mini-review of the role of anandamide in schizophrenia is provided.

Hashish

Article

Jan 1946

A. R. Todd

Der Autor referiert ber die frhere chemische Bearbeitung des Haschischproblems, wobei namentlich die Arbeiten vonCahn (bis 1933) wichtig sind. Die beiden Substanzen Cannabinol und Cannabidiol aus Haschisch sind inaktiv, der Trger der physiologischen Wirkung konnte noch nicht rein dargestellt werden. Synthetische Tetrahydrocannabinole zeigen zum Teil starke Haschischwirkung. Der Autor vermutet, da die Struktur des natrlichen Wirkungstrgers hnlich sein wird wie diejenige der aktiven synthetischen Produkte.

Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffine G, Bayewitch M, Barg J & Vogel Z.Identification of an endogenous 2-monoglyceride, present in canine gut, thatbinds to cannabinoid receptors. Biochem Pharmacol 50: 83−90

Article

Jun 1995
BIOCHEM PHARMACOL

In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.

Rimonabant for Neurocognition in Schizophrenia: A 16-Week Double Blind Randomized Placebo Controlled Trial

Article

Dec 2011

To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia. Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study. In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects. Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects

Article

Nov 2011
BRIT J CLIN PHARMACO

AIMS To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects. Double-blind, randomized, placebo-controlled single and multiple rising dose studies and an open-label, randomized, food effect study were conducted. Plasma and urine PF-04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed. PF-04457845 was rapidly absorbed (median t(max) 0.5-1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady-state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5- to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated. PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.

Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus

Article

Aug 2011
BRIT J PHARMACOL

Background and purpose: To evaluate the hypothesis that activation of somatodendritic 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis. Experimental approach: The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPγS binding in rat brainstem membranes. Key results: CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg·kg(-1) , but not 40 mg·kg(-1) )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. Conclusions and implications: These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT(1A) autoreceptors in the DRN. Linked articles: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes

Article

Dec 2010
BRIT J PHARMACOL

Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.

Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR

Article

Oct 2010
NEUROIMAGE

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

Synthetic Δ-9-Tetrahydrocannabinol (Dronabinol) Can Improve the Symptoms of Schizophrenia

Article

Jul 2009
J CLIN PSYCHOPHARM

We are reporting improvement of symptoms of schizophrenia in a small group of patients who received the cannabinoid agonist dronabinol (synthetic Delta-9-tetrahydrocannabinol). Before this report, cannabinoids had usually been associated with worsening of psychotic symptoms. In a heuristic, compassionate use study, we found that 4 of 6 treatment-refractory patients with severe chronic schizophrenia but who had a self-reported history of improving with marijuana abuse improved with dronabinol. This improvement seems to have been a reduction of core psychotic symptoms in 3 of the 4 responders and not just nonspecific calming. There were no clinically significant adverse effects. These results complement the recent finding that the cannabinoid blocker rimonabant does not improve schizophrenic symptoms and suggest that the role of cannabinoids in psychosis may be more complex than previously thought. They open a possible new role for cannabinoids in the treatment of schizophrenia.

Schizophrenia from a neural circuitry perspective: Advancing toward rational pharmacological therapies

Article

May 2009
J CLIN INVEST

Schizophrenia is a severe disorder that disrupts the function of multiple brain systems, resulting in impaired social and occupational functioning. The etiology and pathogenesis of schizophrenia appear to involve the interplay of a potentially large number of genetic liabilities and adverse environmental events that disrupt brain developmental pathways. In this Review, we discuss a strategy for determining how particular common and core clinical features of the illness are associated with pathophysiology in certain circuits of the cerebral cortex. The identification of molecular alterations in these circuits is providing critical insights for the rational development of new therapeutic interventions.

Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis

Article

May 2009
BRIT J PSYCHIAT

Anandamide is a bioactive lipid binding to cannabinoid receptors. A homeostatic role for anandamide has been suggested in schizophrenia. We investigated its role in initial prodromal states of psychosis. We measured the levels of anandamide and its structural analog oleoylethanolamide in cerebrospinal fluid and serum of patients in the initial prodromal state (n=27) alongside healthy volunteers (n=81) using high-performance liquid chromatograph/mass spectrometry. Cerebrospinal anandamide levels in patients were significantly elevated. Patients with lower levels showed a higher risk for transiting to psychosis earlier. This anandamidergic up-regulation in the initial prodromal course may suggest a protective role of the endocannabinoid system in early schizophrenia.

Time-dependent vascular actions of cannabidiol in the rat aorta

Article

Apr 2009

We have shown that the major active agent of Cannabis sativa, Delta(9)-tetrahydrocannabinol, activates peroxisome proliferator-activated receptor gamma [PPARgamma, O'Sullivan, S.E., Tarling, E.J., Bennett, A.J., Kendall, D.A., Randall, M.D., 2005c. Novel time-dependent vascular actions of delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem. Biophys. Res. Commun. 337, 824-831]. The aim of the present study was to investigate whether another pharmacologically active phytocannabinoid, cannabidiol, similarly activates PPARgamma. Functional vascular studies were carried out in rat aortae in vitro by myography. PPARgamma activation was investigated using reporter gene assays, a PPARgamma competition-binding assay and an adipogenesis assay. Cannabidiol caused time-dependent (over 2 h) vasorelaxation of pre-constricted aortae, sensitive to PPARgamma antagonism (GW9662, 1 microM) and super oxide dismutase inhibition. The vascular effects of cannabidiol were not affected by endothelial denudation, nitric oxide synthase inhibition, pertussis toxin, cannabinoid CB1 or cannabinoid CB2 receptor antagonism, or capsaicin pre-treatment. When aortae were contracted with U46619 in a Ca2+-free buffer, vasorelaxation to cannabidiol was substantially reduced. Furthermore, cannabidiol (1-30 microM) inhibited the contractile response to the re-introduction of Ca2+. In a reporter gene assay, cannabidiol increased the transcriptional activity of PPARgamma. Cannabidiol was also found to bind to PPARgamma and stimulate the differentiation of 3T3-L1 fibroblasts into adipocytes, a PPARgamma-mediated response. These results show that cannabidiol binds to and activates PPARgamma, which partially underlies the time-dependent vascular effects of cannabidiol. However, cannabidiol-induced vasorelaxation in the rat isolated aorta appears to be largely due to calcium channel inhibition.

Determination and Characterization of a Cannabinoid Receptor in Rat Brain

Article

Dec 1988

The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.

The Positive and Negative Syndrome Scale (PANSS) for schizophrenia

Article

Feb 1987
SCHIZOPHRENIA BULL

The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.

Therapeutic Potential of Cannabinoids in Psychosis

Abstract

No full-text available

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