Category Archives: Schizophrenia

Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders.

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“G-protein-coupled receptor (GPCR)-mediated signalling is the most widely used signalling mechanism in cells, and its regulation is important for various physiological functions. The cannabinoid-1 (CB(1)) receptor, a GPCR, has been shown to play a critical role in neural circuitries mediating motivation, mood and emotional behaviours.

 Several recent studies have indicated that impairment of CB(1) receptor-mediated signalling may play a critical role in the pathophysiology of various neuropsychiatric disorders. In this article, the authors briefly review literature relating to the role played by the endocannabinoid system in various neuropsychiatric disorders, and the CB(1) receptor as a potential therapeutic target for the treatment of alcoholism, depression, anxiety and schizophrenia.”

http://www.ncbi.nlm.nih.gov/pubmed/16548770

Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects.

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“Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.”

http://www.ncbi.nlm.nih.gov/pubmed/12505688

http://www.scribd.com/doc/52920296/Cannabidiol-an-Overview-of-Some-Chemical-and-Pharmacological-Aspects-Part-I-Chemical-Aspects

From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

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“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”

http://www.ncbi.nlm.nih.gov/pubmed/23155985

Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

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Abstract

“Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, antioxidant, antiemetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and antioxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9) -tetrahydrocannabinol is already under clinical evaluation in patients with Huntington’s disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9) -tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.”

http://www.ncbi.nlm.nih.gov/pubmed/22625422

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

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“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.”

“Cannabidiol is a non-psychotropic component of marijuana that binds to CB1 receptors with only comparably very low affinity and is devoid of overt cannabimimetic or pro-psychotic properties. Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH).Furthermore, preliminary clinical case reports suggest that cannabidiol might exert antipsychotic effects in schizophrenic patients. In addition, experimental studies show that cannabidiol reduces psychosis-like effects of Δ9-tetrahydrocannabinol and synthetic analogs.“

Read more:: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/

Medical use of cannabis. Cannabidiol: A new light for schizophrenia?

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Abstract

“The medical properties of cannabis have been known for many centuries; its first documented use dates back to 2800 BC when it was described for its hallucinogenic and pain-relieving properties. In the first half of the twentieth century, a number of pharmaceutical companies marked cannabis for indications such as asthma and pain, but since then its use has sharply declined, mainly due to its unpredictable effects, but also for socio-political issues. Recently, great attention has been directed to the medical properties of phytocannabinoids present in the cannabis plant alongside the main constituent Δ(9) -Tetrahydrocannabinol (THC); these include cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). Evidence suggests an association between cannabis and schizophrenia: schizophrenics show a higher use of marijuana as compared to the healthy population. Additionally, the use of marijuana can trigger psychotic episodes in schizophrenic patients, and this has been ascribed to THC. Given the need to reduce the side effects of marketed antipsychotics, and their weak efficacy on some schizophrenic symptoms, cannabinoids have been suggested as a possible alternative treatment for schizophrenia. CBD, a non-psychoactive constituent of the Cannabis sativa plant, has been receiving growing attention for its anti-psychotic-like properties. Evidence suggests that CBD can ameliorate positive and negative symptoms of schizophrenia. Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia.”

http://www.ncbi.nlm.nih.gov/pubmed/23109356

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

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Philosophical Transactions of the Royal Society B: Biological Sciences: 367 (1607)

“Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive ‘multi-targeting’.”  https://www.ncbi.nlm.nih.gov/pubmed/23108552

“Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities”  http://rstb.royalsocietypublishing.org/content/367/1607/3353.long

The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases.

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Abstract

“During immuno-mediated attack of the brain, activation of endocannabinoids represents a protective mechanism, aimed at reducing both neurodegenerative and inflammatory damage through various and partially converging mechanisms that involve neuronal and immune cells. Here, we review the main alterations of the endocannabinoid system (ECS) within the central nervous system and in peripheral blood mononuclear cells, in order to discuss the intriguing observation that elements of the peripheral ECS mirror central dysfunctions of endocannabinoid signaling. As a consequence, elements of blood ECS might serve as novel, non-invasive diagnostic tools of several neurological disorders, and targeting the ECS might be useful for therapeutic purposes. In addition, we discuss the appealing working hypothesis that the presence of type-1 cannabinoid receptors on the luminal side, and that of type-2 cannabinoid receptors on the abluminal side of the blood-brain barrier, could drive a unidirectional transport of AEA in the luminal –> abluminal direction (i.e., from blood to brain), thus implying that blood may be a reservoir of AEA for the brain. On this basis, it can be expected that an unbalance of the endogenous tone of AEA in the blood may sustain a similar unbalance of its level within the brain, as demonstrated in Huntington’s disease, Parkinson’s disease, multiple sclerosis, attention-deficit/hyperactivity disorder, schizophrenia, depression and headache.”

http://www.ncbi.nlm.nih.gov/pubmed/18781987

A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.

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Abstract

“Δ 9-tetrahydrocannabinol (Δ 9-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ 9- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ 9-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.”

http://www.ncbi.nlm.nih.gov/pubmed/22716160

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug

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“The use Cannabis sativa(cannabis) extracts as medicine was described in China and India before the birth of Christ. The therapeutic use of cannabis was introduced in Western medicine in the first half of the 19th century and reached its climax in the last two decades of the same century. At the turn of the century, several pharmaceutical companies were marketing cannabis extracts and tinctures which were prescribed by doctors for many different complaints including pain, whooping cough and asthma, and as a sedative/hypnotic agent. However, the use of cannabis as a medicine almost completely disappeared at about the middle of the 20th century. The main reasons for this disappearance were the variable potency of cannabis extracts, the erratic and unpredictable individual responses, the introduction of synthetic and more stable pharmaceutical substitutes such as aspirin, chloral hydrate and barbiturates, the recognition of important adverse effects such as anxiety and cognitive impairment, and the legal restrictions to the use of cannabis-derived medicines .”

“Today this situation has changed considerably. The main active psychotropic constituent of cannabis, D9-tetrahydrocannabinol (D9-THC), was isolated, identified and synthesized in the 1960’s. Almost three decades later, cannabinoid receptors in the brain were described and cloned and the endogenous cannabinoids were isolated and identified. As a result of these discoveries the interest in cannabis research has remarkably increased. For instance, the number of publications using the key word “brain”, compiled by the ISI Web of Knowledge, increased 26 times from 1960-1964 to 2000-2004, while the number of publications about `cannabis’ increased 78.5 times during the same period. As a consequence, the research on the use of cannabis as medicine has been renewed.”

” A high dose of D9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of D9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.”

“In conclusion, results from pre-clinical and clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. Future trials of this cannabinoid in other psychotic conditions such as bipolar disorder (50) and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly needed.”

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2006000400001&lng=en&nrm=iso&tlng=en