Medical Cannabis Research
Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues
By Ethan Russo | US National Institute of Health | September 14, 2016
This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain. - Full Review
Cannabidiol Rather than Cannabis Sativa Extracts Inhibit Cell Growth and Induce Apoptosis in Cervical Cancer Cells
By Sindiswa T. Lukhele and Lesetja R. Motadi | National Institute of Health | September 1, 2016
Background
Cervical cancer remains a global health related issue among females of Sub-Saharan Africa, with over half a million new cases reported each year. Different therapeutic regimens have been suggested in various regions of Africa, however, over a quarter of a million women die of cervical cancer, annually. This makes it the most lethal cancer amongst black women and calls for urgent therapeutic strategies. In this study we compare the anti-proliferative effects of crude extract of Cannabis sativa and its main compound cannabidiol on different cervical cancer cell lines.
Methods
To achieve our aim, phytochemical screening, MTT assay, cell growth analysis, flow cytometry, morphology analysis, Western blot, caspase 3/7 assay, and ATP measurement assay were conducted.
Results
Results obtained indicate that both cannabidiol and Cannabis sativa extracts were able to halt cell proliferation in all cell lines at varying concentrations. They further revealed that apoptosis was induced by cannabidiol as shown by increased subG0/G1 and apoptosis through annexin V. Apoptosis was confirmed by overexpression of p53, caspase 3 and bax. Apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a decrease in the ATP levels.
Conclusions
In conclusion, these data suggest that cannabidiol rather than Cannabis sativa crude extracts prevent cell growth and induce cell death in cervical cancer cell lines. - Full Review
Cannabigerol is a Novel, Well-Tolerated Appetite Stimulant in Pre-Satiated Rats
By Daniel I Brierley, James Samuels, Marnie Duncan, Benjamin J Whalley, Claire M Williams | Psychopharmacology | August 9, 2016
The appetite-stimulating properties of cannabis are well documented and have been predominantly attributed to the hyperphagic activity of the psychoactive phytocannabinoid, ∆9-tetrahydrocannabinol (∆9-THC). However, we have previously shown that a cannabis extract devoid of ∆9-THC still stimulates appetite, indicating that other phytocannabinoids also elicit hyperphagia. One possible candidate is the non-psychoactive phytocannabinoid cannabigerol (CBG), which has affinity for several molecular targets with known involvement in the regulation of feeding behaviour.
Results
CBG produced no adverse effects on any parameter in the neuromotor tolerability test battery. In the feeding assay, 120–240 mg/kg CBG more than doubled total food intake and increased the number of meals consumed, and at 240 mg/kg reduced latency to feed. However, the sizes or durations of individual meals were not significantly increased.
Conclusions
Here, we demonstrate for the first time that CBG elicits hyperphagia, by reducing latency to feed and increasing meal frequency, without producing negative neuromotor side effects. Investigation of the therapeutic potential of CBG for conditions such as cachexia and other disorders of eating and body weight regulation is thus warranted. - Full Review
Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes
By Russo Ethan B. | Cannabis and Cannabinoid Research. | Volume 1.1, 2016 |
DOI: 10.1089/can.2016.0009 | July 2016
Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking.
Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS. - Full Review
Cannabinoids, Inflammation, and Fibrosis
By Robert B. Zurier and Sumner H. Burstein | The FASEB Journal | July 11, 2016
Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented. Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations—Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)—that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (CT-3, AJA; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances.
Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.—Zurier, R. B., Burstein, S. H. Cannabinoids, inflammation, and fibrosis. - Abstract
Association Between Cerebral Cannabinoid 1 Receptor Availability and Body Mass Index in Patients with Food Intake Disorders and Healthy Subjects
By J Ceccarin, N Weltens, H G Ly, J Tack, L Van Oudenhove and K Van Laere | Translational Psychiatry | July 12, 2016
Although of great public health relevance, the mechanisms underlying disordered eating behavior and body weight regulation remain insufficiently understood. Compelling preclinical evidence corroborates a critical role of the endocannabinoid system (ECS) in the central regulation of appetite and food intake. However, in vivo human evidence on ECS functioning in brain circuits involved in food intake regulation as well as its relationship with body weight is lacking, both in health and disease. Here, we measured cannabinoid 1 receptor (CB1R) availability using positron emission tomography (PET) with [18F]MK-9470 in 54 patients with food intake disorders (FID) covering a wide body mass index (BMI) range (anorexia nervosa, bulimia nervosa, functional dyspepsia with weight loss and obesity; BMI range=12.5–40.6 kg/m2) and 26 age-, gender- and average BMI-matched healthy subjects (BMI range=18.5–26.6 kg/m2). The association between regional CB1R availability and BMI was assessed within predefined homeostatic and reward-related regions of interest using voxel-based linear regression analyses. CB1R availability was inversely associated with BMI in homeostatic brain regions such as the hypothalamus and brainstem areas in both patients with FID and healthy subjects. However, in FID patients, CB1R availability was also negatively correlated with BMI throughout the mesolimbic reward system (midbrain, striatum, insula, amygdala and orbitofrontal cortex), which constitutes the key circuit implicated in processing appetitive motivation and hedonic value of perceived food rewards.
Our results indicate that the cerebral homeostatic CB1R system is inextricably linked to BMI, with additional involvement of reward areas under conditions of disordered body weight. - Full Review
The Bright Side of Psychoactive Substances: Cannabinoid-Based Drugs in Motor Diseases
By R. Coccurelloab & T. Bisogno | National Institute of Health | July 2, 2016
Introduction: psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the “bright side” of e cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework.
Areas covered: we will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson’s disease and Huntington disease.
Expert commentary: despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network. - Abstract
Amyloid Proteotoxicity Initiates an Inflammatory Response Blocked by Cannabinoids
By Antonio Currais, Oswald Quehenberger, Aaron M Armando, Daniel Daugherty, Pam Maher & David Schubert | Aging and Mechanisms of Disease | June 23, 2016
ABSTRACT: The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood. We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ. It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell’s demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death. Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective. Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors. - Full Review
CB2 Cannabinoid Receptor As Potential Target against Alzheimer’s Disease
By Ester Aso and Isidro Ferrer | Institut de Neuropatologia, Servei d’Anatomia Patològica, Bellvitge Biomedical Research Institute (IDIBELL)-Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain 2CIBERNED - Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Madrid, Spain | May 31, 2016
The CB2 receptor is one of the components of the endogenous cannabinoid system, a complex network of signaling molecules and receptors involved in the homeostatic control of several physiological functions. Accumulated evidence suggests a role for CB2 receptors in Alzheimer’s disease (AD) and indicates their potential as a therapeutic target against this neurodegenerative disease. Levels of CB2 receptors are significantly increased in post-mortem AD brains, mainly in microglia surrounding senile plaques, and their expression levels correlate with the amounts of Aβ42 and β-amyloid plaque deposition. Moreover, several studies on animal models of AD have demonstrated that specific CB2 receptor agonists, which are devoid of psychoactive effects, reduce AD-like pathology, resulting in attenuation of the inflammation associated with the disease but also modulating Aβ and tau aberrant processing, among other effects. CB2 receptor activation also improves cognitive impairment in animal models of AD. This review discusses available data regarding the role of CB2 receptors in AD and the potential usefulness of specific agonists of these receptors against AD.
Conclusions and Future Perspectives
Taken together, the experimental observations discussed in the present review indicate that AD induces CB2 receptor expression and that targeting CB2 receptors has beneficial effects in AD. Specifically, CB2 receptor agonists reduce inflammatory responses linked to Aβ production and deposition, facilitate Aβ clearance, increase cell viability in the presence of Aβ, and promote glucose uptake in brain. Moreover, CB2 activity likely reduces tau hyper-phosphorylation and oxidative stress damage caused by Aβ peptides (Figure 1). As a result of the combination of these effects, among others, CB2 receptor agonists induce cognitive improvement in AD models.
Considering the evidence of pleiotropic activity and lack of undesirable psychoactive effects of CB2 receptors, compounds acting on such cannabinoid receptors represent a promising therapy against AD. Nevertheless, there is still no information regarding the efficacy or toxicity in human beings of compounds specifically targeting CB2 receptors, which might exhibit some side effects such as immune suppression (Pertwee, 2005). For these reasons, progress toward clinical practice requires further investigation. - Full Review
Associations Between Cannabis Use and Physical Health Problems in Early Midlife
A Longitudinal Comparison of Persistent Cannabis vs Tobacco Users
By Madeline H. Meier, PhD; Avshalom Caspi, PhD; Magdalena Cerdá, DrPH; Robert J. Hancox, MD; HonaLee Harrington, BA; Renate Houts, PhD; Richie Poulton, PhD; Sandhya Ramrakha, PhD; W. Murray Thomson, PhD8; Terrie E. Moffitt, PhD | JAMA Psychiatry | June 1, 2016
Importance After major policy changes in the United States, policymakers, health care professionals, and the general public seek information about whether recreational cannabis use is associated with physical health problems later in life.
Objective To test associations between cannabis use over 20 years and a variety of physical health indexes at early midlife.
Design, Setting, and Participants Participants belonged to a representative birth cohort of 1037 individuals born in Dunedin, New Zealand, in 1972 and 1973 and followed to age 38 years, with 95% retention (the Dunedin Multidisciplinary Health and Development Study). We tested whether cannabis use from ages 18 to 38 years was associated with physical health at age 38, even after controlling for tobacco use, childhood health, and childhood socioeconomic status. We also tested whether cannabis use from ages 26 to 38 years was associated with within-individual health decline using the same measures of health at both ages.
Exposures We assessed frequency of cannabis use and cannabis dependence at ages 18, 21, 26, 32, and 38 years.
Main Outcomes and Measures We obtained laboratory measures of physical health (periodontal health, lung function, systemic inflammation, and metabolic health), as well as self-reported physical health, at ages 26 and 38 years.
Results The 1037 study participants were 51.6% male (n = 535). Of these, 484 had ever used tobacco daily and 675 had ever used cannabis. Cannabis use was associated with poorer periodontal health at age 38 years and within-individual decline in periodontal health from ages 26 to 38 years. For example, cannabis joint-years from ages 18 to 38 years was associated with poorer periodontal health at age 38 years, even after controlling for tobacco pack-years (β = 0.12; 95% CI, 0.05-0.18; P <.001). Additionally, cannabis joint-years from ages 26 to 38 years was associated with poorer periodontal health at age 38 years, even after accounting for periodontal health at age 26 years and tobacco pack-years (β = 0.10; 95% CI, 0.05-0.16; P <.001) However, cannabis use was unrelated to other physical health problems. Unlike cannabis use, tobacco use was associated with worse lung function, systemic inflammation, and metabolic health at age 38 years, as well as within-individual decline in health from ages 26 to 38 years.
Conclusions and Relevance Cannabis use for up to 20 years is associated with periodontal disease but is not associated with other physical health problems in early midlife. - Abstract
Cannabinoid Receptor Type-1: Breaking the Dogmas
Authors: Arnau Busquets Garcia, Edgar Soria-Gomez, Luigi Bellocchio, and Giovanni Marsicano | National Institute of Health | May 24, 2016
Abstract
The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB 1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB 1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB 1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB 1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.
Introduction
The endocannabinoid system (ECS) is composed of G protein-coupled cannabinoid receptors, namely cannabinoid receptor-1 (CB 1) and cannabinoid receptor-2 (CB 2) 1, 2; the endogenous cannabinoids called endocannabinoids, such as the lipids anandamide and 2-arachidonoylglycerol 3, 4; and the enzymes involved in their synthesis and inactivation 5. The family of endocannabinoids has recently grown to include a group of peptide ligands (so-called pepcans) and other lipid molecules, such as lipoxin and pregnenolone, interestingly acting as allosteric enhancers or signal-specific inhibitors (SSIs) of CB 1 receptors 6.
One of the main characteristics of the ECS is its broad distribution throughout the body. In this review, we will specifically focus our attention on the CB 1 receptor-dependent functions in the nervous system (particularly the brain). The CB 1 receptor is considered the most abundant metabotropic receptor in the brain. It was cloned in 1990 and its distribution has been well characterized in both rodents 8, 9 and humans 10. These receptors are particularly rich in the central nervous system 11, 12, where they control a wide spectrum of physiological and pathological conditions, including brain development, learning and memory, motor behavior, regulation of appetite, body temperature, pain perception, inflammation, and they are involved in various psychiatric, neurological, and neurodevelopmental disorders.
This review highlights recent findings that challenge or extend accepted “dogmas” of CB 1 receptor signaling. Thus, it discusses where CB 1 receptors are localized, the importance of CB 1 receptors outside the brain, and new strategies to pharmacologically act on these receptors. Importantly, the understanding of where, which, and how CB 1 receptor function is mandatory to improve the pharmacological strategies to act on this promising therapeutic target. - Full Review
Cannabinoids for the Treatment of Schizophrenia: An Overview
By Capasso, Anna; Sobarzo-Sánchez, Eduardo; Fazel Nabavi, Seyed; Rastrelli, Luca | Current Topics in Medicinal Chemistry, Volume 16, Number 17, July 2016, pp. 1916-1923 | Publication Date: July 1, 2016
Cannabinoids are found to be very useful in psychiatry because of their antipsychotic properties suggesting a therapeutic use as neuroleptic agents in limiting psychotic diseases.
Cannabinoids treatments are both able to reduce the typical symptoms of schizophrenia and to slow down the disease aggravation. In the present review, we reported recent studies supporting the idea that the cannabinoid system may modulate the activity of the striatum and temporal cortex linked to psychosis and schizophrenia. Furthermore, anatomical, electrophysiological, pharmacological and biochemical data suggest that the psychotic disorders related to the impaired cannabinoid system may lead to the development of novel compounds that selectively target specific elements of the cannabinoid system. - Abstract
Gastric Acid Inhibitory and Gastric Protective Effects of Cannabis and Cannabinoids
By Abdel-Salam | Asian Pacific Journal of Tropical Medicine | April 2016
Introduction
Cannabis is the most commonly abused illicit substance worldwide. The two commonly used cannabis preparations are herbal cannabis or marijuana (prepared from the dried flowering tops and leaves) and hashish (consists of dried cannabis resin and compressed flowers). Both are derived from the female plant of Cannabis sativa Linn (family Cannabidaceae). Research into cannabis led to discovery of its active constituents or cannabinoids, a terpeno-phenol compounds; more than 70 of which have been isolated. The most studied cannabinoids are Δ9-tetrahydrocannabinol (THC), cannabinol, cannabidiol, cannabigerol, cannabichromene, Δ9-tetrahydrocannabivarin, cannabidivarin and others. Δ9-THC is the primary constituent that is responsible for the psychotropic properties of recreational cannabis.
Cannabinoids mediate their biological effects through interaction with cannabinoid receptors, which belong to the superfamily of G protein-coupled receptors. There are at least two cannabinoid receptor subtypes: the CB1 receptor, essentially located in the central nervous system, but also in peripheral tissues, and the CB2 receptor, found only at the periphery especially on immune cells. Most of cannabis effects in the central nervous system are mediated by CB1 receptors. These are expressed at brain areas that control movements, memory, cognition and emotion and in the spinal cord where they mediate retrograde inhibition of neuronal activity.
Cannabinoid receptors can also be activated by a number of endogenous ligands, the endocannabinoids. The main endocannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) are selective agonists at the CB1 and CB2 receptors, respectively. Both are derivatives of arachidonic acid, that are produced and released ‘on demand’ by cleavage of membrane lipid precursors and are hydrolysed by the fatty acid amide hydrolase anandamide or monoglyceride lipase, respectively. Other endocannabinoids are noladin ether and virodhamine. The cannabinoid receptors, endocannabinoids as well as the enzymes responsible for their synthesis or degradation, collectively constitute the ‘endocannabinoid system’.
Cannabis sativa has a wide-world reputation as a psychotropic drug. Cannabis are usually smoked, but may also be eaten, mixed in cakes or cookies or drunk in a liquid infusion. Only recently, did cannabis and cannabinoid-based medicines come to attention as a remedy for different medical conditions. The sublingual oromucosal spray Sativex, composed of whole plant extract containing both Δ9-THC and cannabidiol (CBD) [THC: CBD=1:1] have recently been approved for the treatment of pain and spasticity in multiple sclerosis. Dronabinol (Marinol) and nabilone (Cesamet) are two oral formulations of a synthetic THC approved for the treatment of nausea and vomiting that complicate chemotherapy and which are refractory to conventional antiemetic therapy. These agents are also being used to improve appetite to treat weight loss associated with human immunodeficiency virus infection and cancer. Medicinal cannabis is also being used for a variety of medical conditions including chronic pain, depression, arthritis, and neuropathy. The endocannabinoid system is a target for the treatment of neurodegenerative disease eg., tics in Tourette syndrome, levodopa-induced dyskinesia in Parkinson s disease and some forms of tremor and dystonia.
Cannabinoid receptors and their endogenous ligands (anandamide and 2-arachidonylglycerol) have been identified in the gastrointestinal tract and are involved in mediation of several gastrointestinal functions eg., relaxation of the lower oesophageal sphincter, gastric acid secretion, gastric emptying, gastrointestinal motility and fluid secretion. Evidence thus suggests that cannabinoid-based medicines might be beneficial in a number of gastrointestinal disorders.
The aim of this review is to compile and discuss the available data pertaining to the effect of cannabis and/or cannabinoids on gastric acid secretion and gastric mucosal integrity.
Conclusions
Cannabis and/or individual cannabinoids inhibit gastric acid secretion. The inhibitory effect of cannabis/cannabinoid agonists on gastric acid secretion is likely to be mediated via CB1 receptors. The inhibitory effect might be mediated through activation of CB1 receptor located on the vagal efferent pathways. There is also an evidence for a possible direct effect for cannabis on the CB1 receptors located on parietal cells. Cannabis could also inhibit secretion by decreasing central efferent vagus activity. There appears to be no densistization to the action of cannabis following long-term administration of the herb. Cannabis inhibits the development of gastric ulcers induced by pyloric-ligation (Shay rat), restraint induced ulcers, and NSAIDs. Exogenous administration of endocannabinoids or increasing the levels of endogenous cannabinoids resulted in a gastric protection. The gastroprotective effect of cannabis could be blocked by a CB1 antagonist. Activation of central cannabinoid receptors results in gastric mucosal protection. Cannabis thus exerts antioxidant and anti-inflammatory effects in the gastric mucosa. It is possible that a vasodilatory action is involved in the gastric protective effects of cannabis and or cannabinoids. Casnnabinoids-based medicines might find utility in treatment of peptic ulcer disease including gastroesophageal reflux. - Full PDF
Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress–Related Genes
By Arkaitz Carracedo, Meritxell Gironella, Mar Lorente, Stephane Garcia, Manuel Guzmán, Guillermo Velasco, and Juan L. Ivanna | The Journal of Cancer Research | (Cancer Res 2006; 66(13): 6748-55)
Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue.
In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB2 receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress–related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer. - Abstract
The Use of Cannabinoids in Animals and Therapeutic Implications for Veterinary Medicine: a Review
Authors: L. Landa, A. Sulcova, P. Gbelec | Veterinarni Medicina, 61, 2016 (3): 111–122
ABSTRACT: Cannabinoids/medical marijuana and their possible therapeutic use have received increased atten- tion in human medicine during the last years. This increased attention is also an issue for veterinarians because particularly companion animal owners now show an increased interest in the use of these compounds in veteri- nary medicine. This review sets out to comprehensively summarise well known facts concerning properties of cannabinoids, their mechanisms of action, role of cannabinoid receptors and their classification. It outlines the main pharmacological effects of cannabinoids in laboratory rodents and it also discusses examples of possible beneficial use in other animal species (ferrets, cats, dogs, monkeys) that have been reported in the scientific lit- erature. Finally, the article deals with the prospective use of cannabinoids in veterinary medicine. We have not intended to review the topic of cannabinoids in an exhaustive manner; rather, our aim was to provide both the scientific community and clinical veterinarians with a brief, concise and understandable overview of the use of cannabinoids in veterinary medicine.
Keywords: cannabinoids; medical marijuana; laboratory animals; companion animals; veterinary medicine - Full Review
Using Medical Marijuana To Stop Seizures in Kids
Desperate for relief, parents are taking unusual steps to help children plagued with seizures. The relief, however, comes in a most unlikely form: marijuana.
By Science Daily | Source: Texas A&M University | February 8, 2016
As many as 30 percent of people with epilepsy — or about one million Americans — still have seizures while on Food and Drug Administration (FDA)-approved treatments. It’s left many who suffer from uncontrollable seizures — or their parents, as many of them are children — turning to medical marijuana and its derivatives in an attempt to take back control of a disease with no cure.
A seizure is an abnormal electrical storm in the brain that causes sudden alteration in consciousness, sensation and behavior that can manifest from an eye flicker to full-body convulsions. People with medication-resistant (also called intractable) epilepsy suffer from consequences of recurrent seizures, which could damage the brain and adversely impact their quality of life. This is commonly observed in children with certain types of devastating pediatric epilepsy, such as Lennox-Gastaut, Doose and Dravet syndromes.
Stories about desperate parents seeking anything to relieve their children’s seizures abound, but how much scientific evidence is there for cannabis’ effectiveness?
D. Samba Reddy, Ph.D., R.Ph., professor in the Department of Neuroscience and Experimental Therapeutics at the Texas A&M Health Science Center College of Medicine, studies novel therapies for epilepsy. He recently published an article, with co-author Victoria Golub, in the Journal of Pharmacology and Experimental Therapeutics about the current state of research into medical marijuana for treating epilepsy. - Full Article
Medicinal Cannabis: In Vitro Validation of Vaporizers for the Smoke-Free Inhalation of Cannabis
Christian Lanz, Johan Mattsson, Umut Soydaner, Rudolf Brenneisen |
Department of Clinical Research, Laboratory of Phytopharmacology, Bioanalytics and Pharmacokinetics, University of Bern, Bern, Switzerland, 2 Center of Laboratory Medicine, University Institute of Clinical Chemistry, Inselspital, University Hospital Bern, Bern, Switzerland | January 19, 2016
1 Department of Clinical Research, Laboratory of Phytopharmacology, Bioanalytics and Pharmacokinetics, University of Bern, Bern, Switzerland, 2 Center of Laboratory Medicine, University Institute of Clinical Chemistry, Inselspital, University Hospital Bern, Bern, SwitzerlandInhalation by vaporization is a promising application mode for cannabis in medicine. An in vitro validation of 5 commercial vaporizers was performed with THC-type and CBD-type cannabis. Gas chromatography/mass spectrometry was used to determine recoveries of total THC (THCtot) and total CBD (CBDtot) in the vapor. High-performance liquid chromatog- raphy with photodiode array detection was used for the quantitation of acidic cannabinoids in the residue and to calculate decarboxylation efficiencies. Recoveries of THCtot and CBDtot in the vapor of 4 electrically-driven vaporizers were 58.4 and 51.4%, 66.8 and 56.1%, 82.7 and 70.0% and 54.6 and 56.7% for Volcano Medic1, Plenty Vaporizer1, Arizer Solo1 and DaVinci Vaporizer1, respectively. Decarboxylation efficiency was excellent for THC (! 97.3%) and CBD (! 94.6%). The gas-powered Vape-or-SmokeTM showed recover- ies of THCtot and CBDtot in the vapor of 55.9 and 45.9%, respectively, and a decarboxylation efficiency of ! 87.7 for both cannabinoids. However, combustion of cannabis was observed with this device. Temperature-controlled, electrically-driven vaporizers efficiently decarbox- ylate inactive acidic cannabinoids and reliably release their corresponding neutral, active cannabinoids. Thus, they offer a promising application mode for the safe and efficient administration of medicinal cannabis. - Link to Article
Cannabinoids: A Potent Anti-Inflammatory Agent Against Neurodegenerative Disorders
BY Chandermehak Singh, Jasbir Singh, Raman Saini, Kanika Sharma, Rashmi Mittal,
Narender Chaudhry | Department of Biotechnology, Maharishi Markendeshwar University, Mullana, Haryana-133203, India | November 2015
Abstract
Cannabinoid based drugs exhibits promising results against neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease in animal models and humans. Cannabinoid based drugs either acts in receptor dependent or receptor independent fashion and are known to exhibit antiepileptic, anti-nausea, anti-emetic, anti-inflammatory, anxiolytic, anti-psychotic, and anti- ischemic properties. Psychoactive and non-psychoactive cannabinoids based drugs majorly contains Δ9- THC and CBD. Activation of CB1 and CB2 receptors plays a vital role in regulating the inflammatory issues. Cannabinoid inhibits the pro-inflammatory signals, inhibits the inflammatory cytokines production, interrupts the JAK/STAT pathway and furthermore promotes the phagocytosis of Aβ and thus acts as a potent anti-inflammatory drug. The anti-inflammatory potential of these drugs has led to the testing of these drugs against other human diseases also. This review article describes the role of cannabinoids in combating the issues of neurodegenerative disorders by acting as an anti-inflammatory agent.
Conclusion
From all the evidences presented in this review, it can be clearly said that neuro- inflammation are key mediators of various neurodegenerative disorders. Neurodegenerative disorders such as AD, PD and HD are life threatening. Cannabinoids plays a miraculous role in combating the issues of neurodegeneration. Cannabinoids acts as an anti-inflammatory agent and thus efficiently inhibits the inflammatory signaling pathways. They inhibits the pro-inflammatory signals, inhibits the inflammatory cytokines production, interrupts the JAK/STAT pathway thus acts as an effective measure to overcome the complication of neurodegeneration. Enormous potential of cannabinoids to act as an anti-inflammatory agent has led to the discovery of therapeutic measures which will help in combating the disease efficiently and will make us observe a drop in mortality rates due to complication of neurodegeneration. - Full Review
Purified Cannabidiol, the Main Non-Psychotropic Component of Cannabis Sativa, Alone, Counteracts Neuronal Apoptosis in Experimental Multiple Sclerosis
S. GIACOPPO1, T. SOUNDARA RAJAN1, M. GALUPPO1, F. POLLASTRO2, G. GRASSI3, P. BRAMANTI1, E. MAZZON | European Review for Medical and Pharmacological Sciences | 2015
Multiple Sclerosis (MS) is a global concern disease leading to a progressive, chronic and demyelinating condi- tion, affecting the central nervous system (CNS). The pathology has an inflammatory/autoimmune origin; nevertheless, neuronal cell death mecha- nisms are not to be underestimated. The present study was designed to test the effects of in- traperitoneal administration of cannabidiol (CBD), the main non-psychotropic cannabinoid of Cannabis sativa (CS), in an experimental mod- el of MS. The aim is to evaluate the capability of CBD administration to thwart the cascade of me- diators involved in MS-induced apoptosis. - Full Abstract
Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine
By Luciano Rezende Vilela, Lindisley Ferreira Gomides,Bruna Araújo David, Maísa Mota Antunes, Ariane Barros Diniz, Fabrício de Araújo Moreira, and Gustavo Batista Menezes | Hindawi Publishing Corporation Mediators of Inflammation | April 7, 2015
Cocaine is a commonly abused illicit drug that causes signiicant morbidity and mortality. he most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inlammatory iniltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD), protects against cocaine toxicity. URB597 (1.0 mg/kg) abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg) reduced acute liver inlammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen) increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. hese indings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inlammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse. - Full Review
Largest Study Yet Show Great Promise for Cannabidiol (CBD) Cannabinoid and Epilepsy in Children
Orrin Devinsky, Elizabeth Thiele, Linda Laux, Daniel Friedman, Anup Patel, Judith Bluvstein, Michael Chez, Charuta Joshi, Roberta Cilio, Francis Filloux, Evan Fertig, Angus Wilfong, Paul D. Lyons, Yong Park, Robert Flamini, Matthew Wong, Ian Miller, Eric Marsh | American Epilepsy Society | 2015
Investigators using the rationale that Cannabidiol (CBD) demonstrates anticonvulsant efficacy in multiple species and models in animal studies, patients received a highly standardized pharmaceutical plant-derived, purified CBD, Epidiolex by GW Pharma.
Children with treatment-resistant epilepsies, including Dravet Syndrome and Lennox-Gastaut Syndrome were administered a 3 month treatment showed a 45.1% reduction in seizures across all patients. 62.7% seizure frequency reduction was seen in Dravet Syndrome patients. - Abstract
The Potential Therapeutic Effects of THC on Alzheimer’s Disease
By Authors: Authors: Cao, Chuanhai; | Li, Yaqiong | Liu, Hui; | Bai, Ge | Mayl, Jonathan | Lin, Xiaoyang; | Sutherland, Kyle | Nabar, Neel | Cai, Jianfeng | College of Pharmacy, University of South Florida, Tampa FL, USA | USF-Health Byrd Alzheimer’s Institute, University of South Florida, Tampa FL, USA | Department of Chemistry, University of South Florida, Tampa FL, USA | College of Medicine, University of South Florida, Tampa FL, USA | Thomas Jefferson University, Philadelphia, PA, USA | April 29, 2014
The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer’s disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial.
From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin’s enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.- Abstract
Neuroprotective Effects of the Cannabinoid Agonist HU210 on Retinal Degeneration.
Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). - Abstract
Cannabis Finds Its Way into Treatment of Crohn’s Disease
Rudolf Schichoa & Martin Storrb
a Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria;
b Department of Medicine II, Klinikum Grosshadern, Ludwig Maximilian University, Munich, Germany
In ancient medicine, cannabis has been widely used to cure disturbances and inflammation of the bowel. A re- cent clinical study now shows that the medicinal plant Cannabis sativa has lived up to expectations and proved to be highly efficient in cases of inflammatory bowel dis- eases (IBD). In a prospective placebo-controlled study, Naftali et al. [1] have shown what has been largely antici- pated from anecdotal reports, i.e. that cannabis prod uces significant clinical benefits in patients with Crohn’s dis- ease. The mechanisms involved are not yet clear but most likely include peripheral actions on cannabinoid (CB) re- ceptors 1 and 2 (CB1 and CB2), and may also include central actions.
The past 10 years have seen a constant rise in publica- tions dealing with the anti-inflammatory effects of CBs and the potential underlying mechanisms. Preclinical data on the ameliorating effect of synthetic and natural CBs in animal models mimicking features of IBD have been rapidly evolving. The reasonable idea that CBs would also be beneficial in IBD patients was mainly based on results from experiments in CB receptor knockout mice and on data using CB receptor agonists and antago- nists. Following a previous publication of a retrospective, observational study by Naftali et al. [2] and a question- naire performed by a different group in patients with ul- cerative colitis and Crohn’s disease [3], both revealing symptom relief and improvement after use of cannabis, Naftali et al. [1] have now presented a placebo-controlled prospective study in 21 patients with Crohn’s disease un- responsive to standard IBD treatment. Although the pri- mary end point of induction of remission was statistical- ly not achieved, they were able to demonstrate that an 8-week treatment with tetrahydrocannabinol (THC)- rich cannabis caused a decrease in the Crohn’s disease activity index in 90% of patients without producing sig- nificant side effects. - Full Abstract
Tetrahydrocannabinolic Acid Reduces Nausea-Induced Conditioned Gaping in Rats and Vomiting in Suncus Murinus
By E M Rock, R L Kopstick, C L Limebeer and L A Parker | British Journal of Pharmacology | September 17, 2013
The cannabis plant is a source of at least 70 phytocannabinoids, including the psychoactive component Δ9-tetrahydrocannabinol (THC). THC is effective in interfering with nausea and vomiting in human cancer patients (see Cotter, 2009 for review). Comparisons of oral THC with the common anti-emetic agents of the time showed that THC was at least as effective (Frytak et al., 1979; Carey et al., 1983; Ungerleider et al., 1984; Crawford and Buckman, 1986; Cunningham et al., 1988; Tramer et al., 2001) if not more effective (Orr et al., 1980; Orr and McKernan, 1981) at reducing nausea and vomiting in human patients.
In animal models, THC reduces vomiting in ferrets (Van Sickle et al., 2001) and has been shown to suppress acute vomiting induced by cisplatin (Darmani, 2001b), SR141716 (SR), a cannabinoid 1 (CB1) receptor antagonist (Darmani, 2001a), radiation (Darmani et al., 2007) and 5-hydroxytryptophan (an indirect 5-HT receptor agonist, Darmani and Johnson, 2004) in Cryptotis parva (least shrews), a well-established animal model for assessing vomiting (see Darmani, 1998). In another animal model for assessing vomiting, Suncus murinus (house musk shrew), THC reduces cisplatin- (Kwiatkowska et al., 2004), LiCl- (Parker et al., 2004) and motion-induced vomiting (Cluny et al., 2008). Additionally, the administration of THC prior to reintroduction to a context previously associated with illness suppressed the expression of conditioned retching in shrews (Parker and Kemp, 2001; Parker et al., 2006).
Using the taste reactivity (TR) test, THC (0.5 mg·kg−1) has also been shown to interfere with the establishment and expression of conditioned gaping in rats produced by cyclophosphamide, a commonly used chemotherapy drug (Limebeer and Parker, 1999) and LiCl (Parker and Mechoulam, 2003; Parker et al., 2003). Unlike conditioned taste avoidance, which can be produced by both rewarding drugs and emetic drugs, conditioned gaping reactions are produced only by drugs that induce vomiting in emetic species, such as shrews (Parker, 2003; Parker et al., 2008). In a rodent model of anticipatory nausea (AN), THC (0.5 mg·kg−1) also reduces contextually elicited conditioned gaping in rats (Limebeer et al., 2006). The THC-induced suppression of nausea-induced behaviours and vomiting can be reversed by administration of the CB1 receptor antagonists SR or AM251, so it seems that the anti-emetic and anti-nausea effects of THC are mediated by the CB1 receptor (Darmani, 2001b; Parker et al., 2004; Darmani and Johnson, 2004; Darmani et al., 2007; Cluny et al., 2008).
THC is formed in cannabis from an acidic precursor, tetrahydrocannabinolic acid (THCA, Gaoni and Mechoulam, 1964). In the fresh plant, THCA is decarboxylated to THC by heating or burning. Interestingly, no psychotomimetic activity was observed with THCA administration to rhesus monkeys (doses ≤ 5 mg·kg−1, i.v.), mice (doses ≤ 20 mg·kg−1, i.p.) and dogs (doses ≤ 7 mg·kg−1; Grunfeld and Edery, 1969), perhaps making THCA a more desirable treatment than THC because it is devoid of psychoactive activity. No in vivo studies to date have evaluated THCA’s mechanism of action, however in vitro, THCA’s ability to inhibit the TNF-α levels in culture supernatants from U937 macrophages was not blocked by administration of the CB1 receptor antagonist AM281, or the cannabinoid 2 receptor (CB2) receptor antagonist AM630 (Verhoeckx et al., 2006). In addition, binding assays indicate that THCA is not active at the CB1 receptor (Ahmed et al., 2008). - Full Review
Cannabidiol for Neurodegenerative Disorders: Important New Clinical Applications for this Phytocannabinoid?
Javier Fernández-Ruiz, Onintza Sagredo, M Ruth Pazos,4 Concepción García, Roger Pertwee, Raphael Mechoulam, and José Martínez-Orgado | US National Library of Medicine National Institutes of Health | 2013
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, anti-oxidant, anti-emetic, 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. - Full Abstract
Effects of Marijuana Smoking on the Lung
By Donald P. Tashkent | American Thoracic Society | January 2013
Regular smoking of marijuana by itself causes visible and microscopic injury to the large airways that is consistently associated with an increased likelihood of symptoms of chronic bronchitis that subside after cessation of use. On the other hand, habitual use of marijuana alone does not appear to lead to significant abnormalities in lung function when assessed either cross-sectionally or longitudinally, except for possible increases in lung volumes and modest increases in airway resistance of unclear clinical significance. Therefore, no clear link to chronic obstructive pulmonary disease has been established. Although marijuana smoke contains a number of carcinogens and cocarcinogens, findings from a limited number of well-designed epidemiological studies do not suggest an increased risk for the development of either lung or upper airway cancer from light or moderate use, although evidence is mixed concerning possible carcinogenic risks of heavy, long-term use. Although regular marijuana smoking leads to bronchial epithelial ciliary loss and impairs the microbicidal function of alveolar macrophages, evidence is inconclusive regarding possible associated risks for lower respiratory tract infection. Several case reports have implicated marijuana smoking as an etiologic factor in pneumothorax/pneumomediastinum and bullous lung disease, although evidence of a possible causal link from epidemiologic studies is lacking. In summary, the accumulated weight of evidence implies far lower risks for pulmonary complications of even regular heavy use of marijuana compared with the grave pulmonary consequences of tobacco. - Abstract
The Endo-Cannabinoid System as a Possible Target to Treat Both the Cognitive and Emotional Features of Post-Traumatic Stress Disorder (PTSD)
Viviana Trezza and Patrizia Campolongo | Frontiers in Behavioral Neuroscience | National Institute of Health | 2013
Post-traumatic stress disorder (PTSD) is a psychiatric disorder of significant prevalence and morbidity, whose pathogenesis relies on paradoxical changes of emotional memory processing. An ideal treatment would be a drug able to block the pathological over-consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. While the latter benefit from antidepressant medications, no drug is available to control the cognitive symptomatology. Endocannabinoids regulate affective states and participate in memory consolidation, retrieval, and extinction. Clinical findings showing a relationship between Cannabis use and PTSD, as well as changes in Endo-Cannabinoid activity in PTSD patients, further suggest the existence of a link between endocannabinoids and maladaptive brain changes after trauma exposure. Along these lines, we suggest that Endo-Cannabinoid degradation inhibitors may be an ideal therapeutic approach to simultaneously treat the emotional and cognitive features of PTSD, avoiding the unwanted psychotropic effects of compounds directly binding cannabinoid receptors. - Full Publication
The Medical Necessity for Medicinal Cannabis: Prospective, Observational Study Evaluating the Treatment in Cancer Patients on Supportive or Palliative Care
By Gil Bar-Sela, Marina Vorobeichik, Saher Drawsheh, Anat Omer, Victoria Goldberg, and Ella Muller | Evidence-Based Complementary and Alternative Medicine | June 24, 2013
Cancer patients using cannabis report better influence from the plant extract than from synthetic products. However, almost all the research conducted to date has been performed with synthetic products. We followed patients with a medicinal cannabis license to evaluate the advantages and side effects of using cannabis by cancer patients. Methods. The study included two interviews based on questionnaires regarding symptoms and side effects, the first held on the day the license was issued and the second 6–8 weeks later. Cancer symptoms and cannabis side effects were documented on scales from 0 to 4 following the CTCAE. The distress thermometer was used also. Results. Of the 211 patients who had a first interview, only 131 had the second interview, 25 of whom stopped treatment after less than a week. All cancer or anticancer treatment-related symptoms showed significant improvement (). No significant side effects except for memory lessening in patients with prolonged cannabis use () were noted. Conclusion. The positive effects of cannabis on various cancer-related symptoms are tempered by reliance on self-reporting for many of the variables. Although studies with a control group are missing, the improvement in symptoms should push the use of cannabis in palliative treatment of oncology patients. - Full Review
Cannabis Induces a Clinical Response in Patients With Crohn’s Disease: A Prospective Placebo-Controlled Study
By TIMNA NAFTALI,* LIHI BAR-LEV SCHLEIDER,‡ IRIS DOTAN,§ EPHRAIM PHILIP LANSKY,jj FABIANA SKLEROVSKY BENJAMINOV,* and FRED MEIR KONIKOFF* | October 2013
*Department of Gastroenterology and Hepatology, Meir Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Kfar Saba; ‡Tikun Olam for Promotion of Medical Cannabis, Tel Aviv; §IBD Center, Department of Gastroenterology, Sourasky Medical Center, Tel Aviv; and jjLaboratory of Applied Metabolomics and Pharmacognosy, Institute of Evolution, University of Haifa, Haifa, Israel
BACKGROUND & AIMS
The marijuana plant Cannabis sativa has been reported to produce beneficial effects for patients with inflammatory bowel diseases, but this has not been investigated in controlled trials. We performed a prospective trial to determine whether cannabis can induce remission in patients with Crohn’s disease.
METHODS
We studied 21 patients (mean age, 40 – 14 y; 13 men) with Crohn’s Disease Activity Index (CDAI) scores greater than 200 who did not respond to therapy with steroids, immuno- modulators, or anti–tumor necrosis factor-a agents. Patients were assigned randomly to groups given cannabis, twice daily, in the form of cigarettes containing 115 mg of D9-tetra- hydrocannabinol (THC) or placebo containing cannabis flowers from which the THC had been extracted. Disease activity and laboratory tests were assessed during 8 weeks of treat- ment and 2 weeks thereafter.
RESULTS
Complete remission (CDAI score, <150) was achieved by 5 of 11 subjects in the cannabis group (45%) and 1 of 10 in the placebo group (10%; P [ .43). A clinical response (decrease in CDAI score of >100) was observed in 10 of 11 subjects in the cannabis group (90%; from 330 – 105 to 152 – 109) and 4 of 10 in the placebo group (40%; from 373 – 94 to 306 – 143; P [ .028). Three patients in the cannabis group were weaned from steroid dependency. Subjects receiving cannabis reported improved appetite and sleep, with no significant side effects.
CONCLUSIONS:
Although the primary end point of the study (induction of remission) was not achieved, a short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free ben- efits to 10 of 11 patients with active Crohn’s disease, compared with placebo, without side effects. - Full Review
Role of the Cannabinoid System in the Transit of Beta-Amyloid Across the Blood Brain Barrier.
Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris D. | US National Library of MedicineNational Institutes of Health | 2013
Emerging evidence suggests beta-amyloid (Aβ) deposition in the Alzheimer’s disease (AD) brain is the result of impaired clearance, due in part to diminished Aβ transport across the blood-brain barrier (BBB). - Abstract
Obesity and Cannabis Use: Results From 2 Representative National Surveys
Yann Le Strat and Bernard Le Foll | American Journal of Epidemology | 2011
The role of cannabis and endocannabinoids in appetite regulation has been extensively studied, but the association of cannabis use with weight in the general population is not known. … The authors conclude that the prevalence of obesity is lower in cannabis users than in nonusers. - Abstract
Cannabidiol (CBD) as Potential Anticancer Drug
US National Institute of Health | Paola Massi, Marta Solinas, Valentina Cinquina, and Daniela Parolaro | Published Online Apr 17, 2012
Cannabinoids in the Treatment of Cancer
Cannabinoids are currently used in cancer patients to palliate wasting, emesis and pain that often accompany cancer. A significant advancement in cannabinoid use in cancer treatment came from the discovery of a potential utility of these compounds for targeting and killing cancer cells. In 1975 Munson et al. demonstrated that the administration of Δ9-THC, Δ8-THC and cannabinol inhibited the growth of Lewis lung adenocarcinoma cells in vitro as well as in vivo after oral administration in mice. The interest in anticarcinogenic properties of cannabinoids was even renewed after the discovery of the eCB system and the cloning of the specific cannabinoid receptors. Since then, several cannabinoids have been shown to exert anti-proliferative and pro-apoptotic effects in various cancer types (lung, glioma, thyroid, lymphoma, skin, pancreas, uterus, breast, prostate and colorectal carcinoma) both in vitro and in vivo. Moreover, other antitumourigenic mechanisms of cannabinoids are currently emerging, showing their ability to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization.
However, the clinical use of Δ9-THC and additional synthetic agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive phyto-cannabinoids, such as CBD, has substantially increased in recent years. Interestingly CBD has no psychotropic activity and, although it has very low affinity for both CB1 and CB2 receptors, it has been recently reported to act with unexpectedly high potency in vitro as antagonist of CB1 receptors in the mouse vas deferense and brain tissues. Additionally, CBD displays inverse agonism at human CB2 receptors. Moreover, other putative molecular targets of CBD are TRPV, 5-HT1A, GPR55 and PPARγ receptors. Besides its beneficial effects in the treatment of pain and spasticity and other CNS pathologies, several reports demonstrated that CBD possesses antiproliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion. - Full Article
Opposite Effects of Δ-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology
By Sagnik Bhattacharyya, Paul D Morrison, Paolo Fusar-Poli, Rocio Martin-Santos, Stefan Borgwardt, Toby Winton-Brown1, Chiara Nosarti, Colin M O’ Carroll, Marc Seal, Paul Allen, Mitul A Mehta, James M Stone, Nigel Tunstall, Vincent Giampietro, Shitij Kapur, Robin M Murray, Antonio W Zuardi, José A Crippa, Zerrin Atakan and Philip K McGuire | Neuropsychopharmacology | November 18 , 2009
Δ-9-tetrahydrocannabinol (Δ-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Δ-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Δ-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Δ-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Δ-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Δ-9-THC. Δ-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Δ-9-tetrahydrocannabinol. Δ-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD’s ability to block the psychotogenic effects of Δ-9-THC. - http://www.nature.com/npp/journal/v35/n3/abs/npp2009184a.html
Cannabinoid Action Induces Autophagy-Mediated Cell Death Through Stimulation of ER Stress in Human Glioma Cells
US National Library of Medicine National Institutes of Health | 2009
Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. - Abstract
Unheated Cannabis Sativa Extracts and Its Major Compound THC-Acid have Potential Immuno-Modulating Properties not Mediated by CB1 and CB2 Receptor Coupled Pathways
By Kitty C.M. Verhoeckx, Henrie A.A.J. Korthoutb, A.P. van Meeteren-Kreikamp, Karl A. Ehlert, Mei Wang, Jan van der Greef, Richard J.T. Rodenburg, Renger F. Witkamp | November 15, 2006
There is a great interest in the pharmacological properties of cannabinoid like compounds that are not linked to the adverse effects of Δ9-tetrahydrocannabinol (THC), e.g. psychoactive properties. The present paper describes the potential immuno-modulating activity of unheated Cannabis sativa extracts and its main non-psychoactive constituent Δ9-tetrahydrocanabinoid acid (THCa). By heating Cannabis extracts, THCa was shown to be converted into THC. Unheated Cannabis extract and THCa were able to inhibit the tumor necrosis factor alpha (TNF-α) levels in culture supernatants from U937 macrophages and peripheral blood macrophages after stimulation with LPS in a dose-dependent manner. This inhibition persisted over a longer period of time, whereas after prolonged exposure time THC and heated Cannabis extract tend to induce the TNF-α level. Furthermore we demonstrated that THCa and THC show distinct effects on phosphatidylcholine specific phospholipase C (PC-PLC) activity. Unheated Cannabis extract and THCa inhibit the PC-PLC activity in a dose-dependent manner, while THC induced PC-PLC activity at high concentrations. These results suggest that THCa and THC exert their immuno-modulating effects via different metabolic pathways. - Abstract
The Diverse CB1 and CB2 Receptor Pharmacology of Three Plant Cannabinoids: Δ9-Tetrahydrocannabinol, Cannabidiol and Δ9-Tetrahydrocannabivarin
Pertwee RG | US National Library of Medicine National Institutes of Health | 2008
Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), (−)-cannabidiol (CBD) and (−)-trans-Δ9-tetrahydrocannabivarin (Δ9-THCV), interact with cannabinoid CB1 and CB2 receptors. - Full Abstract
A Molecular Link Between the Active Component of Marijuana and Alzheimer’s Disease Pathology
By Lisa M. Eubanks, Claude J. Rogers, Albert E. Beuscher, IV, George F. Koob, Arthur J. Olson, Tobin J. Dickerson, and Kim D. Janda | National Institute of Health | October 6, 2006
Since the characterization of the Cannabis sativa-produced cannabinoid, Δ9-tetrahydrocannabinol (THC) (Figure 1), in the 1960’s,1 this natural product has been widely explored as an anti-emetic, anti-convulsive, anti-inflammatory, and analgesic.2 In these contexts, efficacy results from THC binding to the family of cannabinoid receptors found primarily on central and peripheral neurons (CB1) or immune cells (CB2).3 More recently, a link between the endocannabinoid system and Alzheimer’s disease has been discovered4 which has provided a new therapeutic target for the treatment of patients suffering from Alzheimer’s disease.5 New targets for this debilitating disease are critical as Alzheimer’s disease afflicts over 20 million people worldwide, with the number of diagnosed cases continuing to rise at an exponential rate.6,7 These studies have demonstrated the ability of cannabinoids to provide neuroprotection against β-amyloid peptide (Aβ) toxicity.8-10 Yet, it is important to note that in these reports, cannabinoids serve as signaling molecules which regulate downstream events implicated in Alzheimer’s disease pathology and are not directly implicated as effecting Aβ at a molecular level.
One of the primary neuropathological hallmarks of Alzheimer’s disease is deposition of Aβ into amyloid plaques in areas of the brain important for memory and cognition.11 Over the last two decades, the etiology of Alzheimer’s disease has been elucidated through extensive biochemical and neurobiological studies, leading to an assortment of possible therapeutic strategies including prevention of downstream neurotoxic events, interference with Aβ metabolism, and reduction of damage from oxidative stress and inflammation.12 The impairment of the cholinergic system is the most dramatic of the neurotransmitter systems affected by Alzheimer’s disease and as a result, has been thoroughly investigated. Currently, there are four FDA-approved drugs that treat the symptoms of Alzheimer’s disease by inhibiting the active site of acetylcholinesterase (AChE), the enzyme responsible for the degradation of acetylcholine, thereby raising the levels of neurotransmitter in the synaptic cleft.13 In addition, AChE has been shown to play a further role in Alzheimer’s disease by acting as a molecular chaperone, accelerating the formation of amyloid fibrils in the brain and forming stable complexes with Aβ at a region known as the peripheral anionic binding site (PAS).14,15 Evidence supporting this theory was provided by studies demonstrating that the PAS ligand, propidium, is able to prevent amyloid acceleration in vitro, whereas active-site inhibitors had no effect.16 Due to the association between the AChE PAS and Alzheimer’s disease, a number of studies have focused on blocking this allosteric site.17 Recently, we reported a combined computational and experimental approach to identify compounds containing rigid, aromatic scaffolds hypothesized to disrupt protein-protein interactions.18-20 Similarly, THC is highly lipophilic in nature and possesses a fused tricyclic structure. Thus, we hypothesized that this terpenoid also could bind to the allosteric PAS of AChE with concomitant prevention of AChE-promoted Aβ aggregation.
Conclusion
We have demonstrated that THC competitively inhibits AChE, and furthermore, binds to the AChE PAS and diminishes Aβ aggregation. In contrast to previous studies aimed at utilizing cannabinoids in Alzheimer’s disease therapy,8-10 our results provide a mechanism whereby the THC molecule can directly impact Alzheimer’s disease pathology. We note that while THC provides an interesting Alzheimer’s disease drug lead, it is a psychoactive compound with strong affinity for endogenous cannabinoid receptors. It is noteworthy that THC is a considerably more effective inhibitor of AChE-induced Aβ deposition than the approved drugs for Alzheimer’s disease treatment, donepezil and tacrine, which reduced Aβ aggregation by only 22% and 7%, respectively, at twice the concentration used in our studies.7 Therefore, AChE inhibitors such as THC and its analogues may provide an improved therapeutic for Alzheimer’s disease, augmenting acetylcholine levels by preventing neurotransmitter degradation and reducing Aβ aggregation, thereby simultaneously treating both the symptoms and progression of Alzheimer’s disease. - Full Article
Cannabis Alleviates Symptoms Of Crohn’s Disease
By Jeff Hergenrather, MD | O’Shaughnessy’s | Autumn 2005
A pilot study of the effect of canna- bis on Crohn’s disease was conducted in California this summer by physicians in the Society of Cannabis Clinicians. Crohn’s is an inflammatory bowel disease which is disabling and dif- cult to treat. The cause has not been established.
With co-authors Tod Mikuriya, MD, and David Bearman, MD, and statisti- cal support from Milton Harris, PhD, I developed a questionnaire to assess the changes that Crohn’s patients ex- perience when they use cannabis on an “ad lib” basis. We and SCC colleagues identi ed 32 Crohn’s patients. Eighteen expressed willingness to participate and 12 completed questionnaires.
Our results were reported at the International Association for Cannabis as Medicine conference at Leiden Uni- versity in the Netherlands in September.
For all signs and symptoms evalu- ated in the study, the patients described marked improvements with the use of cannabis. Bene cial effects were re- ported for appetite, pain, nausea, vom- iting, fatigue, activity, and depression. Patients also reported that cannabis use resulted in weight gain, fewer stools per day and fewer are-ups of less severity. - Full Article
Antitumor Effects of Cannabidiol, a Nonpsychoactive Cannabinoid, on Human Glioma Cell Lines
Published in The Journal of Phamacology and Experimental Therapeutics | March 2004
Recently, cannabinoids (CBs) have been shown to possess antitumor properties. - Abstract
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