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and Phytocannabinoids: CBD Δ9-THC

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28.05.2018

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  • and Phytocannabinoids: CBD Δ9-THC
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  • Introduction
  • The phytocannabinoids, cannabidiol (CBD), and deltatetrahydrocannabinol ( Δ9-THC) are the most studied extracts from cannabis sativa. Sulphasalazine, THC and CBD proved beneficial in this model of colitis with the dose–response relationship for the phytocannabinoids showing a bell-shaped. The most researched compounds of the plant are dTHC and CBD and therefore plant are also referred to as phytocannabinoids of which dTHC is the main .. () Neural basis of Δtetrahydrocannabinol and cannabidiol: effects.

    and Phytocannabinoids: CBD Δ9-THC

    Findings so far indicate that the effect of cannabis use is much stronger in those with any predisposition for psychosis at baseline than in those without [ Henquet et al.

    Indeed, individuals with a predisposition to psychosis indicated by a positive family history of psychosis have been found to be particularly sensitive to the effects of cannabis [ McGuire et al. Another indicator for a higher psychosis risk is the presence of subclinical psychotic features and again such individuals have been affected by a higher risk of developing a psychotic illness [ Henquet et al. Furthermore those who are at ultra high risk for psychosis have been reported to be more sensitive to the psychotogenic effects of cannabis compared with users in the general population [ Peters et al.

    Because of the reported links between the schizotypal personality and schizophrenia, this type of personality disorder has come under scrutiny in examining the role of cannabis in producing psychotic symptoms.

    Indeed, it has been shown that people scoring high in schizotypy who use cannabis are more likely to have psychosis-like experiences at the time of use, together with unpleasant side effects [ Barkus et al.

    This study has been replicated and it has been confirmed that those with schizotypal personality disorder carry a higher risk of experiencing psychotic symptoms with cannabis use [ Stirling et al. Most recently, another study has provided further support for a strong association between early cannabis use and the development of schizophrenia spectrum disorder symptoms [ Anglin et al.

    The reported vulnerability factors mentioned here imply a strong genetic predisposition and there have been a number of studies looking particularly to specific genes which have been implicated in psychoses. The first such study was carried out by Caspi and colleagues [ Caspi et al. In this longitudinal study, a specific susceptibility gene which has been linked to schizophrenia and bipolar disorder, catechol-O-methyltransferase COMT , was examined in a representative birth cohort followed to adulthood.

    The study found that carriers of the COMT valine allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis before the age of However, the number of people carrying this allele was small in this study. Using a case-only design of people with schizophrenia, Zammit and colleagues re-examined this association but their findings did not support the different effects of cannabis use on schizophrenia according to variation in COMT [ Zammit et al.

    More recently, van Winkel and colleagues looked at the effects of recent cannabis use whilst examining single nucleotide polymorphisms in 42 candidate genes in patients with psychosis and their unaffected siblings [ van Winkel et al. The authors found that genetic variation in serine-threonine protein kinase AKT1 may mediate both short- and long-term effects on psychosis expression associated with cannabis use. Further support for the possible involvement of the AKT1 gene comes from our study with healthy volunteers.

    This study found that, during the encoding and recall conditions of the verbal memory task, the induction of psychotic symptoms by dTHC was correlated with the attenuated striatal and midbrain activation only in those who were G homozygotes of AKT1 and carriers of the 9-repeat allele dopamine transporter DAT1 [ Bhattacharyya et al. Apart from schizotypal personality, the vulnerability factors to the psychotogenic effects of cannabis require replication. It is clear that further work needs to be carried out to explore the biological mechanisms which determine the vulnerability towards a psychotic outcome.

    During the last decade, endocannabinoid research has been one of the fastest growing fields in psychopharmacology, opening ways to discover new medicines for a wide variety of health problems, ranging from metabolic disorders, to glaucoma and schizophrenia.

    The distribution of the endocannabinoid system in the brain is interesting as the very same brain areas are also implicated in psychoses, particularly in schizophrenia.

    Furthermore, complex and intricate involvement of this system with other neurotransmitters such as dopamine, GABA and glutamatergic systems may have implications for the development of a psychotic illness.

    Naturally, due to the recent and constant increase in the availability of higher THC content variants of cannabis around the world, there have been increasing concerns about the health risks, particularly for young people. However, cannabis affects people differently and therefore it is important to understand what makes someone more at risk and how they differ compared with those who do not develop psychotic illness. Here we have provided an overview of the available information on the risk factors which may make an individual more at risk, such as predisposition to psychosis, schizotypal personality and certain susceptibility genes.

    Finding groups who are vulnerable is particularly important so that they can be targeted for early preventative and therapeutic interventions. Such a search would also lead to the discovery of the biochemical mechanisms involved in cannabis and endocannabinoid research and ultimately to a better understanding of how the brain and the body functions.

    Thanks to Ethan Russo and Geoffrey W. Guy for providing the inspiration for Table 1. Also thanks to Dr Sanem Atakan for her help with the editing of the first draft. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

    Conflict of interest statement: The author declare no conflicts of interest in preparing this article. National Center for Biotechnology Information , U. Journal List Ther Adv Psychopharmacol v.

    Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Cannabis is a complex plant, with major compounds such as deltatetrahydrocannabinol and cannabidiol, which have opposing effects. Cannabis, deltatetrahydrocannabinol, cannabidiol, tetrahydrocannabivarin, endocannabinoids, individual sensitivity to cannabis. Introduction Cannabis is a complex plant with over chemical entities of which more than 60 of them are cannabinoid compounds, some of them with opposing effects.

    Brief history of the biochemistry of the cannabis plant Even though cannabis has been used and cultivated by mankind for at least years [ Li, ] our current knowledge on its pharmacological properties is based on studies which have taken place only since the end of the nineteenth century.

    Open in a separate window. Chemical structures of deltatetrahydrocannabinol and cannabidiol. Cannabinoid receptor system Another cornerstone in cannabinoid research was the identification of the specific binding sites of dTHC in the brain [ Devane et al. Cannabinoid 1 and 2 receptors CB1Rs are mainly in the brain, particularly in the substantia nigra, the basal ganglia, limbic system, hippocampus and cerebellum, but are also expressed in the peripheral nervous system, liver, thyroid, uterus, bones and testicular tissue [ Russo and Guy, ; Pagotto et al.

    Functions of the endocannabinoid receptor system Available evidence indicates that we do not yet have a complete understanding of the varied functions of the endocannabinoid system, which is widely distributed both in the brain and in the peripheral system and most glands and organs in the body.

    Cannabis plant The cannabis plant has two main subspecies, Cannabis indica and Cannabis sativa , and they can be differentiated by their different physical characteristics.

    Deltatetrahydrocannabinol and cannabidiol Natural compounds of the cannabis plant are also referred to as phytocannabinoids of which dTHC is the main psychoactive ingredient and has been widely researched both in animals and humans. Intersubject variation in response to the psychotogenic effects of cannabis About Proposed factors determining sensitivity to psychosis in cannabis users.

    Sensitivity to psychosis as determined by: Possible sensitivity factors Study group Predisposition to psychosis Family history of psychotic illness McGuire et al. Conclusion During the last decade, endocannabinoid research has been one of the fastest growing fields in psychopharmacology, opening ways to discover new medicines for a wide variety of health problems, ranging from metabolic disorders, to glaucoma and schizophrenia.

    J Psychoactive Drugs Biochem Biophys Res Commun J Clin Pharmacol AKT1 and DAT1 genotype modulates the effects of deltatetrahydrocannabinol on midbrain and striatal function. Mol Psychiatry 31 January epub ahead of print. Curr Pharm Des Arch Gen Psychiatry J Biol Chem Br J Pharmacol Curr Drug Abuse Rev 5: Eur J Pharmacol Am J Addict Br J Psychiatry Handb Exp Pharmacol Eur Arch Psychiatry Clin Neurosci The State of the Drug Problems in Europe.

    J Affect Disord J Am Chem Soc Methods Mol Med AD-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor release, is blunted by cannabinoid compounds. CBD is effective in an experimental model of Parkinsonism 6-hydroxydopamine-lesioned rats by acting through antioxidant mechanisms independently of cannabinoid receptors.

    In rats lesioned with 3-nitropropionic acid, a toxin inhibitor of the mitochondrial citric acid cycle resulting in a progressive locomotor deterioration resembling that of HD patients, CBD reduces rat striatal atrophy in a manner independent of the activation of cannabinoid adenosine A2A receptors.

    Activation of PPAR, along with CB1 and CB2, mediates numerous analgesic, neuroprotective, neuronal function modulation, antiinflammatory, metabolic, antitumor, gastrointestinal, and cardiovascular effects, both in and outside the ECS. The serotonin receptors have been implicated in the therapeutic effects of CBD.

    In a rat model, CBD was observed to stimulate hippocampal neurogenesis. Neuroprotective effects of CBD in hypoxic—ischemic brain damage model involve adenosine A2 receptors.

    CBD activation of adenosine receptors can enhance adenosine signaling to mediate antiinflammatory and immunosuppressive effects. MS is an autoimmune disease that promotes demyelination of neurons and subsequent aberrant neuronal firing that contributes to spasticity and neuropathic pain. The pathologic changes of MS include neuroinflammation, excitotoxicity, demyelination, and neurodegeneration.

    These pathological features share similarities with other neurodegenerative conditions, including AD and cerebral ischemia. The combination of antiinflammatory, oligoprotective, and neuroprotective compounds that target the ECS may offer symptomatic and therapeutic treatment of MS.

    The use of cannabis-based medicine for the treatment of MS has a long history and its interaction with the ECS shares many of the same pathways of other neurodegenerative conditions. In , the American Academy of Neurology AAN published a review article of 34 studies investigating the use of medical marijuana as extracts, whole plants and synthetic phytocannabinoids for possible neurological clinical benefits.

    They found strong support for symptoms of spasticity and spasticity-related pain, excluding neuropathic pain in the research using oral cannabis extracts. They reported inconclusive support for symptoms of urinary dysfunction, tremor, and dyskinesia. This study was subsequently used to form a consensus statement for their society. In the article they concluded their results based on the strength of the reported research [ Table 3 ].

    Conclusions from Subcommittee of the American Academy of Neurology AAN systematic review on medical marijuana in neurologic diseases published in [ 66 ]. MS animal models using autoimmune encephalomyelitis EAE have been used that demonstrate demyelination, neuroinflammation, and neurological dysfunction associated with infiltration of immune cells into the CNS consistent with the human disease. Upregulation of endocannabinoid tone protects neurons from excitotoxicity in parallel with a therapeutic effect in a mouse model of MS.

    In a week trial with a tolerated dose of 9-THC, subjects had reduced urinary incontinence, and a month follow-up demonstrated an antispasticity effect. CBD acts specifically to enhance adenosine signaling which increases extracellular adenosine, not AG Neuroprotective effects of CBD in hypoxic—ischemic brain damage also involve adenosine A2 receptors. Specifically, CBD diminishes inflammation in acute models of injury and in a viral model of MS through adenosine A2 receptors.

    OPCs are highly vulnerable to inflammation and oxidative stress. Inflammation contributes to demyelinating diseases such as MS. Synthetic cannabinoids studies have shown they can protect OPCs possibly by controlling endoplasmic reticulum ER stress response that modulates the response to inflammatory stimuli. It is an oral-mucosal spray containing a 1: The ability to modify pain may be attributed to a CB receptor-mediated regulation of supraspinal GABAergic and glutamatergic neurons.

    The results of these studies were cited in the AAN review. A meta-analysis in reported that CB receptor-based medications were superior to placebo in the treatment of MS-related neuropathic pain. Overall, the analgesic response to cannabinoids was generally retained over time, at least for the 6—10 weeks follow-up period. CBD is recognized as a nonpsychoactive phytocannabinoid. Both human observational and animal studies, however, have demonstrated a broad range of therapeutic effects for several neuropsychiatric disorders.

    CBD has positive effects on attenuating psychotic, anxiety, and depressive-like behaviors. The mechanisms appear to be related to the CBD's benefit to provide enhanced neuroprotection and inhibition of excessive neuroinflammatory responses in neurodegenerative diseases and conditions. Common features involving neuroprotective mechanisms influenced by CBD—oxidative stress, immune mediators, and neurotrophic factors—are also important in conditions such as posttraumatic stress disorder PTSD , postconcussion syndrome, depression, and anxiety.

    Many studies confirm that the function of the ECS is markedly increased in response to pathogenic events like trauma. This fact, as well as numerous studies on experimental models of brain trauma, supports the role of cannabinoids and their interactions with CB1 and CB2 as part of the brain's compensatory and repair mechanisms following injury. Animal studies indicate that posthead injury administration of exogenous CBD reduces short-term brain damage by improving brain metabolic activity, reducing cerebral hemodynamic impairment, and decreasing brain edema and seizures.

    These benefits are believed to be due to CBD's ability to increase anandamide. Treatment with CBD may also decrease the intensity and impact of symptoms commonly associated with PTSD, including chronic anxiety in stressful environments. In human studies, subjects introduced to fearful contexts exhibited decreased posttest anxiety when treated with CBD. In rodent models, CBD effectively blocked the formation of fearful memories.

    Rat trials also show CBD's potential in fear memory extinction, demonstrated through a significant decrease in freezing time when re-exposed to an anxiety-inducing situation. Antidepressants, used for the treatment of depression and some anxiety disorders, also possess numerous neuroprotective properties, such as preventing the formation of amyloid plaques, elevation of BDNF levels, reduction of microglia activation, and decreased levels of proinflammatory mediators.

    In rat models of neurobehavioral disorders, CBD demonstrated attenuation of acute autonomic responses evoked by stress, inducing anxiolytic and antidepressive effects by activating 5HT1A receptors in a similar manner as the pharmaceutical buspirone that is approved for relieving anxiety and depression in humans.

    A double-blind, randomized clinical trial with CBD reported a significant clinical improvement similar to the antipsychotic amisulpride, but with less side effects. Human imaging studies have demonstrated CBD affects brain areas involved in the neurobiology of psychiatric disorders. A study has showed that a single dose of CBD, administered orally in healthy volunteers, alters the resting activity in limbic and paralimbic brain areas while decreasing subjective anxiety associated with the scanning procedure.

    In healthy volunteers treated with CBD and submitted to a presentation of fearful faces, there was a decrease of the amygdala and anterior and posterior cingulate cortex activities and a disruption in the amygdala—anterior cingulated cortex connectivity. Interestingly, THC, administered prior to a traumatic insult in human case studies and animal models has had measurable neuroprotective effects.

    In general, conditions associated with chronic stress appear to be positively responsive to phytocannabinoids. Studies in rat models reported that cannabinoids prevented the effects of acute stress on learning and memory and improved neuroplasticity, behavioral, and neuroendocrine measures of anxiety and depression.

    Cancer is a disease characterized by uncontrolled division of cells and their ability to spread. Novel anticancer agents are often tested for their ability to induce apoptosis and maintain steady-state cell population. In the early s, phytocannabinoids were shown to inhibit tumor growth and prolong the life of mice with lung adenocarcinoma. Later studies have demonstrated cannabinoids inhibited tumor cell growth and induced apoptosis by modulating different cell signaling pathways in gliomas, lymphoma, prostate, breast, skin, and pancreatic cancer cells as well.

    Glioblastoma multiforme GBM is the most frequent class of malignant primary brain tumors. CBD has also been shown to reduce the growth of different types of tumor xenografts including gliomas. The mechanism of action of CBD is thought to be increased production of ROS in glioma cells, thereby inducing cytotoxicity or apoptosis and autophagy. CBD also reduces angiogenesis through actions on both tumor and endothelial cells. Median survival was greater than days compared with days in the placebo group.

    Reports of cannabis use in the treatment of epilepsy appear as far back as BC. Scientific reports appear in from neurologists using Indian hemp to treat epilepsy with dramatic success. CBD, however, produces antiepileptiform and anticonvulsant effects in both in vitro and in vivo models. More recently in , Cunha et al. Each patient received — mg daily of CBD or placebo along with antiepileptic drugs for up to 4 months. In the placebo group 1 of 8 responded with fewer seizures. These all suggest that CBD, the nonpsychoactive compound of cannabis, potentially can be helpful for controlling medication refractory seizures.

    As with most cannabinoid research to date, conducting studies can be difficult due to limited legal access to medical grade marijuana and phytocannabinoid extracts. Hemp-derived CBD, however, has recently experienced less regulation and as a result research using CBD for refractory epilepsy has experienced a resurgence.

    CBD's overall effect appears to result in reduction of neuronal hyperactivity in epilepsy. Anandamide affects excitability in neuronal networks by activating the transient receptor potential TRP cation channel. Endogenous cannabinoids appear to affect the initiation, propagation, and spread of seizures.

    Studies have identified defects in the ECS in some patients with refractory seizure disorders, specifically having low levels of anandamide and reduced numbers of CB1 receptors in CSF and tissue biopsy. Although this study exclusively looked for effects on seizure incidence, no evidence suggests that the antiseizure effects of CBD are limited to the treatment of this condition.

    Development of synthetic forms of CBD is also in progress to treat seizure and other disorders responsive to the phytocannabinoid CBD. A comprehensive safety and side effect review of CBD in on both animal and human studies described an excellent safety profile of CBD in humans at a wide variety of doses. CBD does have interactions with common hepatic drug -metabolizing enzymes, belonging to the cytochrome P family.

    Therefore, interactions with drug transporters and interactions with drugs must be considered. In contrast to THC, CBD does not alter heart rate, blood pressure, or body temperature, does not induce catalepsy, nor alter psychomotor or psychological functions. The AAN review of 34 articles on MS using cannabinoids of various forms noted several adverse effects. Reported symptoms included nausea, increased weakness, behavioral or mood changes or both , suicidal ideation or hallucinations, dizziness or vasovagal symptoms or both , fatigue, and feelings of intoxication.

    Psychosis, dysphoria, and anxiety were associated with higher concentrations of THC. However, no direct fatalities or overdoses have been attributed to marijuana, even in recreational users of increasingly potent marijuana possibly due to lack of endocannabinoid receptors in the brainstem.

    Like other cannabinoids, CBD produces bell-shaped dose—response curves and can act by different mechanisms according to its concentration or the simultaneous presence of other cannabinoid-ligands.

    Ultimately, prescribing medical marijuana either as a primary treatment or adjunctive therapy will require extreme care and knowledge about the patient's goals and expectations for treatment. States that have allowed medical marijuana have generally required competency trainings and certification prior to prescribing. There are general screening questions that should be considered before recommending marijuana to a patient.

    At minimum, these questions should include the following: Although these medications are often cited in human clinical research, their general use is limited based both on side effects and indication constraints. Although federal and state laws are inconsistent about the legality of cannabis production, its increasingly documented health benefits make it once again relevant in medicine.

    Current research indicates the phytocannabinoids have a powerful therapeutic potential in a variety of ailments primarily through their interaction with the ECS.

    CBD is of particular interest due to its wide-ranging capabilities and lack of side effects in a variety of neurological conditions and diseases. Because of the rapid legalization of medical marijuana by the majority of state legislatures in the U.

    Because of federal restrictions on human research in the U. This review of the neurological benefits of phytocannabinoids has demonstrated significant benefits for neuroprotection and disease reductions in a wide variety of neurological diseases and conditions in humans. The Authors report the following conflicts: National Center for Biotechnology Information , U. Journal List Surg Neurol Int v. Published online Apr Author information Article notes Copyright and License information Disclaimer.

    Received Feb 5; Accepted Feb This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4. This article has been cited by other articles in PMC.

    Cannabidiol, deltatetrahydrocannabinol, endocannabinoid system, neurological disease, phytocannabinoids. Open in a separate window. Cannabinoid receptors Phytocannabinoid compounds and extracts can come from both hemp and marijuana subspecies, including CBD.

    Activation of neuronal CB1 receptors Activation of neuronal CB1 receptors results in inhibition of adenylyl cyclase and decreased neurotransmitter release through blockade of voltage-operated calcium channels. Cultured microglial dells A study of cultured microglial cells showed c-interferon and granulocyte macrophage-colony stimulating factor GM-CSF , known as inflammatory response activators of microglial cell, were accompanied by significant CB2 receptor upregulation.

    Research on the endocannabinoid system Research on the ECS is fervently ongoing with wide-ranging discoveries. Neuroprotective benefits of phytocannabinoids CBD research in animal models and humans has shown numerous therapeutic properties for brain function and protection, both by its effect on the ECS directly and by influencing endogenous cannabinoids.

    Neurodegenerative diseases Overview Neurodegenerative diseases include a large group of conditions associated with progressive neuronal loss leading to a variety of clinical manifestations. Cannabis is taken as self-medication by patients with IBD in order to relieve symptoms such as abdominal pain, diarrhoea and reduced appetite Garcia-Planella et al. Synthetic cannabinoid CB receptor agonists inhibit inflammation and tissue damage in different animal models of colitis, an effect attributed to stimulation of CB 1 and CB 2 receptors Massa et al.

    It is well known that cannabis possesses immunosuppressive properties and that the main component responsible for this profile of action is THC. In both in vivo and in vitro, THC impairs cell-mediated and humoural immunity, actions that could be beneficial in auto-inflammatory disorders including IBD Massi et al. In support of this, THC was effective in attenuating autoimmune responses in an experimental model of diabetes multiple low-dose streptozotocin injections Li et al.

    In addition to THC, cannabis contains a number of non-psychotropic compounds, with - -cannabidiol CBD being the most abundant and the most extensively studied Mechoulam, ; Pertwee, Importantly, CBD has been also demonstrated to possess potent anti-inflammatory and immunomodulatory properties which, together with a lack of psychotropic activity and low toxicity, make it a very promising therapeutic candidate for a variety of inflammatory and pain associated disorders, including IBD.

    CBD is a very potent antioxidant, which results in reduction of the level of reactive oxygen species in the course of inflammation and protection from tissue damage Malfait et al. CBD treatment has proven effective in different animal models of inflammation, such as collagen-induced arthritis, non-obese diabetic mice, acute carrageenan-induced inflammation in the rat paw, and it was shown to normalize croton oil-induced hypermotility in mice Capasso et al.

    Notably it was reported that CBD was able to delay and attenuate colitis in interlukin IL knockout mice, but the results of the experiment were not published Malfait et al. A confirmation of this observation was provided in a recent study, which demonstrated efficacy of CBD pretreatment in dinitrobenzene sulphonic acid DNBS -induced colitis in mice Borrelli et al.

    As the two phytocannabinoids modulate the immune system and differ in their pharmacological profile, their combination could be more beneficial than either drug alone Russo and Guy, ; Pertwee, Additionally CBD could not only potentiate the therapeutic effects of THC, but also attenuate some of its undesirable effects, such as disorientation, mental clouding, sedation, anxiety, dysphoria and tachycardia Karniol et al. Therefore the aim of the present study was to characterize the effects of the two phytocannabinoids, administered alone and in combination, in the 2,4,6-trinitrobenzene sulphonic acid TNBS -induced model of colitis in the rat.

    In addition, the effects of sulphasalazine on macroscopic damage, myeloperoxidase MPO activity and in vitro responses of colonic longitudinal muscle strips were evaluated in order to compare the effects of THC and CBD with a standard treatment for IBD Baumgart and Sandborn, Our results demonstrated that treatment with THC and CBD reduced inflammation and motility disturbances associated with colitis.

    The effects of THC alone and in combination with CBD were similar to and, in some aspects, better than those of sulphasalazine, suggesting potential value of phytocannabinoids for the treatment of IBD. All animal care and experimental procedures were conducted in accordance with the Animals Scientific Procedures Act and were approved by the University of Hertfordshire Ethics Committee.

    They were housed in standard cages 2—6 rats per cage and provided with free access to food and tap water. Colitis was induced as described by Boughton-Smith et al.

    Briefly, the animals were fasted for 20—24 h with free access to water. Colitis was induced under light isoflurane anaesthesia by administering an enema of 6. In a preliminary series of experiments control animals received phosphate-buffered saline PBS. Rats were matched in their body weights before food withdrawal. After enema administration the animals were kept in a head-down position until they recovered from anaesthesia 1—2 min to prevent the solution leaking out.

    After this procedure the animals were placed in separate cages with free access to food and water. The rats were killed 3 days later by carbon dioxide asphyxiation. The abdominal cavity was opened via a midline incision; the colon was removed and immediately placed in fresh Krebs—Henseleit solution with the following composition in mM: The colon was cleaned of fat and mesentery, cut open longitudinally, gently flushed clean with Krebs solution and scored for visible damage.

    The degree of inflammation was quantified using a 0—13 scale, according to the criteria presented in Table 1. This wide scale was applied to optimally reflect the differences in the severity of inflammation between animals. The damage assessed visually is referred to as the macroscopic damage score MDS. Scale adapted from those used previously Appleyard and Wallace, ; Poli et al. The tissue was suspended in the bathing solution by threads.

    One end of the tissue was attached to a hook at the bottom of the bath and the other end to an isometric tension transducer Pioden Controls Ltd.

    In experiments with electrical field stimulation EFS , the tissue was attached to a hook between two parallel platinum wire electrodes.

    An initial load of 1 g was applied. The tissues were left to equilibrate for at least 30 min before experiments were commenced. Wet and dry after 24 h at room temperature tissue weights were determined and amplitude of contraction was calculated per gram of dry weight. This normalization procedure was used because of the presence of oedema, as well as possible morphological changes of the smooth muscle layers in the inflamed colon as reported by Wells et al.

    The experiments were recorded with a MacLab data acquisition system Chart v 3. Spontaneous activity was recorded for 10 min. The parameters measured were the amplitude of low-frequency contractions ALF and their duration D. Cumulative dose—response curves to carbachol were constructed and the final bath concentrations were: These experiments were designed to study neurally mediated responses to electrical stimulation of the enteric nerves.

    Frequency—response curves were constructed at a voltage supramaximal for 5 Hz, 0. The frequencies studied were 1, 3, 5, 8, 10 and 15 Hz. Carbachol was applied after the contractile response to the last frequency 15 Hz. EFS was started 4—5 min after carbachol application, when the contractile response became stable.

    Subsequent frequencies were applied after recovery to the baseline. All EFS-evoked responses were tetrodotoxin-sensitive data not shown. A MPO assay was used to quantify inflammation. The enzyme activity is considered to be an index of neutrophil infiltration because MPO is predominantly found in these cells Krawisz et al.

    In the first step of the procedure the enzyme was extracted from the tissue according to the protocol of Bradley et al.

    The supernatant was kept on ice and used for the enzyme assay. The protocol was modified to form an end point assay where the reaction is stopped with acid solution and the absorbance is measured at nm Microplate reader, Multiskan Ascent, Labsystems Oy, Helsinki, Finland. MPO activity was expressed as an equivalent to the activity of the standard nanograms of HRP converting the same amount of TMB substrate for 3 min at room temperature.

    Total protein was measured as well as described below. Briefly, bovine serum albumin was used as the standard. Supernatants, as in the MPO assay, were used.

    After mixing all the reagents, plates were incubated at room temperature for 30 min, and the absorbance was measured at nm on a plate reader. To assess the effects of various drugs on colonic inflammation the substances were tested using a short-time dosing regimen. The first dose was administered 0. Drugs were administered i. To study the effects of CBD, four doses were applied: Three doses of THC were applied: In order to assess the effects of combined treatment with THC and CBD, two mixtures of the two compounds were used co-administered in one vehicle solution.

    Three doses were given in total, every 24 h. In order to keep the dosing regimen as close to the i.

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    Research into the effects of the plant led to the discovery of cannabinoids, which of different cannabinoids, such as THC (Δ9-tetrahydrocannabinol) and CBD. A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid Cannabidiol (CBD) is another major constituent of the plant. There are at least different cannabinoids isolated from cannabis, . Delta tetrahydrocannabinol (Δ9-THC, THC) and deltatetrahydrocannabinol (Δ8-THC ), through. 1 -Δ 9 -tetrahydrocannabinol (THC); 2 -cannabidiol (CBD). from publication: Endocannabinoid system and anticancer properties of cannabinoids | Cannabinoids.

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