Article

Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats

May 2002
Neuroreport 13(5):567-70

DOI:10.1097/00001756-200204160-00006

Source
PubMed

Authors:

Hebrew University of Jerusalem

Rats display conditioned rejection reactions during an oral infusion of a flavor previously paired with an emetic drug; considerable evidence indicates that these rejection reactions reflect nausea. Here we report that cannabidiol, a major non-psychoactive cannabinoid found in marijuana and its synthetic dimethylheptyl homolog interfere with nausea elicited by lithium chloride and with conditioned nausea elicited by a flavor paired with lithium chloride. These results suggest that cannabinoids without psychoactive side-effects may have therapeutic value in the treatment of chemotherapy-induced nausea.

Pisanti Pharm & Ther corrected proof

Data

Full-text available

Mar 2017

Therapeutic Potential of Cannabinoids in Counteracting Chemotherapy-induced Adverse Effects: An Exploratory Review

Article

Dec 2014
PHYTOTHER RES

Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed. Copyright © 2014 John Wiley & Sons, Ltd.

Phytocannabinoids Reduce Inﬂammation of Primed Macrophages and Enteric Glial Cells

Preprint

Full-text available

Aug 2023

Inflammatory bowel diseases (IBD) includes Crohn's disease and ulcerative colitis, are idiopathic chronic relapsing inflammatory disorders of the intestinal tract. Different studies indicate that phytocanna-binoids, could play a possible role in the treatment of IBD by relieving the symptoms involved in the dis-ease. Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative-anti-inflammatory effect of nine-selected pure cannabinoids in J774A1 macrophages cells and enteric glial cells (EGC’s) triggered to undergo inflammation with lipopolysaccharide (LPS). The an-ti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNF tran-scription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and tran-scription in EGC’s. Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti- inflammatory effect in both J774A1 macrophages and EGC’s compared to the other phy-tocannabinoids tested herein. We then performed RNA-seq analysis of EGC’s exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGC’s revealed 23 differ-entially expressed genes (DEG) compared to treatment with only LPS. Pretreatment with THC resulted in 26 DEG and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments we used the Ingenuity platform. We show that THC treatment affected the mTOR and RAR signaling pathway while THC-COOH affected mainly the IL6 signaling pathway.

"Breaking bud": the effect of direct chemical modifications of phytocannabinoids on their bioavailability, physiological effects, and therapeutic potential

Article

Full-text available

Jan 2023

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two "major cannabinoids". However, their incorporation into clinical and nutraceutical preparations is challenging, owing to their limited bioavailability, low water solubility, and variable...

Breaking bud: the effect of direct chemical modifications of phytocannabinoids on their bioavailability, physiological effects, and therapeutic potential.

Preprint

Full-text available

Jan 2023

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two ”major cannabinoids”. However, their incorporation into clinical and nutraceutical preparations is challenging, owing to their limited bioavailability, low water solubility, and variable pharmacokinetic profiles. Understanding the organic chemistry of the major cannabinoids provides us with potential avenues to overcome these issues through derivatization. The resulting labile pro-drugs offer ready cannabinoid release in vivo, have augmented bioavailability, or demonstrate interesting pharmacological properties in their own right. This review identifies, tabulates, and discusses a subset of these advanced derivatization strategies for the major cannabinoids, where the starting material is the pure phytocannabinoid itself, and the final product either a cannabinoid pro-drug, or a novel pharmacoactive material.

TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids

Article

Full-text available

Sep 2022
INT J MOL SCI

The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, the most abundant cannabinoids are Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids either directly or indirectly modulate ion channel function. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel responsible for mediating several modalities of pain, and it is expressed in both the peripheral and the central pain pathways. Activation of TRPV1 in sensory neurons mediates nociception in the ascending pain pathway, while activation of TRPV1 in the central descending pain pathway, which involves the rostral ventral medulla (RVM) and the periaqueductal gray (PAG), mediates antinociception. TRPV1 channels are thought to be implicated in neuropathic/spontaneous pain perception in the setting of impaired descending antinociceptive control. Activation of TRPV1 also can cause the release of calcitonin gene-related peptide (CGRP) and other neuropeptides/neurotransmitters from the peripheral and central nerve terminals, including the vagal nerve terminal innervating the gut that forms central synapses at the nucleus tractus solitarius (NTS). One of the adverse effects of chronic cannabis use is the paradoxical cannabis-induced hyperemesis syndrome (HES), which is becoming more common, perhaps due to the wider availability of cannabis-containing products and the chronic use of products containing higher levels of cannabinoids. Although, the mechanism of HES is unknown, the effective treatment options include hot-water hydrotherapy and the topical application of capsaicin, both activate TRPV1 channels and may involve the vagal-NTS and area postrema (AP) nausea and vomiting pathway. In this review, we will delineate the activation of TRPV1 by cannabinoids and their role in the antinociceptive/nociceptive and antiemetic/emetic effects involving the peripheral, spinal, and supraspinal structures.

Empirical Evaluation of Inflorescences’ Morphological Attributes for Yield Optimization of Medicinal Cannabis Cultivars

Article

Full-text available

Apr 2022

In recent decades with the reacknowledgment of the medicinal properties of Cannabis sativa L. (cannabis) plants, there is an increased demand for high performing cultivars that can deliver quality products for various applications. However, scientific knowledge that can facilitate the generation of advanced cannabis cultivars is scarce. In order to improve cannabis breeding and optimize cultivation techniques, the current study aimed to examine the morphological attributes of cannabis inflorescences using novel image analysis practices. The investigated plant population comprises 478 plants ascribed to 119 genotypes of high−THC or blended THC−CBD ratio that was cultivated under a controlled environment facility. Following harvest, all plants were manually processed and an image of the trimmed and refined inflorescences extracted from each plant was captured. Image analysis was then performed using in-house custom-made software which extracted 8 morphological features (such as size, shape and perimeter) for each of the 127,000 extracted inflorescences. Our findings suggest that environmental factors play an important role in the determination of inflorescences’ morphology. Therefore, further studies that focus on genotype X environment interactions are required in order to generate inflorescences with desired characteristics. An examination of the intra-plant inflorescences weight distribution revealed that processing 75% of the plant’s largest inflorescences will gain 90% of its overall yield weight. Therefore, for the optimization of post-harvest tasks, it is suggested to evaluate if the benefits from extracting and processing the plant’s smaller inflorescences outweigh its operational costs. To advance selection efficacy for breeding purposes, a prediction equation for forecasting the plant’s production biomass through width measurements of specific inflorescences, formed under the current experimental methodology, was generated. Thus, it is anticipated that findings from the current study will contribute to the field of medicinal cannabis by improving targeted breeding programs, advancing crop productivity and enhancing the efficacy of post-harvest procedures.

Cannabinoids and Cancer Chemotherapy-Associated Adverse Effects

Article

Nov 2021

The use of cannabis is not unfamiliar to many cancer patients, as there is a long history of its use for cancer pain and/or pain, nausea, and cachexia induced by cancer treatment. To date, the US Food and Drug Administration has approved 2 cannabis-based pharmacotherapies for the treatment of cancer chemotherapy-associated adverse effects: dronabinol and nabilone. Over the proceeding decades, both research investigating and societal attitudes toward the potential utility of cannabinoids for a range of indications have progressed dramatically. The following monograph highlights recent preclinical research focusing on promising cannabinoid-based approaches for the treatment of the 2 most common adverse effects of cancer chemotherapy: chemotherapy-induced peripheral neuropathy and chemotherapy-induced nausea and vomiting. Both plant-derived and synthetic approaches are discussed, as is the potential relative safety and effectiveness of these approaches in relation to current treatment options, including opioid analgesics.

Synthesis, characterization and stress-testing of a robust quillaja saponin stabilized oil-in-water phytocannabinoid nanoemulsion

Article

Full-text available

Dec 2021

Background This study describes the design, optimization, and stress-testing of a novel phytocannabinoid nanoemulsion generated using high-pressure homogenization.

\text {QNaturale}^{\circledR }

QNaturale Ⓡ , a plant-derived commercial emulsifier containing quillaja saponin, was used to stabilize the lipid phase droplets in water. Stress-testing was performed on this nanoemulsion in order to evaluate its chemical and colloidal stability under the influence of different environmental factors, encompassing both physical and chemical stressors. Methods Extensive optimization studies were conducted to arrive at an ideal nanoemulsion formulation. A coarse emulsion containing 16.6 wt% CBD-enriched cannabis distillate and 83.4 wt% carrier (soybean) oil dispersed in 10 wt%

\text {QNaturale}^{\circledR }

QNaturale Ⓡ (1.5 wt% quillaja saponin) solution after 10 homogenization cycles at a pressure of 30,000 psi produced a stable nanoemulsion. This nanoemulsion was then subjected to the stress studies. Results The optimized nanoemulsion had an average droplet diameter of ca. 120 nm and average droplet surface ζ potentials of ca. -30 mV. It was imaged and characterized by a variety of protocols. It proved to be stable to droplet agglomeration and phase separation upon storage under ambient conditions for 6 weeks, as well as under a variety of physical stressors such as heat, cold, dilution, and carbonation. pH values ≤2 and moderately high salt concentrations (> 100 mM), however, destabilized the nanoemulsion, eventually leading to phase separation. Cannabis potency, determined by HPLC, was detrimentally affected by any changes in the nanoemulsion phase stability. Conclusions Quillaja saponin stabilized cannabidiol(CBD)-enriched nanoemulsions are stable, robust systems even at low emulsifier concentrations, and are therefore significant from both a scientific as well as a commercial perspective.

Therapeutic Potential of Cannabidiol, Cannabidiolic Acid, and Cannabidiolic Acid Methyl Ester as Treatments for Nausea and Vomiting

Article

Jun 2021

Introduction: Nausea and vomiting are the most distressing symptoms reported by oncology patients undergoing anticancer treatment. With the currently available treatments, vomiting and especially nausea remain problematic, highlighting the need for alternative treatments. Discussion: Here we review in vitro and in vivo evidence for the effectiveness of the nonpsychoactive cannabinoid cannabidiol (CBD) in managing nausea and vomiting. In addition, we also review the evidence for CBD's acidic precursor, cannabidiolic acid (CBDA), and a methylated version of CBDA (CBDA-ME) in these phenomena. Finally, we explore the potential role of CBD in the treatment of cannabinoid hyperemesis syndrome. Conclusions: CBD has demonstrated efficacy in reducing nausea and vomiting, with CBDA and CBDA-ME being more potent. The data suggest a need for these compounds to be evaluated in clinical trials for their ability to reduce nausea and/or vomiting.

Development and validation of a LC-HRMS method for the quantification of cannabinoids and their metabolites in human plasma

Article

Jan 2021
EUR J PHARM SCI

The resurgence of Cannabis therapeutic discoveries have led to the need for sensitive and selective analytical methods for the detection of cannabinoids and their metabolites in biological matrices. High resolution mass spectrometry (HRMS) enables good sensitivity and provides more selectivity due to its accurate mass measurement of the targeted compounds. The aim of this study was to develop and validate a sensitive liquid chromatography high resolution mass spectrometry (LC-HRMS) method for the quantitative analysis of cannabidiol (CBD), cannabinol (CBN), Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and its major metabolites 11-Hydroxy-Δ⁹-THC and 11-Nor-9-carboxy-Δ⁹-THC in human plasma. The method utilized a simple liquid-liquid extraction of the cannabinoids from plasma samples followed by an isocratic chromatographic separation and detection by ESI-HRMS Q-Exactive plus platform. The lower limit of quantification (LLOQ) was 0.2 ng/ mL for the targeted cannabinoids and its metabolites with sample volume of 0.5 mL plasma. The method was linear from 0.2 to 100.0 ng/mL with an average correlation coefficient of >0.995 using weighted (1/x) linear least-squares regression. No significant carry-over was noticed for all analytes and the extraction recovery ranged from 60.4 % to 85.4 %. Dilution results indicated no influence on the accuracy of analysis. The method's intra-day and inter-day precision (CV %) ranged from 2.90 to 10.80 % and accuracy within -0.9 to 7.0 from nominal. Matrix effect ranged from 1.1 % to 49.8 %. The analytes were stable in the autosampler for 6 and 12 h, respectively. This method was sensitive and can be applicable to cannabinoids pharmacokinetics study.

Development of Water-Soluble Electrospun Fibers for the Oral Delivery of Cannabinoids

Article

Jan 2021
AAPS PHARMSCITECH

Cannabidiol (CBD) and cannabigerol (CBG) are two active pharmaceutical ingredients, derived from cannabis plant. In the present study, CBD and CBG were formulated with polyvinyl(pyrrolidone) (PVP) and Eudragit L-100, using electrohydrodynamic atomization (electrospinning). The produced fibers were smooth and uniform in shape, with average fiber diameters in the range of 700–900 nm for PVP fibers and 1–5 μm for Eudragit L-100 fibers. The encapsulation efficiency for both CB and CBG was high (over 90%) for all formulations tested. Both in vitro release and disintegration tests of the formulations in simulated gastric fluids (SGF) and simulated intestinal fluids (SIF) indicated the rapid disintegration and dissolution of the fibers and the subsequent rapid release of the drugs. The study concluded that the electrospinning process is a fast and efficient method to produce drug-loaded fibers suitable for the per os administration of cannabinoids.

Cannabidiol Interferes with Establishment of Δ 9 -Tetrahydrocannabinol-Induced Nausea Through a 5-HT 1A Mechanism

Article

Dec 2020

Introduction: Cannabinoid hyperemesis syndrome (CHS) is characterized by intense nausea and vomiting brought on by the use of high-dose Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis. Cannabidiol (CBD), a nonpsychotropic compound found in cannabis, has been shown to interfere with some acute aversive effects of THC. In this study, we evaluated if CBD would interfere with THC-induced nausea through a 5-HT1A receptor mechanism as it has been shown to interfere with nausea produced by lithium chloride (LiCl). Since CHS has been attributed to a dysregulated stress response, we also evaluated if CBD would interfere with THC-induced increase in corticosterone (CORT). Materials and Methods: The potential of CBD (5 mg/kg, ip) to suppress THC-induced conditioned gaping (a measure of nausea) was evaluated in rats, as well as the potential of the 5-HT1A receptor antagonist, WAY-100635 (WAY; 0.1 mg/kg, ip), to reverse the suppression of THC-induced conditioned gaping by CBD. Last, the effect of CBD (5 mg/kg, ip) on THC-induced increase in serum CORT concentration was evaluated. Results: Pretreatment with CBD (5 mg/kg, ip) interfered with the establishment of THC-induced conditioned gaping (p=0.007, relative to vehicle [VEH] pretreatment), and this was reversed by pretreatment with 0.1 mg/kg WAY. This dose of WAY had no effect on gaping on its own. THC (10 mg/kg, ip) significantly increased serum CORT compared with VEH-treated rats (p=0.04). CBD (5 mg/kg, ip) pretreatment reversed the THC-induced increase in CORT. Conclusions: CBD attenuated THC-induced nausea as well as THC-induced elevation in CORT. The attenuation of THC-induced conditioned gaping by CBD was mediated by its action on 5-HT1A receptors, similar to that of LiCl-induced nausea.

CB2 Receptor in Microglia: The Guardian of Self-Control

Article

Full-text available

Dec 2020
INT J MOL SCI

Microglia are key to maintaining the homeostasis of the brain. These immune cells of the brain can be our biggest ally in fighting infections, but can worsen pathology or hinder recovery when uncontrolled. Thus, understanding how microglia contribute to neuroinflammatory processes and how their activity can be controlled is of great importance. It is known that activation of endocannabinoid system, and especially the cannabinoid type 2 receptor (CB2R), decreases inflammation. Alongside its non-psychoactive effect, it makes the CB2R receptor a perfect target for treating diseases accompanied by neuroinflammation including neurodegenerative diseases. However, the exact mechanisms by which CB2R regulates microglial activity are not yet understood. Here, we review the current knowledge on the roles of microglial CB2R from in vitro and in vivo studies. We look into CB2R function under physiological and pathological conditions and focus on four different disease models representing chronic and acute inflammation. We highlight open questions and controversies and provide an update on the latest discoveries that were enabled by the development of novel technologies. Also, we discuss the recent findings on the role of microglia CB2R in cognition and its role in neuron–microglia communication.

Synthesis, Characterization and Stress-Testing of a Novel Quillaja Saponin Stabilized Oil-in-Water Phytocannabinoid Nanoemulsion

Preprint

Full-text available

Oct 2020

div>This study describes the design, optimization, and stress-testing of a novel phytocannabinoid nanoemulsion generated using high-pressure homogenization. QNaturale®, a plant-derived commercial emulsifier containing quillaja saponin, was used to stabilize the lipid phase droplets in water. Optimization studies revealed that after 10 homogenization cycles at a pressure of 30,000 psi in the presence of 10 wt% QNaturale® (1.5 wt% quillaja saponin), average nanoemulsion droplet diameters were ca. 120 nm and average droplet surface zeta-potentials were ca. -30 mV for a lipid phase comprising 16.6 wt% CBD-enriched cannabis extract and 83.4 wt% carrier (soybean) oil. The optimized nanoemulsion proved to be stable to droplet agglomeration and phase separation upon storage under ambient conditions for 6 weeks, as well as under a variety of physical stressors such as heat, cold, dilution, and carbonation. pH values under 2 and moderately high salt concentrations (> 100 mM), however, destabilized 0the CD_CBD nanoemulsion, eventually leading to phase separation. Cannabis potency, determined by HPLC, was detrimentally affected by any changes in the nanoemulsion phase stability. Quillaja saponin stabilized cannabidiol (CBD)-enriched nanoemulsions are stable, robust systems even at low emulsifier concentrations, and are therefore significant from both a scientific as well as a commercial perspective.</div

Cannabis Use in Pregnant and Breastfeeding Women: Behavioral and Neurobiological Consequences

Article

Full-text available

Nov 2020

Nowadays, cannabis is the most consumed illicit drug. The global prevalence of the use of cannabis in 2017 was estimated in 188 million of people, 3.8% of worldwide population. Importantly, the legalization of cannabis in different countries, together with the increase in the apparent safety perception, may result in a great variety of health problems. Indeed, an important concern is the increase in cannabis use among pregnant and breastfeeding women, especially since the content of delta9-tetrahidrocannabinol (THC) is currently around 2-fold higher than it was 15–20 years ago. The purpose of this study was to review cannabis use during pregnancy and breastfeeding including epidemiological aspects, therapeutic or preventive strategies, and experimental considerations and results from animal models of perinatal cannabis exposure to analyze the underlying neurobiological mechanisms and to identify new therapeutic approaches. A recent report revealed that among pregnant women aged 15–44, last month cannabis use prevalence was over 4.9%, raising to 8.5% in the 18–25-year-old age range. Pre- and post-natal exposure to cannabis may be associated with critical alterations in the newborn infants that are prolonged throughout childhood and adolescence. Briefly, several reports revealed that perinatal cannabis exposure was associated with low birth weight, reduction in the head circumference, cognitive deficits (attention, learning, and memory), disturbances in emotional response leading to aggressiveness, high impulsivity, or affective disorders, and higher risk to develop a substance use disorder. Furthermore, important neurobiological alterations in different neuromodulatory and neurotransmission systems have been associated with cannabis consumption during pregnancy and lactation. In spite of the evidences pointing out the negative behavioral and neurobiological consequences of cannabis use in pregnant and breastfeeding women, there are still limitations to identify biomarkers that could help to establish preventive or therapeutic approaches. It is difficult to define the direct association specifically with cannabis, avoiding other confusing factors, co-occurrence of other drugs consumption (mainly nicotine and alcohol), lifestyle, or socioeconomic factors. Therefore, it is necessary to progress in the characterization of short- and long-term cannabis exposure-related disturbances.

Comprehending and Improving Cannabis Specialized Metabolism in the Systems Biology Era

Article

Jun 2020
PLANT SCI

Cannabis sativa is a source of food, fiber and specialized metabolites such as cannabinoids, with psychoactive and pharmacological effects. Due to its expanding and increasingly-accepted use in medicine, cannabis cultivation is acquiring more importance and less social stigma. Humans initiated different domestication episodes whose later spread gave rise to a plethora of landrace cultivars. At present, breeders cross germplasms from different gene pools depending on their specific use. The fiber (hemp) and drug (marijuana) types of C. sativa differ in their cannabinoid chemical composition phenotype (chemotype) and also in the accumulation of terpenoid compounds that constitute a strain’s particular flavor and scent. Cannabinoids are isoprenylated polyketides among which cannabidiolic acid (CBDA) and (−)-trans-Δ⁹-tetrahydrocannabinol acid (THCA) have been well-documented for their many effects on humans. Here, we review the most studied specialized metabolic pathways in C. sativa, showing how terpenes and cannabinoids share both part of the isoprenoid pathway and the same biosynthetic compartmentalization (i.e. glandular trichomes of leaves and flowers). We enlist the several studies that have deciphered these pathways in this species including physical and genetic maps, QTL analyses and localization and enzymatic studies of cannabinoid and terpene synthases. In addition, new comparative modeling of cannabinoid synthases and phylogenetic trees are presented. We describe the genome sequencing initiatives of several accessions with the concomitant generation of next-generation genome maps and transcriptomic data. Very recently, proteomic characterizations and systems biology approaches such as those applying network theory or the integration of multi-omics data have increased the knowledge on gene function, enzyme diversity and metabolite content in C. sativa. In this revision we drift through the history, present and future of cannabis research and on how second- and third-generation sequencing technologies are bringing light to the field of cannabis specialized metabolism. We also discuss different biotechnological approaches for producing cannabinoids in engineered microorganisms. Cannabis sativa L. belongs to a genus of flowering plants with annual-growth and dioecious behaviour, native to Central and South Asia and with a long history of human use. Research in this species has grown exponentially in the last decade thanks to the unbanning of its cultivation in several world regions. This has permitted studying how the converging action of human- and nature-driven evolution of C. sativa has resulted in a plethora of valuable and complex specialized metabolites (SM). These are the center of attention of this review. Here, we cover how the emergence of genome-wide studies and the integration of big data analysis (i.e. systems biology, sysbio) is enabling us to comprehend the genetic regulation of cannabis secondary metabolism. Despite focusing on the outreach of genomic platforms and sysbio approaches, we also cover important aspects of cannabis history, effects of SM on human physiology and latest biotechnological approaches, all of which need to be acknowledged to understand the past, present and future of cannabis research.

Cannabinoids: The Lows and the Highs of Chemotherapy-Induced Nausea and Vomiting

Article

Feb 2019

Despite remaining one of the most widely abused drugs worldwide, Cannabis sativa exhibits remarkable medicinal properties. The phytocannabinoids, cannabidiol and Δ-9-tetrahydrocannabinol, reduce nausea and vomiting, particularly during chemotherapy. This is attributed to their ability to reduce the release of serotonin from enterochromaffin cells in the small intestine, which would otherwise orchestrate the vomiting reflex. Although there are many preclinical and clinical studies on the effects of Δ-9-tetrahydrocannabinol during nausea and vomiting, little is known about the role that cannabidiol plays in this scenario. Since cannabidiol does not induce psychotropic effects, in contrast to other cannabinoids, its use as an anti-emetic is of great interest. This review aims to summarize the available literature on cannabinoid use, with a specific focus on the nonpsychotropic drug cannabidiol, as well as the roles that cannabinoids play in preventing several other adverse side effects of chemotherapy including organ toxicity, pain and loss of appetite.

Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy: A Systematic Review

Article

Full-text available

Feb 2019
ALCOHOL CLIN EXP RES

There is substantial interest in the therapeutic potential of cannabidiol (CBD), a nonpsychoactive cannabinoid found in plants of the genus Cannabis. The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a candidate pharmacotherapy for alcohol use disorder (AUD). Using a comprehensive search strategy, 303 unique potential articles were identified and 12 ultimately met criteria for inclusion (8 using rodent models, 3 using healthy adult volunteers, and 1 using cell culture). In both rodent and cell culture models, CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus. In rodent models, CBD was found to attenuate alcohol‐induced hepatotoxicity, specifically, alcohol‐induced steatosis. Finally, findings from preclinical rodent models also indicate that CBD attenuates cue‐elicited and stress‐elicited alcohol seeking, alcohol self‐administration, withdrawal‐induced convulsions, and impulsive discounting of delayed rewards. In human studies, CBD was well tolerated and did not interact with the subjective effects of alcohol. Collectively, given its favorable effects on alcohol‐related harms and addiction phenotypes in preclinical models, CBD appears to have promise as a candidate AUD pharmacotherapy. This is further bolstered by the absence of abuse liability and its general tolerability. A clear limitation to the literature is the paucity of human investigations. Human preclinical and clinical studies are needed to determine whether these positive effects in model systems substantively translate into clinically relevant outcomes.

Uso de la marihuana medicinal en enfermedades reumáticas

Article

Full-text available

Sep 2017

Dario Scublinsky

La marihuana medicinal ha sido propuesta en los últimos años como una solución a algunos problemas médicos refractarios a otros tratamientos. En este trabajo se realiza una breve revisión desde la historia moderna de los cannabinoides y la farmacología del THC, hasta la evidencia actual de la utilidad de estas sustancias en las enfermedades reumáticas.

Cannabidiol modulates serotonergic transmission and prevents allodynia and anxiety-like behavior in a model of neuropathic pain

Article

Full-text available

Aug 2018

Clinical studies indicate that cannabidiol (CBD), the primary non-addictive component of cannabis that interacts with the serotonin (5-HT) 1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact in models of neuropathic pain are unknown. First, using in-vivo single unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN), which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 mg/kg/day, subcutaneously, s.c, for 7 days) increased 5-HT firing via desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury (SNI) model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze (EPMT), open field (OFT), and novelty suppressed feeding tests (NSFT). Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Anti-allodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), while the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly via TRPV1 activation, reduces anxiety via 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.

Food Intake and Eating Behavior After Bariatric Surgery

Article

Jul 2018

Obesity is an escalating global chronic disease. Bariatric surgery is a very efficacious treatment for obesity and its comorbidities. Alterations to gastrointestinal anatomy during bariatric surgery result in neurological and physiological changes affecting hypothalamic signaling, gut hormones, bile acids, and gut microbiota, which coalesce to exert a profound influence on eating behavior. A thorough understanding of the mechanisms underlying eating behavior is essential in the management of patients after bariatric surgery. Studies investigating candidate mechanisms have expanded dramatically in the last decade. Herein we review the proposed mechanisms governing changes in eating behavior, food intake, and body weight after bariatric surgery. Additive or synergistic effects of both conditioned and unconditioned factors likely account for the complete picture of changes in eating behavior. Considered application of strategies designed to support the underlying principles governing changes in eating behavior holds promise as a means of optimizing responses to surgery and long-term outcomes.

Cannabidiol: State of the art and new challenges for therapeutic applications

Article

Feb 2017

Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ(9)-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ(9)-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.

Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders

Article

Jun 2016

Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency. The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models. The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some. In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors. Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases. In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders. Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.

Phytocannabinoids and Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders

Article

Full-text available

May 2016

Background: Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs. These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors. Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases. Methods: In this study, starting from the endocannabinoid mechanism of action in neuronal signaling, we highlight and discuss potential application and recent patents of cannabimimetic drugs in neurological disorders. Results: The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression. Conclusions: Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.

Cannabidiol, a constituent of cannabis sativa, induces waking in rats

Conference Paper

Jan 2006

Endocannabinoid Mechanisms Influencing Nausea

Article

Dec 2015
INT REV NEUROBIOL

One of the first recognized medical uses of δ9-tetrahydrocannabinol was treatment of chemotherapy-induced nausea and vomiting. Although vomiting is well controlled with the currently available non-cannabinoid antiemetics, nausea continues to be a distressing side effect of chemotherapy and other disorders. Indeed, when nausea becomes conditionally elicited by the cues associated with chemotherapy treatment, known as anticipatory nausea (AN), currently available antiemetics are largely ineffective. Considerable evidence demonstrates that the endocannabinoid system regulates nausea in humans and other animals. In this review, we describe recent evidence suggesting that cannabinoids and manipulations that enhance the functioning of the natural endocannabinoid system are promising treatments for both acute nausea and AN.

Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine

Article

Full-text available

Apr 2015
MEDIAT INFLAMM

Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The 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 inflammatory infiltrate. 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 inflammation 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. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.

Cannabidiol Indirectly Activates 5-HT 1A Somatodendritic Autoreceptors to Attenuate Vomiting and Nausea

Article

Erin M Rock

The Role of Cannabinoids and the Endocannabinoid System in the Treatment and Regulation of Nausea and Vomiting

Chapter

Dec 2024

Despite using the recommended anti-emetic treatments, control of nausea and vomiting is still an unmet need for cancer patients undergoing chemotherapy treatment. Few properly controlled clinical trials have evaluated the potential of exogenously administered cannabinoids or manipulations of the endogenous cannabinoid (eCB) system to treat nausea and vomiting. In this chapter, we explore the pre-clinical and human clinical trial evidence for the potential of exogenous cannabinoids and manipulations of the eCB system to reduce nausea and vomiting. Although there are limited high-quality human clinical trials, pre-clinical evidence suggests that cannabinoids and manipulations of the eCB system have anti-nausea/anti-emetic potential. The pre-clinical anti-nausea/anti-emetic evidence highlights the need for further evaluation of cannabinoids and manipulations of eCBs and other fatty acid amides in clinical trials.

Cannabis: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin

Article

Full-text available

Jul 2023
REV INVEST CLIN

The consumption of Cannabis sativa plant, known as marijuana in the Western world, for different purposes (therapeutic, intoxicating, and spiritual) due to its psychoactive effects, can be traced back to ancient times. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.

Assessment of cannabis craving using the Marijuana Craving Questionnaire

Article

Feb 2006

Cannabis is the most widely used illicit drug in the United States, with 14.6 million current users. Cannabis-dependent individuals presenting for treatment typically report cannabis craving; however, the phenomenon has received little research attention. In the absence of a valid, multidimensional questionnaire to assess cannabis craving, we developed the Marijuana Craving Questionnaire (MCQ). The MCQ consists of four constructs or factors that characterize cannabis craving: compulsivity, emotionality, expectancy, and purposefulness. A separate score is calculated for each factor. The MCQ can be used to measure cue-elicited craving in a research setting or natural craving in cannabis-dependent individuals presenting for treatment. Either the 47-item or 12-item version can be used, and standardized instructions for completion of the MCQ should be given. The MCQ can be administered using a paper and pencil form or a computerized version. In a research setting, the MCQ should be administered immediately after cue presentation and repeated frequently to capture the full time course. In a treatment setting, the MCQ should be administered at intake and during and at the end of treatment.

Evaluation of Sex Differences in the Potential of Δ 9 -Tetrahydrocannabinol, Cannabidiol, Cannabidiolic Acid, and Oleoyl Alanine to Reduce Nausea-Induced Conditioned Gaping Reactions in Sprague-Dawley Rats

Article

Aug 2022

Introduction: Cancer patients report nausea as a side effect of their chemotherapy treatment. Using the pre-clinical rodent model of acute nausea-lithium chloride (LiCl)-induced conditioned gaping-our group has demonstrated that exogenous cannabinoids may have antinausea potential. Materials and Methods: With the goal of evaluating the role of sex as a factor in pre-clinical research, we first compared the conditioned gaping reactions produced by varying doses of LiCl in male and female rats using the taste reactivity test (Experiment 1). Results: LiCl produced dose-dependent conditioned gaping similarly in male and female rats with the highest dose (127.2 mg/kg) producing robust conditioned gaping, with this dose used in subsequent experiments. Next, we examined the antinausea potential of THC (Experiment 2), CBD (Experiment 3), cannabidiolic acid (CBDA; Experiment 4) and oleoyl alanine (OlAla; Experiment 5) in both male and female rats. THC, CBD, CBDA, and OlAla dose dependently reduced conditioned gaping in both male and female rats in a similar manner. Conclusions: These results suggest that cannabinoids may be equally effective in treating nausea in both males and females.

Evidence For Cannabidiol Modulation of Serotonergic Transmission in a Model of Osteoarthritis via in vivo PET Imaging and Behavioral Assessment

Article

Full-text available

Jun 2022

Background Preclinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis, has a wide range of reported pharmacological effects such as analgesic and anxiolytic actions; however, the exact mechanisms of action for these effects have not been examined in chronic osteoarthritis (OA). Similar to other chronic pain syndromes, OA pain can have a significant affective component characterized by mood changes. Serotonin (5-HT) is a neurotransmitter implicated in pain, depression, and anxiety. Pain is often in comorbidity with mood and anxiety disorders in patients with OA. Since primary actions of CBD are analgesic and anxiolytic, in this first in vivo positron emission tomography (PET) imaging study, we investigate the interaction of CBD with serotonin 5-HT1A receptor via a combination of in vivo neuroimaging and behavioral studies in a well-validated OA animal model. Methods The first aim of this study was to evaluate the target involvement, including the evaluation of modulation by acute administration of CBD, or a specific target antagonist/agonist intervention, in control animals. The brain 5-HT1A activity/availability was assessed via in vivo dynamic PET imaging (up to 60 min) using a selective 5-HT1A radioligand ([¹⁸F]MeFWAY). Tracer bindings of 17 ROIs were evaluated based on averaged SUVR values over the last 10 min using CB as the reference region. We subsequently examined the neurochemical and behavioral alterations in OA animals (induction with monosodium iodoacetate (MIA) injection), as compared to control animals, via neuroimaging and behavioral assessment. Further, we examined the effects of repeated low-dose CBD treatment on mechanical allodynia (von Frey tests) and anxiety-like (light/dark box tests, L/D), depressive-like (forced swim tests, FST) behaviors in OA animals, as compared to after vehicle treatment. Results The tracer binding was significantly reduced in control animals after an acute dose of CBD administered intravenously (1.0 mg/kg, i.v.), as compared to that for baseline. This binding specificity to 5-HT1A was further confirmed by a similar reduction of tracer binding when a specific 5-HT1A antagonist WAY1006235 was used (0.3 mg/kg, i.v.). Mice subjected to the MIA-induced OA for 13–20 days showed a decreased 5-HT1A tracer binding (25% to 41%), consistent with the notion that 5-HT1A plays a role in the modulation of pain in OA. Repeated treatment with CBD administered subcutaneously (5 mg/kg/day, s.c., for 16 days after OA induction) increased 5-HT1A tracer binding, while no significant improvement was observed after vehicle. A trend of increased anxiety or depressive-like behavior in the light/dark box or forced swim tests after OA induction, and a decrease in those behaviors after repeated low-dose CBD treatment, are consistent with the anxiolytic action of CBD through 5HT1A receptor activation. There appeared to be a sex difference: females seem to be less responsive at the baseline towards pain stimuli, while being more sensitive to CBD treatment. Conclusion This first in vivo PET imaging study in an OA animal model has provided evidence for the interaction of CBD with the serotonin 5-HT1A receptor. Behavioral studies with more pharmacological interventions to support the target involvement are needed to further confirm these critical findings.

Regulatory Effect of Cannabidiol (CBD) on Decreased β-Catenin Expression in Alopecia Models by Testosterone and PMA Treatment in Dermal Papilla Cells

Article

Full-text available

Jun 2021

Objectives: The hair follicle is composed of more than 20 kinds of cells, and mesoderm derived dermal papilla cells and keratinocytes cooperatively contribute hair growth via Wnt/β-catenin signaling pathway. We are to investigate β-catenin expression and regulatory mechanism by CBD in alopecia hair tissues and dermal papilla cells. Methods: We performed structural and anatomical analyses on alopecia patients derived hair tissues using microscopes. Pharmacological effect of CBD was evaluated by β-catenin expression using RT-PCR and immunostaining experiment. Results: Morphological deformation and loss of cell numbers in hair shaft were observed in alopecia hair tissues. IHC experiment showed that loss of β-catenin expression was shown in inner shaft of the alopecia hair tissues, indicating that β-catenin expression is a key regulatory function during alopecia progression. Consistently, β-catenin expression was decreased in testosterone or PMA treated dermal papilla cells, suggesting that those treatments are referred as a model on molecular mechanism of alopecia using dermal papilla cells. RT-PCR and immunostaining experiments showed that β-catenin expression was decreased in RNA level, as well as decreased β-catenin protein might be resulted from ubiquitination. However, CBD treatment has no changes in gene expression including β-catenin, but the decreased β-catenin expression by testosterone or PMA was restored by CBD pretreatment, suggesting that potential regulatory effect on alopecia induction of testosterone and PMA. Conclusion: CBD might have a modulating function on alopecia caused by hormonal or excess of signaling pathway, and be a promising application for on alopecia treatment.

Bioactive Terpenoids in Cannabis: A Critical Review

Article

Full-text available

Mar 2021

Terpenoids, also referred as terpenes have been used extensively in drug related industry due to pharmaceutical properties. These have driven the emergence of studies on terpenoid from plant. Cannabis sativa plant is one of the common natural sources of terpenoids and cannabinoids. The cannabis produces and accumulates terpenoids in grandular trichomes. The grandular trichomes are abundant on the surface of female inflorescence. About 140 terpenoids are known in cannabis and some of them have medicinal potential in treatment of pain, inflammatory, cognition, epilepsy and immune functioning. The biological effect of terpenoid from cannabis is mainly attributed to limonene, myrcene, pinene, linalool, ß-caryophyllene, caryophyllene oxide, nerolidol and phytol. The different composition of terpenoids are responsible in exhibit the unique organoleptic properties and influence the medicinal qualities of difference cannabis strains and varieties. This article aims to review the cannabis plant for terpenoid, terpenoid biosynthesis and its pharmacological activities. The terpenoids from cannabis could be valuable natural resources for drug development.

Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies

Article

Mar 2021

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines (CBM) for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are: 1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; 2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and 3) to identify important directions for future research. In service of these goals, this review a) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; b) describes pharmacokinetics of cannabinoids in rodents and humans; and c) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.

Effect of Natural Products on Improvement of Blood Pathophysiology for Management of Sickle Cell Anemia

Chapter

Nov 2020

Sickle cell anemia (SCA) is an inherited disorder in the β-globin chain of hemoglobin that affects millions of people around the world, especially children. This disease prevalently occurs in some Mediterranean and Saharan Africa. For the treatment of SCA patients, a wide range of drugs have been explored by targeting antisickling activity, γ-globulin induction, antiplatelet effect, etc., but hardly a few drugs have shown potential to combat with this complex disease phenomenon. In spite of unprecedented advances in modern system of medicine, people in the disease-prone area have been taking traditional medicinal plants or plant-derived products to increase the life span of patients. Moreover, numerous clinical trials have been going on for the use of natural products under the purview of symptomatic management of SCA. This chapter is focused on the effect of natural products in pure form or characterized phytoconstituents on particularly inhibition of hemoglobin polymerization. This summarized information will be beneficial for further exploration of new therapeutics in the treatment arena of SCA.

Effect of Natural Products on Improvement of Blood Pathophysiology for Management of Sickle Cell Anemia

Book

Nov 2020

Medicinal Applications of Cannabidiol from the Genus Cannabis L.. In: Singh B. (eds) Botanical Leads for Drug Discovery.

Chapter

Oct 2020

Cannabis L. belongs to Cannabaceae family known as ‘hemp’ and has been used as a mind-altering drug as described in prehistoric societies of Eurasia and Africa. A total of 100 phytocannabinoids have been reported from Cannabis sativa L. till date, owing to their therapeutic values. The two primary constituents present in Cannabis are non-psychoactive cannabidiol (CBD) and psychoactive Δ9-tetrahydrocannabinol (THC). CBD has enormous potential for the development as a drug candidate as depicted by diverse clinical and preclinical studies for the treatment of various neuropsychiatric disorders, arthritis, cancer and other diseases. Regardless of its therapeutic importance and interaction with the endocannabinoid system (ECS), definite pharmacological mechanism is not clearly established. Apart from medicinal research, there are a number of aspects which should be taken under consideration such as opinion of FDA, legal aspects of cannabis and international scenario during the drug development based on this plant.

The cannabinoid system: from the point of view of a chemist

Chapter

May 2004

This book provides a comprehensive overview of the psychiatry and neuroscience of Cannabis sativa (marijuana), with particular emphasis on psychotic disorders. It outlines developments in our understanding of the human cannabinoid system, and links this knowledge to clinical and epidemiological facts about the impact of cannabis on mental health. Clinically focused chapters review not only the direct psychomimetic properties of cannabis, but also the impact consumption has on the courses of evolving or established mental illness such as schizophrenia. A number of controversial issues are critically explored, including whether a discrete 'cannabis psychosis' exists, and whether cannabis can actually cause schizophrenia. Effects of cannabis on mood, notably depression, are reviewed, as are its effects on cognition. This book will be of interest to all members of the mental health team, as well as to neuroscientists and those involved in drug and alcohol research.

Cannabis in Oncology and Symptom Management

Chapter

Jul 2020

Marijuana has been used for medicinal purposes for over 5000 years. Shen Nung in the “Great Herbal” (2737 BC) described the drug as a liberator of sin and delight giver. Majority of controlled clinical trials supporting the medical use of cannabis/marijuana have been conducted with purified cannabinoids or single extract of Cannabis sativa (equimolecular proportion of Delta9-THC and CBD). At this time in the United States, the FDA has approved three cannabinoid medications for medicinal purposes (however, not for pain) including dronabinol, cannabidiol, and nabilone. The European Medicines Agency and Health Canada have similarly approved those approved by the FDA in addition to nabiximols. Cannabis is currently available for medicinal use in 33 States in America and for non-medicinal use in 10 states, although both remain illegal under federal law. In Canada, cannabis was legalized for non-medicinal use as of 2018. Crude cannabis is by far the most frequent source of cannabinoids for patients worldwide, few studies examine the therapeutic value of cannabis oils (for ingestion or topical use), or vaporized herbal cannabis. Cannabis affects the brain through interaction with the endogenous cannabinoid system inclusive of cannabinoid receptors and endogenous ligands. Acute intoxication with cannabis results in marked changes in mentation and impairs cognition. The acute effects on behavior, mood and cognition are biphasic and dose-dependent. Controversy remains regarding persistent effects of cannabis following cessation in domains of behavior, cognition, brain, and brain function.

Reviewer comments

Data

Full-text available

Sep 2018

Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science

Article

Aug 2018

Eric P Baron

Background.—Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/ cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described. Most of the existing literature reports on the cannabinoids Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain. Objective.—Review the medical literature for the use of cannabis/cannabinoids in the treatment of migraine, headache, facial pain, and other chronic pain syndromes, and for supporting evidence of a potential role in combatting the opioid epidemic. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis. Summarize the individual medicinal benefits of these substances, including analgesic and anti-inflammatory properties. Conclusion.—There is accumulating evidence for various therapeutic benefits of cannabis/cannabinoids, especially in the treatment of pain, which may also apply to the treatment of migraine and headache. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards. Further research is anticipated to optimize breeding of strain-specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and diseasetargeted therapies.

Methods Evaluating Cannabinoid and Endocannabinoid Effects on Gastrointestinal Functions

Chapter

Jan 2005

This chapter briefly describes the physiological neural mechanisms by which diverse neurotransmitter receptor systems control several aspects of gastrointestinal functions such as motility, secretion, feeding, and emesis. The current techniques used to study the effects of cannabinoids on these gastrointestinal functions are then sequentially described, starting with isolated gastrointestinal muscle preparations and ultimately evolving to whole animal models. Both Δ9-tetrahydrocannibinol (Δ9-THC) and well-studied representatives of other classes of exogenous cannabinoid CB1/CB2 receptor agonists inhibit gastrointestinal motility, peristalsis, defecation, and secretions via cannabinoid CB1 receptors since the CB1 (SR141716A)- and not the CB2 (SR144528)-receptor antagonist reverses these effects in a dose-dependent manner. In addition, exogenous cannabinoids inhibit vomiting produced by diverse emetic stimuli in a SR141716A-sensitive manner in different animal models of emesis. Often these cannabinoids produce hyperphagic effects under laboratory conditions in most human and animal models of feeding. Administration of SR141716A by itself can produce effects opposite to cannabinoid agonists (e.g., increases in gastrointestinal motility and secretions, hyperphagia and vomiting), which suggests an important role for endocannabinoids in these gastrointestinal functions. Indeed, the presence of cannabinoid CB1 receptor markers, endocannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG), their metabolic enzymes, and an endocannabinoid reuptake system have been confirmed in the gastrointestinal tract (GIT). The well-studied endocannabinoid anandamide also seems to reduce both gastrointestinal motility and secretion while producing hyperphagia. On the other hand, while the less well-investigated endocannabinoid 2-AG is a potent emetogen, anandamide may possess weak antiemetic activity.

The pharmacological history of cannabis

Article

Full-text available

Jan 2014

Ethan Budd Russo

Daño inflamatorio y estrés oxidativo en la Enfermedad de Alzheimer. Efecto de polifenoles y cannabinoides

Thesis

Full-text available

Jun 2014

Diana Aguirre-Rueda

Several studies indicate that the accumulation of Aβ1-42 peptide in Alzheimer's disease is the inducer of the inflammatory process with the activation of glial cells producing and releasing inflammatory cytokines (Eikelenboom and van Gool., 2004; Zhu, X et al., 2004). The presence of these inflammatory molecules induced by Aβ1-42 stimulates the production of reactive oxygen species and free radicals by glial cells increasing the levels of oxidative stress (Jiménez-Jiménez et al., 2006; Sutherland et al., 2013; Phillips et al., 2013; Gubandru et al., 2013). Collectively, inflammation and oxidative stress, indicating a key role in the development and progression of Alzheimer's disease. Currently, there is no cure for Alzheimer's disease and the pharmacological therapeutic targets to delay and control their symptoms to improve the welfare and quality of life of the patient. Because of the side effects that these drugs have, since several years are being developed lines of research to study the different effects (neuroprotective, antioxidant and anti-inflammatory) of natural compounds based on the action on different signaling pathways associated with inflammation and oxidative stress. Among have been proposed polyphenols and cannabinoids. The studies were performed in primary cultures of astrocytes, because they are the cells involved in the inflammatory response and found in greater amounts in the brain. They have employed the techniques of direct and indirect immunofluorescence, MTT, Western-blot, ELISA and HPLC assay for the various determinations in the different experimental conditions (control, treated with Aβ1-42 peptide and pre-treatment with polyphenols and cannabinoids). Our results indicate that pre-treatment with polyphenols or cannabinoids are able to reduce inflammation and oxidative stress induced by Aβ1-42 peptide, decreasing of pro-inflammatory and oxidant molecules (IL-1β, TNF-α, COX -2, iNOS, GSSG/GSH) and increased anti-inflammatory and anti-oxidant molecules (PPAR-γ, SOD Cu/Zn). These results support the hypothesis that inflammation and oxidative stress mechanisms contribute significantly to the pathogenesis of Alzheimer's disease and suggest the use of natural compounds such as polyphenols or cannabinoids to reduce the progression of damage.

Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum

Article

Jun 2004
LIFE SCI

V GUIMARAES

Preclinical and clinical studies suggest that cannabidiol (CBD), a major component of Cannabis sativa, could produce antipsychotic effects without causing extra-pyramidal side-effects. In the present paper we employed the detection of Fos protein to investigate neuronal activation in the dorsal striatum and nucleus accumbens of male Wistar rats after systemic administration of CBD (120 mg/kg), haloperidol (1 mg/kg) or clozapine (20 mg/kg). Only haloperidol was able to increase the number of Fos immunoreactive neurons (FIr) in the dorsal striatum (vehicle: 0.07 ± 0.07/0.1 mm², haloperidol: 28.3 ± 8.9/0.1 mm², p < 0.01). In contrast, both haloperidol and CBD significantly increased FIr in the nucleus accumbens (Vehicle: 0 ± 0/0.1 mm², haloperidol: 7.2 ± 2.7/0.1 mm², CBD: 4.0 ± 1.9/0.1 mm², p < 0.05). Clozapine also produced a barely significant increase in FIr (3.0 ± 1.7/0.1 mm², p = 0.062). These results show that CBD is able to induce FIr in a limbic- but not in a motor-related area.

Development and application of a LC-MS/MS method for the analysis of plasma bioavailabilities of different cannabinoids after the administration of "Cannabis sativa L." extracts and MarinolTM

Article

Jan 2008

Sandra B. Grauwiler

Discriminating the Effects of Cannabis sativa and Cannabis indica: A Web Survey of Medical Cannabis Users

Article

Sep 2014
J ALTERN COMPLEM MED

Objective: To evaluate the opinions of medical cannabis (MC) users on the effects of Cannabis indica vs. those of Cannabis sativa on conditions and symptoms through an online survey. Design: Survey of 95 non-randomly assigned MC users. A two-sided chi-square test followed by Bonferroni post hoc multiple comparison and Fisher exact test were used to determine correlations. The Cronbach α was used to determine internal consistency. Setting: Announcements on 13 MC websites with links to SurveyMonkey.com. Participants: Self-identified MC users. Intervention: Web survey. Outcome measures: Species effects were compared regarding health symptoms, conditions, purpose, route, and trust in product label. Results: Trust in the purity, the route of administration, or the purpose (recreational vs. medicinal) did not differ between the two species. A preference for C. indica was statistically significant for pain management (p=0.001), helping with sedation (p=0.015), and sleep (p<0.001). C. sativa was preferred for euphoria (p<0.001) and enhancing energy (p=0.022). The conditions reaching statistical significance for C. indica preference were: nonmigraine headaches (p=0.042), glaucoma (p=0.036), neuropathy (p=0.024), spasticity (p=0.048), seizures (p=0.031), insomnia (p<0.001), and joint pain (p=0.048). For C. sativa, no conditions reached significance. The MC websites' descriptions of effects that agreed with the survey results are listed. Some conditions had very few respondents. The internal consistency/reliability (Cronbach α) was adequate for the condition scale but not for the symptom survey. Conclusion: In this anonymous Web survey, which had limitations, the two species had different effect associations on symptoms and conditions, possibly because of ingredient differences. Future surveys and subsequent prospective definitive trials are needed to confirm the findings.

Cannabidiol and (−) Delta-9-tetrahydrocannabinol are neuroprotective

Article

Full-text available

Aug 1998

The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (-)Delta9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-D-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-D-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.

From the Cover: The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

Article

Full-text available

Sep 2000

The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-gamma production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.

Statistical Principles of Experimental Design

Article

Jan 1962

B.J. Winer

Marihuana, The Forbidden Medicine

Article

Oct 1995

Robert L. DuPont

Conditioned suppression of drinking: A measure of the CR elicited by a lithium-conditioned flavor*1

Article

Nov 1980

Linda A. Parker

The CR elicited by an exposure to a lithium-conditioned flavor CS+ was measured in a paradigm which closely approximated traditional conditioned suppression of licking. Rats were first trained to discriminate between a lithiumpaired flavored solution (CS+) and an equally familiar, but safe, flavored solution (CSc). Then, while they consumed a differently flavored test solution, the rats were intraorally infused with either the CS+ or the CSc flavored solution. The immediate aftereffect of the CS+ exposure on consumption of the Test Solution (TS) measured the CR. The CS+ exposure suppressed the consumption of both a novel flavored TS and an unflavored water TS. The strength of the suppressive CR was influenced by the nature of the TS and by the dose of lhe lithium US.

Emetic drugs produce conditioned rejection reactions in the taste reactivity test

Article

Jan 1998

Linda A. Parker

In the taste reactivity test, rats display a distinctive pattern of rejection reactions during exposure to an unconditionally aversive flavored solution, such as quinine. We review evidence that these rejection reactions are also displayed during exposure to a flavor previously paired with an emetic drug, but not during exposure to a flavor previously paired with a rewarding drug. These results suggest that flavor avoidance produced by emetic drugs is mediated by a conditioned taste aversion, but flavor avoidance produced by rewarding drugs is not mediated by such a conditioned taste aversion. The conditioned rejection reactions elicited by flavors paired with emetic drugs may reflect conditioned sickness. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

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

Article

Apr 1964

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

Article

Oct 2001
BRIT J PHARMACOL

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

Nonconsummatory and consummatory CRs elictied by lithium-and amphetamine-paired flavors

Article

Aug 1982

Linda A. Parker

Various behavioral CRs elicited by saccharin solution previously paired with either lithium or amphetamine were measured in a series of four experiments. With one conditioning trial, lithium (Experiment 1), but not amphetamine (Experiment 2), produced nonconsummatory behavioral evidence of conditioning in the form of chin-rub CRs; both drugs, however, produced strong flavor aversions. With 3 conditioning trials, lithium- and amphetamine-paired flavors elicited a pattern of agitated activity, characterized by increased general activity, rearing duration, and body temperature, when the flavor was forcibly presented through an intraoral cannula (Experiment 3). When the flavor was presented in a single-bottle test (Experiment 4), 3 conditioning trials produced a similar pattern of agitated activity characterized by increased general activity, rearing (duration and frequency), stretching (duration and frequency), and limb flicking. Although both drugs supported the pattern of increased agitation-related CRs, only the lithium-paired flavors elicited chin-rub CRs (Experiments 1, 3, and 4). The difference between the drug conditions was not the result of a greater saccharin aversion in the lithium-conditioned group than in the amphetamine-conditioned group (Experiment 4). The results are related to findings that suggest that flavor aversions are mediated by a shift in the hedonic properties of the drug-paired flavors.

Statistical Principles In Experiment Al Design

Book

Jan 1971

B. J. Winer

The abstract for this document is available on CSA Illumina.To view the Abstract, click the Abstract button above the document title.

Antiemetic effect of delta-9-THC in patients receiving cancer chemotherapy. N Eng J Med 293: 795-797

Article

Nov 1975

Anecdotal accounts suggested that smoking marihuana decreases the nausea and vomiting associated with cancer chemotherapeutic agents. Oral delta-9-tetrahydrocannabinol was compared with placebo in a controlled, randomized, "double-blind" experiment. All patients were receiving chemotherapeutic drugs known to cause nausea and vomiting of central origin. Each patient was to serve as his own control to determine whether tetrahydrocannabinol had an antiemetic effect. Twenty-two patients entered the study, 20 of whom were evaluable. For all patients an antiemetic effect was observed in 14 of 20 tetrahydrocannabinol courses and in none of 22 placebo courses. For patients completing the study, response occurred in 12 of 15 courses of tetrahydrocannabinol and in none of 14 courses of placebo (P less than 0.001). No patient vomited while experiencing a subjective "high". Oral tetrahydrocannabinol has antiemetic properties and is significantly better than a placebo in reducting vomiting caused by chemotherapeutic agents.

Chin rub CRs may reflect conditioned sickness elicited by a lithium-paired sucrose solution

Article

Jan 1992
PHARMACOL BIOCHEM BE

Rats were given a single conditioning trial in which 20% sucrose solution was paired with an intraperitoneal (IP) injection of lithium chloride (127.2 mg/kg), d-amphetamine (3 mg/kg) or physiological saline. Thirty min before a subsequent 10-min taste reactivity (TR) test and a 1-h conditioned taste avoidance (CTA) test the rats were injected IP with either the antiemetic agent, trimethobenzamide (5 mg/kg) [corrected] or with physiological saline solution. The lithium-paired, but not the amphetamine- or saline-paired, sucrose solution elicited the aversive TR responses of chin rubs, paw pushes and gapes. Trimethobenzamide suppressed the aversive TR response of chin rubs in the lithium-conditioned group, but not in a group given unconditionally aversive quinine solution. The CTA test was not sensitive to the antiemetic properties of trimethobenzamide, although the drug enhanced sucrose preference overall. The results suggest that chin rub responses may measure conditioned sickness.

Zuardi AW, Rodrigues JA, Cunha JM. Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology (Berl) 104: 260-264

Article

Feb 1991

The effects of cannabidiol (CBD) were compared to those produced by haloperidol in rats submitted to experimental models predictive of antipsychotic activity. Several doses of CBD (15-480 mg/kg) and haloperidol (0.062-1.0 mg/kg) were tested in each model. First, CBD increased the effective doses 50% (or) ED50 of apomorphine for induction of the sniffing and biting stereotyped behaviors. In addition, both CBD and haloperidol reduced the occurrence of stereotyped biting induced by apomorphine (6.4 mg/kg), increased plasma prolactin levels and produced palpebral ptosis, as compared to control solutions. However, CBD did not induce catalepsy even at the highest doses, in contrast to haloperidol. Such a pharmacological profile is compatible with that of an "atypical" antipsychotic agent, though the mechanism of action is uncertain and may not be identical to that of the dopamine antagonists.

Marihuana Chemistry

Article

Jul 1970

Raphael Mechoulam

Antiemetic Activity of N-Methyllevonantradol and Nabilone in Cisplatin-Treated Cats

Article

Aug 1981

The comprehensive emetic response to xenobiotics can be quantified by monitoring the physiological forces which effectuate vomiting. A unique sequence of thoracic pressure pulses, generated by the somatic muscles of ventilation, can be measured by means of a central venous catheter. This unambiguous emetic endpoint is used to record emetic latency, repetitions and duration of action, all on an established time base and dependent of stomach content. Deslanoside (160 micrograms/kg) produced emesis in 15 cats beginning in 4.4 +/- 1.9 min (mean +/- S.D.). Subsequent emetic episodes were related in time in a log-linear but biphasic manner. Cisplatin (7.5 mg/kg) had an emetic latency of 71 +/- 18 mn in 7 cats. Additional events also had a long-linear temporal relationship for up to 400 min. This quantified emetic profile of cisplatin served as a measure for assessing antiemetic activity of N-metyllevonantradol (Pfizer), nabilone (Lilly) and prochlorperazine. The cannabinoids all evinced dose dependent antiemetic activity in terms of either complete protection, or increased latency to the first emetic episode and reduced number of episodes in those animals not completely protected. By comparison prochlorperazine afforded only minimal protection.

Rewarding drugs produce taste avoidance, but not taste aversion

Article

Feb 1995
NEUROSCI BIOBEHAV R

Linda A. Parker

Paradoxically, drugs that animals will self-administer also produce conditioned taste avoidance at similar dosage levels. The present review presents evidence that the taste avoidance produced by these rewarding drugs differs qualitatively from the taste avoidance produced by the nonrewarding, emetic drug, lithium chloride. An analysis of data pooled across 6 experiments compares the nature of flavor-drug associations produced by various rewarding drugs (amphetamine, cocaine, methamphetamine, methylphenidate, morphine, nicotine and phencyclidine) with that produced by lithium. The data from the groups conditioned with the rewarding drugs and with lithium were combined into the two categories of low/moderate and high doses. When assessed by the CTA test, the rewarding drugs did not differ from lithium in the strength of the CTA at low/moderate or at high doses. However, when assessed by the TR test, lithium produced more prominent aversive taste reactions than did the rewarding drugs. These findings suggest that the flavor-drug association produced by lithium and rewarding drugs differs qualitatively. With the large pooled data set we also assessed the relationship among the various TR categories, resulting in two factors of "Ingestion" and "Aversion" accounting for 55% of the total variability within the data.

Delta-9-tetrahydrocannabinol interferes with the establishment and the expression of conditioned rejection reactions produced by cyclophosphamide: A rat model of nausea

Article

Jan 2000
NEUROREPORT

Reliable animal models of nausea are necessary to better understand the neurobiology of nausea and to assess treatment effectiveness. We present such a model based on conditioned rejection reactions in rats. Our results demonstrate that delta-9-tetrahydrocannabinol (THC), a treatment reported to reduce chemotherapy-induced nausea in humans, also reduces conditioned rejection reactions in rats. Rats were administered THC or vehicle prior to a pairing of saccharin solution with cyclophosphamide or saline during conditioning and/or prior to test. THC interfered with the establishment of cyclophosphamide-induced conditioned rejection during conditioning and with the expression of conditioned rejection during testing. Our results confirm that the conditioned rejection reaction in the rat is a useful animal model of nausea.

The antiemetic drug ondansetron interferes with lithium-induced conditioned rejection reactions, but not lithium-induced taste avoidance in rats

Article

Nov 2000

Conditioned rejection reactions displayed in the taste reactivity test are exclusively produced by treatments that elicit nausea. The present experiments demonstrate that pretreatment with the antinausea agent ondansetron interferes with both the establishment and the expression of conditioned rejection reactions. Ondansetron did not interfere with lithium-induced taste avoidance in either a 1-bottle or a 2-bottle test. In fact, when rejection reactions were measured during a consumption test, ondansetron selectively attenuated rejection reactions, with only a slight modification of consumption. These results suggest that conditioned rejection reactions, but not conditioned taste avoidance, reflect nausea in rats that can be attenuated by ondansetron pretreatment.

Δ9-Tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB(1) receptors in the least shrew

Article

May 2001
PHARMACOL BIOCHEM BE

Nissar Darmani

We have recently shown that the cannabinoid CB1 receptor antagonist, SR 141716A, produces emesis in the least shrew (Cryptotis parva) in a dose- and route-dependent manner. This effect was blocked by delta-9-tetrahydrocannabinol (Δ9-THC). The present study investigates the cannabinoid receptor mechanisms by which Δ9-THC produces its antiemetic effects against cisplatin (20 mg/kg, ip)-induced emesis as well as its cannabimimetic activity profile (motor reduction) in the least shrew. Intraperitoneal administration of Δ9-THC (1, 2.5, 5 and 10 mg/kg) dose-dependently reduced both the percentage of animals vomiting (ID50 = 1.8 ± 1.6 mg/kg) and the frequency of vomits (ID50 = 0.36 ± 1.18 mg/kg) in a potent manner. The lowest significantly effective antiemetic dose of Δ9-THC for the latter emesis parameters was 2.5 mg/kg. Although Δ9-THC reduced the frequency of vomits up to 98%, it failed to completely protect all tested shrews from vomiting (80% protection). The cannabinoid CB1 antagonist (SR 141716A) and not the CB2 antagonist (SR 144528), reversed the antiemetic effects of Δ9-THC in a dose-dependent fashion. Δ9-THC (1, 5, 10 and 20 mg/kg, ip) suppressed locomotor parameters (spontaneous locomotor activity, duration of movement and rearing frequency) in a biphasic manner and only the 20-mg/kg dose simultaneously suppressed the triad of locomotor parameters to a significant degree. Subcutaneous (1-10 mg/kg) and intraperitoneal (0.05-40 mg/kg) injection of some doses of SR 141716A caused significant reductions in one or more components of the triad of locomotor parameters but these reductions were not dose dependent. Subcutaneous injection of SR 141716A (0.2, 1, 5 and 10 mg/kg) reversed the motor suppressant effects of a 20-mg/kg dose of Δ9-THC (ip) in a dose-dependent manner. Relative to its motor suppressant effects, Δ9-THC is a more potent antiemetic agent. Both effects are probably mediated via CB1 receptors in distinct loci.

The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2

Article

Nov 2001
EUR J PHARMACOL

Nissar Darmani

The dibenzopyran cannabinoids (delta-9 (Delta9)-tetrahydrocannabinol and nabilone) are clinically used to suppress nausea and vomiting produced by chemotherapeutic agents such as cisplatin. The purpose of this investigation was to investigate the antiemetic potential of the aminoalkylindole cannabinoid receptor agonist WIN 55, 212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate] against cisplatin-induced vomiting. Different doses of WIN 55, 212-2 (0, 1, 2.5 and 5 mg/kg, i.p.) reduced both the frequency of cisplatin (20 mg/kg, i.p.)-induced emesis (ID(50)=0.5 mg/kg) as well as the percentage of shrews vomiting (ID50=1.2 mg/kg) in a dose-dependent manner. Significant reductions in emesis frequency occurred from 2.5 mg/kg dose of WIN 55, 212-2, whereas significant total protection from vomiting was afforded at its 5 mg/kg dose. The antiemetic actions of a 5-mg/kg dose of WIN 55, 212-2 against cisplatin (20 mg/kg, i.p.)-induced vomiting were reversed by nonemetic subcutaneous doses (0, 0.25, 0.5 and 1 mg/kg) of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] (ID50=0.27 and 0.47 mg/kg, respectively) but not by a 5-mg/kg dose of the cannabinoid CB2 receptor antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methybenzyl) pyrazole-3-carboxamide]. The effects of the cited doses of WIN 55, 212-2 were also investigated on several motor parameters (spontaneous locomotor activity, duration of movement and rearing frequency). Significant reductions in motor parameters were only observed at its highest tested dose (ID50=1.97, 2.75 and 2.8 mg/kg; respectively). SR 141716A (0, 0.5, 1, 5 and 10 mg/kg) also reversed the motor suppressant effects of a 5-mg/kg dose of WIN 55, 212-2 (ID50=0.39, 0.1 and 0.3 mg/kg, respectively) and significant reversals were seen from its 0.5 and 1 mg/kg doses. These results suggest that WIN 55, 212-2 reduces both emesis and indeces of locomotion via the stimulation of cannabinoid CB1 receptors. However, cannabinoid CB1 receptors in different loci are most likely responsible for the antiemetic and motor suppressive effects of WIN 55, 212-2 since reduction in the frequency of vomiting occurred at lower doses relative to its sedative actions.

Jan 1995
143-151

L A Parker

Parker LA. Neurosci Biobehav Rev 19, 143-151 (1995).

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983-986

L A Parker
K B Mcleod

Parker LA and McLeod KB. Pharm Biochem Behav 40, 983-986 (1991).

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845-852

T Bisogno

Bisogno T et al. Br J Pharmacol 134, 845-852 (2001).

Jan 1999
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3769-3772

C L Limebeer
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Limebeer CL and Parker LA. NeuroReport 10, 3769-3772 (1999).

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795-797

S E Sallan
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140-153

M L Pelchat

Pelchat ML et al. J Comp Physiol Psychol 97, 140-153 (1983).

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A J Hampson

Hampson AJ et al. Proc Natl Acad Sci USA 95, 8268-8273 (1998).

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371-384

C L Limebeer
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Limebeer CL and Parker LA. J Exp Psychol Anim Behav Proc 26, 371-384 (2000).

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L E Mccarthy
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McCarthy LE and Borison HL. J Clin Pharmacoll 21, 30S-37S (1981).

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A M Malfait

Malfait AM et al. Proc Natl Acad Sci USA 97, 9561-9566 (2000).

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Marihuana, the forbidden medicine

Jan 1997

L Greenspoon
J B Bakalar

Greenspoon L and Bakalar JB. Marihuana, the forbidden medicine. New Haven: Yale University Press; (1997).

Jan 2000
371

Limebeer

Jan 1983
140

Pelchat

Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats

Abstract

No full-text available

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