ArticleLiterature Review

The Future of Cannabinoids as Analgesic Agents: A Pharmacologic, Pharmacokinetic, and Pharmacodynamic Overview

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Abstract

For thousands of years, physicians and their patients employed cannabis as a therapeutic agent. Despite this extensive historical usage, in the Western world, cannabis fell into disfavor among medical professionals because the technology available in the 1800s and early 1900s did not permit reliable, standardized preparations to be developed. However, since the discovery and cloning of cannabinoid receptors (CB1 and CB2) in the 1990s, scientific interest in the area has burgeoned, and the complexities of this fascinating receptor system, and its endogenous ligands, have been actively explored. Recent studies reveal that cannabinoids have a rich pharmacology and may interact with a number of other receptor systems-as well as with other cannabinoids-to produce potential synergies. Cannabinoids-endocannabinoids, phytocannabinoids, and synthetic cannabinoids-affect numerous bodily functions and have indicated efficacy of varying degrees in a number of serious medical conditions. Nevertheless, despite promising preclinical and early clinical data, particularly in the areas of inflammation and nociception, development challenges abound. Tetrahydrocannabinol (THC) and other CB1 receptor agonists can have an undesirable CNS impact, and, in many cases, dose optimization may not be realizable before onset of excessive side effects. In addition, complex botanically derived cannabinoid products must satisfy the demanding criteria of the U.S. Food and Drug Association's approval process. Recent agency guidance suggests that these obstacles are not insurmountable, although cannabis herbal material ("medical marijuana") may present fatal uncertainties of quality control and dosage standardization. Therefore, formulation, composition, and delivery system issues will affect the extent to which a particular cannabinoid product may have a desirable risk-benefit profile and acceptable abuse liability potential. Cannabinoid receptor agonists and/or molecules that affect the modulation of endocannabinoid synthesis, metabolism, and transport may, in the future, offer extremely valuable tools for the treatment of a number of currently intractable disorders. Further research is warranted to explore the therapeutic potential of this area.

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... predominantly expressed in immune system tissues (Mccarberg and Barkin, 2007). CB1R and CB2R can also be indirectly activated by the inhibition of fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL), two of the enzymes responsible for the metabolization of endocannabinoids. ...
... In addition to a favorable safety and tolerability profile in humans (Machado Bergamaschi et al., 2011), CBD has shown analgesic (Karst et al., 2003), neuroprotective (Patricio et al., 2020), anticonvulsant (Mccarberg and Barkin, 2007;Arumugam et al., 2011), antiemetic (Rock et al., 2012), antispasmodic (Baker et al., 2000) and anti-inflammatory properties (Mccarberg and Barkin, 2007;van den Elsen et al., 2014). Its neuroprotective effect is mainly associated with antioxidant and antiinflammatory action as well as the modulation of multiple brain biological targets. ...
... In addition to a favorable safety and tolerability profile in humans (Machado Bergamaschi et al., 2011), CBD has shown analgesic (Karst et al., 2003), neuroprotective (Patricio et al., 2020), anticonvulsant (Mccarberg and Barkin, 2007;Arumugam et al., 2011), antiemetic (Rock et al., 2012), antispasmodic (Baker et al., 2000) and anti-inflammatory properties (Mccarberg and Barkin, 2007;van den Elsen et al., 2014). Its neuroprotective effect is mainly associated with antioxidant and antiinflammatory action as well as the modulation of multiple brain biological targets. ...
Article
Nanotechnology has been widely used to improve stability, efficacy, release control and biopharmaceutical aspects of natural and synthetic cannabinoids. In this review, the main types of cannabinoid-based nanoparticles (NPs) reported so far are addressed, taking into account the advantages and disadvantages of each system. Formulation, preclinical and clinical studies performed with colloidal carriers were individually analyzed. Lipid-based nanocarriers have been recognized for their high biocompatibility and ability to improve both solubility and bioavailability. Δ9-tetrahydrocannabinol-loaded lipid systems designed to treat glaucoma, for example, showed superior in vivo efficacy in comparison to market formulations. The analyzed studies have shown that product performance can be modulated by varying particle size and composition. In the case of self-nano-emulsifying drug delivery systems, the reduced particle size shortens the time to reach high plasma concentrations while the incorporation of metabolism inhibitors extend the plasma circulation time. The use of long alkyl chain lipids in NP formulations, in turn, is strategized to achieve intestinal lymphatic absorption. Polymer NPs have been prioritized when a sustained or site-specific cannabinoid release is desirable (e.g., CNS-affecting diseases/cancer). The functionalization of the surface of polymer NPs makes their action even more selective whereas surface charge modulation is highlighted to provide mucoadhesion. The present study identified promising systems for targeted applications, making the process of optimizing new formulations more effective and faster. Although NPs have shown a promising role in the treatment of several difficult-to-treat diseases, more translational studies should be performed to confirm the benefits reported here.
... Understanding the pharmacology of cannabis is essential as it helps to understand the side effects associated with cannabis and its proposed medical benefits. The main constituent that is responsible for the psychoactive properties is tetrahydrocannabinol [6]. In the central nervous system, there are 2 main subtypes of the cannabinoid receptors. ...
... The CB1 receptors are most populated in the following regions: cortex, hippocampus, basal ganglia, cerebellum, and spinal cord [7]. In contrast, the CB2 receptors are most populated in those cells that are responsible for immune mediation [6]. Hence, the CB1 receptor has a consequential mediating effect on memory, cognition, and movement [1]. ...
... This in turn results in a decreased concentration of cAMP in the cell. Thus, activation would in turn result in the inhibition of neurotransmission [6]. ...
Article
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Cannabis, also known as marijuana, has 9-tetrahydrocannabinol as the main constituent. There has been strict legislation governing the utilization of cannabis locally and worldwide. However, there has been an increasing push to make cannabis legalized, in view of its potential medical and therapeutic effects, for various medical disorders ranging from development disorders to cancer treatment, and being an adjunctive medication for various neurological conditions. It is the aim of this review paper to explore the evidence base for its proposed therapeutic efficacy and to compare the evidence base supporting its proposed therapeutic efficacy with its known and well-researched medical and psychiatric side effects.
... Cannabidiol (CBD) is a naturally occurring non-psychoactive cannabinoid compound that is found in the cannabis plant (Cannabis sativa L.). CBD was previously explored for various medical conditions and gained significant attention in recent years for its potential analgesic [127,128], anti-inflammatory [129][130][131], neuroprotective [132], anticonvulsant [129], antiemetic [133], and spasmolytic [134] properties. CBD emerged as a prospective candidate for the treatment of neuropathic pain due to its potential analgesic and anti-inflammatory effects [127][128][129][130][131]. CBD interacts with the endocannabinoid system (ECS) in the body, which plays a role in regulating various physiological processes, including pain perception [18,135,136]. ...
... CBD was previously explored for various medical conditions and gained significant attention in recent years for its potential analgesic [127,128], anti-inflammatory [129][130][131], neuroprotective [132], anticonvulsant [129], antiemetic [133], and spasmolytic [134] properties. CBD emerged as a prospective candidate for the treatment of neuropathic pain due to its potential analgesic and anti-inflammatory effects [127][128][129][130][131]. CBD interacts with the endocannabinoid system (ECS) in the body, which plays a role in regulating various physiological processes, including pain perception [18,135,136]. ...
Article
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Neuropathic pain is a debilitating condition characterized by abnormal signaling within the nervous system, resulting in persistent and often intense sensations of pain. It can arise from various causes, including traumatic nerve injury, neuropathy, and certain diseases. We present an overview of current and emerging pharmacotherapies for neuropathic pain, focusing on novel drug targets and potential therapeutic agents. Current pharmacotherapies, including tricyclic antidepressants, gabapentinoids, and serotonin norepinephrine re-uptake inhibitors, are discussed, as are emerging treatments, such as ambroxol, cannabidiol, and N-acetyl-L-cysteine. Additionally, the article highlights the need for further research in this field to identify new targets and develop more effective and targeted therapies for neuropathic pain management.
... In vivo, SCRAs target the same biological receptors as THC, namely the cannabinoid receptors CB 1 and CB 2 . CB 1 receptors are located in the central nervous system (CNS) and peripheral nervous system, while CB 2 receptors are predominantly expressed in immune cells [59] and are less prevalent in some CNS tissues [60][61][62]. ...
... THC acts as a partial agonist of both receptors, but the psychoactive effects of the drug are primarily attributed to the agonism of CB 1 [59,63]. Agonism of the CB 1 receptor down-regulates adenylyl cyclase and decreases cAMP signalling [23,64]. ...
Article
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Background: Synthetic cannabinoid receptor agonists (SCRAs) are the most diverse class of new psychoactive substances worldwide, with approximately 300 unique SCRAs identified to date. While the use of this class of drug is not particularly prevalent, SCRAs are associated with several deaths every year due to their severe toxicity. Methods: A thorough examination of the literature identified 15 new SCRAs with a significant clinical impact between 2015 and 2021. Results: These 15 SCRAs have been implicated in 154 hospitalizations and 209 deaths across the US, Europe, Asia, and Australasia during this time period. Conclusion: This narrative review provides pharmacodynamic, pharmacokinetic, and toxicologic data for SCRAs as a drug class, including an in-depth review of known pharmacological properties of 15 recently identified and emerging SCRAs for the benefit of researchers, policy makers, and clinicians who wish to be informed of developments in this field.
... The ECS comprises receptors and endogenous ligands. Initially believed to have effect primarily on the ECS, CBD is now known to have a complex signaling mechanism not yet fully understood [12,13]. Despite their similar molecular structure, THC has affinity for the two well-characterized cannabinoid receptors, cannabinoids receptors 1 and 2 (CB 1 and CB 2 , respectively), while CBD has limited affinity for these receptors [12,13]. ...
... Initially believed to have effect primarily on the ECS, CBD is now known to have a complex signaling mechanism not yet fully understood [12,13]. Despite their similar molecular structure, THC has affinity for the two well-characterized cannabinoid receptors, cannabinoids receptors 1 and 2 (CB 1 and CB 2 , respectively), while CBD has limited affinity for these receptors [12,13]. Indeed, CBD can activate and silence classical receptors, has effect on non-cannabinoid receptors, and may inhibit endogenous cannabinoid uptake and THC receptor binding-possibly through negative allosteric modulation of CB 1 [14]. ...
Article
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Purpose of Review This review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence. Recent Findings CBD has potential for relief of symptoms of pain, sleep, and mood disturbance in rheumatology patients, but sound clinical evidence is lacking. CBD is safe when accessed from a regulated source, whereas wellness products are less reliable regarding content and contaminants. Dosing for symptom relief has not yet been established. Summary As many rheumatology patients are trying CBD as a self-management strategy, the healthcare community must urgently accrue sound evidence for effect.
... There are also eighteen different chemical classes of substances, such as nitrogen compounds, amino acids, hydrocarbons, carbohydrates, terpenes, organics, and fatty acids [8,10]. The most important active compounds in cannabis are the psychoactive cannabinoid [11,12] delta-9-tetrahydrocannabinol (THC) [13,14], due to its lipophilic structure, enabling it to cross the blood-brain barrier, and nonpsychoactive cannabidiol (CBD) [15,16] (Figure 1). ...
... In addition, THC can act as an agonist of G-protein-coupled receptors (GPR55 and GPR18), the peroxisome proliferator-activated receptor (PPARγ), and transient receptor potential channels (TRPA1, TRPV2, TRPV3, and TRPV4), and as an antagonist of transient receptor potential channel TRPM8 and 5-HT3 receptor A, and can increase anandamide and adenosine levels [38,48]. Numerous studies have shown that CBD possesses analgesic [16,49], neuroprotective [40], anticonvulsant [11], antiemetic [50], spasmolytic [51], and anti-inflammatory [11,12,52] properties ( Figure 3). Unlike THC, CBD has a very low affinity for both CB1 and CB2 receptors, with K i of 4359 and 2860 nM, respectively [47]. ...
Article
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Cannabis (Cannabis sativa L.) plants from the family Cannabidaceae have been used since ancient times, to produce fibers, oil, and for medicinal purposes. Psychoactive delta-9-tetrahydrocannabinol (THC) and nonpsychoactive cannabidiol (CBD) are the main pharmacologically active compounds of Cannabis sativa. These compounds have, for a long time, been under extensive investigation, and their potent antioxidant and inflammatory properties have been reported, although the detailed mechanisms of their actions have not been fully clarified. CB1 receptors are suggested to be responsible for the analgesic effect of THC, while CB2 receptors may account for its immunomodulatory properties. Unlike THC, CBD has a very low affinity for both CB1 and CB2 receptors, and behaves as their negative allosteric modulator. CBD activity, as a CB2 receptor inverse agonist, could be important for CBD anti-inflammatory properties. In this review, we discuss the chemical properties and bioavailability of THC and CBD, their main mechanisms of action, and their role in oxidative stress and inflammation.
... The analgesic actions of both exogenous CB and eCB occur via stimulation of CB receptors and possibly TRPV1 receptors [10]. However, direct-acting agonists are often plagued with side effects such as psychoactive and motor effects [11]. ...
... However, no postural hypotension was observed with ASP3652. Localacting CB agonists are often plagued with side effects such as psychotropic and motor effects [11]. In contrast, no CNS side effects induced by centrally acting CB agonists were observed and the results of the ARCI-M, POMS, and BL-VAS showed no notable trends for the mood status. ...
Article
IntroductionInhibitors of fatty acid amide hydrolase (FAAH) increase the levels of endocannabinoids and have shown analgesic and anti-inflammatory activity in animal models. ASP3652 is a peripherally acting FAAH inhibitor in development for the treatment of chronic bladder and pelvic pain disorders. Here we describe the safety, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of ASP3652 administered in healthy non-elderly and elderly male and female volunteers.Methods Study 1 was a combined single-ascending dose and food-effect study in which ASP3652 was given as single doses (1–600 mg) or matching placebo in healthy subjects. Study 2 was a multiple ascending dose study in which ASP3652 or matching placebo was administered in multiple oral doses (10–300 mg bid and 600 mg qd for 14 days) to healthy subjects. In both studies, the levels of ASP3652, FAAH, endocannabinoids (eCBs) and safety were evaluated.ResultsASP3652 was readily absorbed to reach Cmax at 1 h after a single dose. Steady state was reached within 3 days after the start of multiple dosing. The Cmax and AUC of ASP3652 increased in a slightly more than dose-proportional manner after a single dose of ASP3652 at 30–600 mg. There was some accumulation (15–38%) based on Cmax and AUC12h upon multiple doses. Cmax was 47% lower in combination with food. There was no significant effect of gender or age on the pharmacokinetics of ASP3652. FAAH activity was inhibited in a dose-dependent manner in all dose groups after single and multiple doses of ASP3652, paralleled by an increase in plasma levels of anandamide (AEA). The incidence of adverse events following multiple doses was similar across all treatment groups including the placebo group.Conclusions Single and multiple doses of ASP3652 were safe and well tolerated and increased endogenous cannabinoid plasma levels.
... Les effets de la consommation de cannabis résultent principalement de la liaison du THC et du CBD à deux types de récepteurs cannabinoïdes : CB1 et CB2. Les récepteurs CB1 sont retrouvés très majoritairement dans le SNC (neurones, cellules gliales) mais également dans le système nerveux périphérique, les leucocytes ainsi que dans les organes suivants : rate, coeur, organes reproducteurs, appareil urinaire et système gastro-intestinal [16,19,24,28,[45][46][47]. Les récepteurs CB2 se trouvent quant à eux majoritairement dans les cellules immunitaires (leucocytes) et les organes lymphoïdes (rate, amygdales) [22,28,47]. ...
... Les effets de la consommation de cannabis résultent principalement de la liaison du THC et du CBD à deux types de récepteurs cannabinoïdes : CB1 et CB2. Les récepteurs CB1 sont retrouvés très majoritairement dans le SNC (neurones, cellules gliales) mais également dans le système nerveux périphérique, les leucocytes ainsi que dans les organes suivants : rate, coeur, organes reproducteurs, appareil urinaire et système gastro-intestinal [16,19,24,28,[45][46][47]. Les récepteurs CB2 se trouvent quant à eux majoritairement dans les cellules immunitaires (leucocytes) et les organes lymphoïdes (rate, amygdales) [22,28,47]. Il semblerait qu'un autre type, les récepteurs CB3, soient également présents chez les mammifères, mais leur rôle physiologique est pour l'instant peu connu [48]. ...
Article
Medicinal properties of cannabis (Cannabis sativa L.) are known for centuries, however, we observe in recent years a renewed interest for the plant and more specifically for two cannabinoids delta-9-tetrahydrocannabinol and cannabidiol. These molecules mainly act on the endocannabinoid system via the CB1 and CB2 cannabinoid receptors. Pharmacokinetics studies of cannabinoids highlight high inter- and intra-individual variabilities depending on the mode of consumption (occasional or chronic) and according to administration routes (smoked, sublingual, oral). Many studies have been conducted to determine the mechanisms of action of these cannabinoids and their interest in different pathologies. They need to be confirmed by validated clinical studies. The evolution of French law in 2013 authorized cannabis and its derivatives for medical purpose, which allowed the marketing authorization for a drug containing cannabinoids: Sativex®. The arrival of these molecules complicates the interpretation of cannabinoid assays with the need to define biomarkers that distinguish drug treatment from recreational use of cannabis. The purpose of this review is to summarize current knowledge regarding pharmacology, toxicology, potential clinical interest, legislation and analytical aspects of therapeutic cannabinoids.
... In addition to altering levels of dopamine and GABA, Δ9-THC has been found to alter levels of other addiction-related neurochemicals, including glutamate and kynurenine (Leventhal et al. 2020). While effects of CBD on neurochemicals have not been as extensively studied as Δ9-THC, CBD is reported to affect the mesolimbic dopamine system and the serotonin 5-HT1A receptor system (McCarberg and Barkin 2007). Similarly, the amino acid tryptophan (Trp) is a critical component of numerous metabolic functions (McFall et al. 1990; Micale and Drago 2018;Newmeyer et al. 2016). ...
Article
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Background While the use of orally consumed Cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC) containing products, i.e. “edibles”, has expanded, the health consequences are still largely unknown. This study examines the effects of oral consumption of whole Cannabis and a complex Cannabis extract on neurochemicals, endocannabinoids (eCB), and physiological parameters (body temperature, heart rate) in mice. Methods In this pilot study, C57BL/6 J mice were treated with one of the following every other day for 2 weeks: a complex Cannabis extract by gavage, whole Cannabis mixed with nutritional gel through free feeding, or purified THC/CBD by intraperitoneal (i.p.) injection. Treatments were conducted at 4 doses ranging from 0–100 mg/kg/day of CBD with THC levels of ≤ 1.2 mg/kg/day for free feeding and gavage and 10 mg/kg/day for i.p. Body temperature and heart rate were monitored using surgically implanted telemetry devices. Levels of neurochemicals, eCB, THC, CBD, and 11-OH-THC were measured using mass spectrometry 48 h after the final treatment. Statistical comparisons were conducted using ANOVA and t-tests. Results Differences were found between neurochemicals in the brains and plasma of mice treated by i.p. (e.g. dopamine, p < 0.01), gavage (e.g., phenylalanine, p < 0.05) and in mice receiving whole Cannabis (e.g., 3,4-dihydroxyphenylacetic DOPAC p < 0.05). Tryptophan trended downward or was significantly decreased in the brain and/or plasma of all mice receiving Cannabis or purified CBD/THC, regardless of dose, compared to controls. Levels of the eCB, arachidonoyl glycerol (2-AG) were decreased in mice receiving lowest doses of a complex Cannabis extract by gavage, but were higher in mice receiving highest doses compared to controls (p < 0.05). Plasma and brain levels of THC and 11-OH-THC were higher in mice receiving 1:1 THC:CBD by i.p. compared to those receiving 1:5 or 1:10 THC:CBD. Nominal changes in body temperature and heart rate following acute and repeated exposures were seen to some degree in all treatments. Conclusions Changes to neurochemicals and eCBs were apparent at all doses regardless of treatment type. Levels of neurochemicals seemed to vary based on the presence of a complex Cannabis extract, suggesting a non-linear response between THC and neurochemicals following repeated oral dosing. Supplementary Information The online version contains supplementary material available at 10.1186/s42238-024-00219-x.
... In recent years, despite their harmful effects (Volkow et al. 2016), cannabinoids have generated a great deal of interest because of their potential therapeutic use for psychiatric disorders, such as anxiety, sleep disorders, mood disorders, or post-traumatic stress disorder (see Sarris et al. 2020 for review). The psychoactive effects of cannabinoids are mediated principally by Δ9-tetrahydrocannabinol (THC) that acts as an agonist at the type-1 cannabinoid (CB1) receptor, a central component of the endocannabinoid system (ECS), primarily expressed in the central nervous system, but also expressed -together with the type-2 cannabinoid (CB2) receptor-in the peripheral nervous system and other peripheral organs and tissues (Iversen 2003;Matsuda et al. 1990;McCarberg and Barkin 2007;Munro et al. 1993). Elimination half-lives for THC are in the range of 20-30 h (Grotenhermen 2003), although it is also subjected to enterohepatic recirculation, which contributes to lengthen the duration of its effects for several days (Ashton 1999;Huestis 2007). ...
Article
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Rationale Schedule-induced drinking (SID) reproduces an excessive and repetitive behavioural pattern that has led to propose this procedure as an animal model to study compulsive behaviours. Although it is known that cannabis can cause several adverse effects, in recent years there has been great interest in the medical application of cannabis derivatives for obsessive-compulsive related disorders. Objectives The present study investigated the effects of repeated THC administration on rates of previously acquired SID, as well as the possible alteration of its temporal distribution along inter-food intervals. Methods Male Wistar rats acquired SID under a 30 min fixed-time 30-sec food delivery schedule (from 30 to 43 sessions to reach a stable level). Thereafter, 5 or 10 mg/kg daily i.p. injections of THC or vehicle were repeatedly administered for 7 days to evaluate the effects on SID. Results Repeated THC administration at a dose of 5 mg/kg resulted in an increase on licking. Surprisingly, no effects on SID were observed with the 10 mg/kg dose. However, magazine entries were reduced with both THC doses. THC also modified the temporal distributions of licking and magazine entries during inter-food intervals. Conclusions The present results show that repeated THC administration may (i) increase induced licking at moderate doses, (ii) reduce magazine entries, and (iii) affect the temporal pattern of SID. These findings suggest that THC does not appear to be beneficial to reduce compulsive behaviour in this animal model, while another collateral effect of THC —such as a greater habitual-like behaviour— needs to be considered.
... Cannabis use disorder has been attributed to increased hospitalization and overall healthcare-associated expenditure. [29] Nevertheless, there's limited information available about the efficacy of treatment and management of cannabis-related disorders. [30] In the Indian scenario, the consumption of cannabis is also influenced by several innate cultural beliefs, perceptions, and consumption during festive celebrations, despite the legal consequences of such an act. ...
Article
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Cannabis derivatives have been conventionally employed globally for their curative and restorative properties for various ailments. However, its recreational use and consequent legal restrictions have substantially cramped its scientific research. An emerging interest regarding the profound therapeutic potential of cannabinoids has been observed among clinicians. Despite a rich cultural background, high-quality research on cannabinoids is lacking in the Indian scenario. This review readdresses the challenges on this front and brings an insight into the current status of cannabinoids and their utility in scientific exploration. Cannabinoids have a significant medicinal value in various clinical disorders. Its use so far has been based on scarce resources and corroborations, as evidence-based substantiation is limited. Through this review article, we emphasize the remarkable role enacted by cannabinoids in the treatment of various clinical disorders and an utterly significant need to formulate stringent research methodologies to promote its systematic investigation.
... CBD is a partial agonist of cannabinoid receptors 1 and 2 (CB1 and CB2) [22,23]. Additionally, CBD activates transient ion receptor ion channels (TRPV1, TRVP2) [24][25][26][27][28][29], peroxisome proliferating activated receptor α (PPAR α), and PPAR γ, inhibits GPR55 [28][29][30], and increases endocannabinoid anandamide (AEA) concentration by blocking its hydrolysis [31]. ...
Article
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Platinum-derived chemotherapy medications are often combined with other conventional therapies for treating different tumors, including colorectal cancer. However, the development of drug resistance and multiple adverse effects remain common in clinical settings. Thus, there is a necessity to find novel treatments and drug combinations that could effectively target colorectal cancer cells and lower the probability of disease relapse. To find potential synergistic interaction, we designed multiple different combinations between cisplatin, cannabidiol, and intermittent serum starvation on colorectal cancer cell lines. Based on the cell viability assay, we found that combinations between cannabidiol and intermittent serum starvation, cisplatin and intermittent serum starvation, as well as cisplatin, cannabidiol, and intermittent serum starvation can work in a synergistic fashion on different colorectal cancer cell lines. Furthermore, we analyzed differentially expressed genes and affected pathways in colorectal cancer cell lines to understand further the potential molecular mechanisms behind the treatments and their interactions. We found that synergistic interaction between cannabidiol and intermittent serum starvation can be related to changes in the transcription of genes responsible for cell metabolism and cancer’s stress pathways. Moreover, when we added cisplatin to the treatments, there was a strong enrichment of genes taking part in G2/M cell cycle arrest and apoptosis.
... The plant Cannabis sativa L. (hemp) comprises a wide variety of phytocannabinoid and terpene compounds, including the constituent cannabidiol (CBD) [1]. In recent years, CBD has gained increasing interest due to its potential health benefits [2][3][4][5]. While considerable research has been undertaken to identify and characterize the compounds in hemp as well as identify their potential health benefits, analyzing human pharmacokinetics, and developing a variety of hemp products, there is a clear need for determining the safety of these compounds [6][7][8]. ...
Article
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HempChoice® Hemp Oil Extract (Geocann, LLC) is an extract of the aerial parts of hemp (Cannabis sativa L.) primarily comprised of 55–75% cannabidiol (CBD), 1–15% other phytocannabinoids and 1–15% terpenes. The results of multiple safety studies demonstrated that it was non-mutagenic in an Ames and mammalian cell micronucleus.test and was well tolerated in a 14-day range-finding study at dose levels up to 96.03.mg/kg BW/day. In the 90-day study, no HempChoice® Hemp Oil Extract-related significant changes were noted in weekly BW, daily BW gain, food consumption, functional observational battery or motor activity assessment. In addition, no HempChoice® Hemp Oil Extract related mortalities, abnormal clinical observations and ophthalmological changes were reported. Some HempChoice® Hemp Oil Extract-related changes were reported in the hematology and clinical chemistry parameters evaluated. These changes were not outside the normal range and were considered reversible during the 28-day recovery period. No macroscopic findings were reported, and histopathological changes related to HempChoice® Hemp Oil Extract exposure were limited to adaptive changes in the liver which were not observed in the recovery group animals. The no observed adverse effect level (NOAEL) for HempChoice® Hemp Oil Extract was determined to be 185.90 mg/kg BW/day in male and female Sprague-Dawley rats.
... CBD is a partial agonist of CB1 and CB2 receptors [224,225]; it stimulates TRPV1, TRVP2, 5-HT1A, and PPAR γ, inhibits GPR55, and increases endogenous AEA concentration by blocking its hydrolysis [226]. One of the best described anticancer effects of CBD is the activation of NOXA, suppressing mTOR/AKT signaling and MAPK [28]. ...
Article
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Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
... Treatment with centrally acting cannabinoid receptor agonists is often plagued with psychoactive and motor effects [10]. ASP3652 is an orally available, small molecule FAAH inhibitor with minimal central nervous system penetration. ...
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PurposeThe primary purpose of this study was to evaluate the effect of the fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on efficacy and safety in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). The secondary purpose was to evaluate phenotyping based on Hunner’s lesions (HL).Methods In this randomized trial, adult female patients with moderate/severe IC/BPS received 12 weeks of treatment with an oral dose of ASP3652 (50, 150, or 300 mg twice daily) or placebo. A Bayesian model was employed using accumulating data to adjust the randomization probability and to analyze the primary efficacy variable (change from baseline to end of treatment in Mean Daily Pain [MDP; range 0–10]). Study outcomes and patient characteristics of patients with and without HL (HL+ and HL−) were compared.ResultsIn total, 287 patients were randomized. The 300 mg dose group (n = 97) showed the largest effect, i.e., a mean change from baseline to end of treatment of −1.73 in MDP. However, the mean difference from placebo was 0.02. The probability that this dose was better than placebo was 13.5%. Adverse event incidence was low and similar between study groups. HL+ patients were older and had more severe symptoms than HL−. An association was suggested in HL+ patients between changes in micturition frequency and MDP (R = 0.41 [95% CI 0.18, 0.63]), which was not observed in HL− (R = 0.04 [95% CI −0.16, 0.29]).ConclusionASP3652 was safe and well tolerated, but did not show efficacy in IC/BPS. The observed differences between HL+ and HL− suggest that IC/BPS diagnosis and treatment may be approached differently in these two phenotypes.Trial registration: EudraCT number 2011-004555-39, date of registration: 2012-05-07.
... The signaling mechanism for CBD is complex and still poorly understood, but effects are not simply due to binding to CB1 or CB2 receptors. In fact, CBD has limited affinity for the cannabinoid receptors, may inhibit THC binding to receptors, can activate and silence classical cannabinoid receptors, and also has effect on non-cannabinoid receptors (8,9). Furthermore, CBD has a multiplicity of other actions including being an indirect antagonist of CB1 and CB2 receptors, an inverse agonist of CB2 receptor, an inhibitor of endogenous cannabinoid uptake, can act as a full antagonist of the G-protein-coupled receptor 55(GPR55), and has activating effects ( serotonin 1a receptor (5-HT 1A ), G-protein-coupled receptor 18 (GPR18) and the transient receptor potential cation channel subfamily V member 1 (TRPV1)). ...
Article
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Cannabidiol (CBD), a major metabolite of Cannabis sativa, is popularized as a medicinal product, with potential for analgesic, antiinflammatory, and antioxidant effects. CBD may hold promise as a treatment in rheumatic diseases, but evidence to date remains preclinical. Preclinical effects on pain and inflammation is encouraging, but clinical study is lacking, with only a single study in knee osteoarthritis reporting a promising effect on symptoms. CBD products are freely available over the counter and marketed as food supplements or wellness products. The World Health Organization has identified pure CBD as safe and without abuse potential, but products are not subject to drug regulatory standards, leading to inconsistency in manufacturing practices and quality of products. Not only have molecular concentrations of CBD been identified as inaccurate, but concerns exist regarding contaminants, including heavy metals, pesticides, microbes, and mycotoxins, as well as added tetrahydrocannabinol. Drug‐drug interactions pose a potential risk due to metabolism via the cytochrome P450 enzyme pathway. Patients wishing to use CBD should obtain a product with certification of Good Manufacturing Practices, initiate treatment with a nighttime low dose, and have defined outcome goals within a reasonable time frame. Treatments should not be managed by nonmedical dispensary personnel. The hope that CBD may be a useful therapy must be substantiated by sound scientific study.
... Compared with THC, which is a partial agonist of cannabinoid receptor 1 (CB1, located mainly in the central nervous system, but also present in organs, tissues, and peripheral nervous system) and CB2 (expressed in immune tissues, gastrointestinal tract, and in low concentrations in the central nervous system) receptors of the endogenous cannabinoid system, CBD has a weak affinity for the sites of the receptors (the orthostatic ones). Moreover, it was reported to possibly inhibit THC binding to CB1 through other mechanisms [40][41][42]. ...
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Cannabis sativa L. is a plant long used for its textile fibers, seed oil, and oleoresin with medicinal and psychoactive properties. It is the main source of phytocannabinoids, with over 100 compounds detected so far. In recent years, a lot of attention has been given to the main phytochemicals present in Cannabis sativa L., namely, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Compared to THC, CBD has non-psychoactive effects, an advantage for clinical applications of anti-tumor benefits. The review is designed to provide an update regarding the multi-target effects of CBD in different types of cancer. The main focus is on the latest in vitro and in vivo studies that present data regarding the anti-proliferative, pro-apoptotic, cytotoxic, anti-invasive, anti-antiangiogenic, anti-inflammatory, and immunomodulatory properties of CBD together with their mechanisms of action. The latest clinical evidence of the anticancer effects of CBD is also outlined. Moreover, the main aspects of the pharmacological and toxicological profiles are given.
... 5 Cannabidiol (CBD), the nonpsychoactive component of cannabis, is reported to have analgesic effects. 5,7 CBD is an inhibitor of both CYP2C9 and CYP3A4, effecting CYP3A4 to a greater extent than CYP2C9. 5 Naturally, other medications that are metabolized or activated by these cytochrome enzymes may be affected by cannabis use. ...
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Objective To report a probable interaction between warfarin and edible cannabis that resulted in an elevated international normalized ratio (INR) without bleeding complications. Case Summary A 35-year-old Middle Eastern male on warfarin long term with an INR goal of 2.5 (accepted range: 2.0-3.0). The patient has generally been stable on warfarin 10 mg daily from 2010 to 2018, until INR suddenly increased to 7.2 following 1 month of edible cannabis ingestion and cannabis smoking. Patient denied any signs and symptoms of bleeding. No other reasonable causes of the elevation in INR were apparent. The patient was advised to hold 2 doses of warfarin and discontinue cannabis use. The INR dropped below 4 upon discontinuation of cannabis with dose adjustments to warfarin. Discussion The elevation in INR can be explained by the inhibition of CYP2C9 by cannabis use causing decreased metabolism of warfarin. The interaction between warfarin and cannabis was determined to be probable using the Horn Drug Interaction Probability Scale. Conclusions There are no previous reports of interactions between edible cannabis and warfarin, with very few case reports describing the interaction with other forms of cannabis. Close monitoring of INR in patients with concomitant cannabis is recommended for proper warfarin management.
... It is through this link that THC exerts its psychoactive and analgesic effects [13]. Cannabidiol has low affinity for both types of receptors [69,70]. It has been described that this compound exerts its activity through non-cannabinoid receptors [30,69]. ...
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Although the medicinal properties of Cannabis species have been known for centuries, the interest on its main active secondary metabolites as therapeutic alternatives for several pathologies has grown in recent years. This potential use has been a revolution worldwide concerning public health, production, use and sale of cannabis, and has led inclusively to legislation changes in some countries. The scientific advances and concerns of the scientific community have allowed a better understanding of cannabis derivatives as pharmacological options in several conditions, such as appetite stimulation, pain treatment, skin pathologies, anticonvulsant therapy, neurodegenerative diseases, and infectious diseases. However, there is some controversy regarding the legal and ethical implications of their use and routes of administration, also concerning the adverse health consequences and deaths attributed to marijuana consumption, and these represent some of the complexities associated with the use of these compounds as therapeutic drugs. This review comprehends the main secondary metabolites of Cannabis, approaching their therapeutic potential and applications, as well as their potential risks, in order to differentiate the consumption as recreational drugs. There will be also a focus on the analytical methodologies for their analysis, in order to aid health professionals and toxicologists in cases where these compounds are present.
... Cannabis is another substance that is often used to manage chronic pain (Manchikanti et al., 2006), and more people have reported access to, and use of cannabis following the legalization for medical purposes in many states (Cerdá et al., 2012). Cannabis plant-derived products include the well know delta-9-THC (cannabinoid receptor-1 agonist), as well as other compounds like cannabidiol (McCarberg and Barkin, 2007). Although preliminary evidence from randomized controlled trials provides evidence for the efficacy of cannabis for pain management (Deshpande et al., 2015;Hill, 2015;Jensen et al., 2015), results remain mixed regarding the long-term consequences of cannabis use, particularly in the context of chronic pain (Deshpande et al., 2015;Hill et al., 2017). ...
Article
Objectives: Opioid misuse constitutes a significant public health problem and is associated with a host of negative outcomes. Despite efforts to curb this increasing epidemic, opioids remain the most widely prescribed class of medications. Prescription opioids are often used to treat chronic pain despite the risks associated with use, and chronic pain remains an important factor in understanding this epidemic. Cannabis is another substance that has recently garnered attention in the chronic pain literature, as increasing numbers of individuals use cannabis to manage chronic pain. Importantly, the co-use of substances generally is associated with poorer outcomes than single substance use, yet little work has examined the impact of opioid-cannabis co-use. Methods: The current study examined the use of opioids alone, compared to use of opioid and cannabis co-use, among adults (n = 450) with chronic pain on mental health, pain, and substance use outcomes. Results: Results suggest that, compared to opioid use alone, opioid and cannabis co-use was associated with elevated anxiety and depression symptoms, as well as tobacco, alcohol, cocaine, and sedative use problems, but not pain experience. Conclusions: These findings highlight a vulnerable population of polysubstance users with chronic pain, and indicates the need for more comprehensive assessment and treatment of chronic pain.
... Cannabis research is complicated by the complexity of the cannabinoid system, variability in the types and dosages, lack of regulation and quality control, and legal issues. 7 The World Health Organization, American Medical Association, and the National Academies of Sciences, Engineering, and Medicine have called for additional quality research on the effects of cannabis and its various cannabinoids. 8,9 Individuals with a history of spinal cord injury (SCI) or TBI commonly experience chronic symptoms, including pain, insomnia, spasticity, and mood disorders, that affect quality of life. ...
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Objective: To describe the prevalence of cannabis use in an adult sample with spinal cord injury (SCI) or traumatic brain injury (TBI) in Colorado, and to describe the self-reported reasons and side effects of cannabis use in this sample. Design: Mixed methods observational study, using focus group data and telephone survey SETTING: Community PARTICIPANTS: Colorado adults who have sustained SCI or moderate to severe TBI and have received services through the rehabilitation hospital conducting the study. Interventions: None; Measures: Survey RESULTS: Focus group participants identified issues that were then included in the survey development. Seventy percent of the 116 surveyed reported cannabis use pre-injury (67% SCI, 74% TBI) with 48% reporting use after injury (53% SCI, 45% TBI). Overall, the most common reason for use was recreational (67%), followed by reducing stress/anxiety (62.5%), and improving sleep (59%). Among the respondents with SCI, the most common reasons for use were to reduce spasticity (70%), recreation (63%), and to improve sleep (63%). Among those with TBI, reasons endorsed were recreational (72%), reducing stress/anxiety (62%), and improving sleep (55%). Smoking was the most common method of use. Conclusions: A majority of this sample report using cannabis prior to injury, and approximately half report using cannabis post-injury. Both groups report recreational use, while the group with SCI also highly endorses using cannabis to address chronic medical conditions. Clinicians should be aware of the high prevalence of cannabis use in these populations and the impact such use may have on the individual's medical management. Further research in this area is needed.
... This manuscript is timely and important since there is an expanding body of both laboratory and clinical literature often supporting the efficacy of cannabis in mitigating pain even in patients with neuropathic pain. 2,3 Medical cannabis programs now exist in 13 States in the United States and these authors report that numbers of authorized medical cannabis users in the State of Washington are in the 20,000 range. A recent survey in Canada has shown that 10 perfect of patients with chronic non-cancer pain currently used cannabis for pain relief. ...
... Treatment with centrally acting CB agonists can induce cannabinoidlike side effects, such as psychoactive and motor effects. 7 Peripheral FAAH inhibition may not induce these central effects. ASP3652 is an orally available small molecule FAAH inhibitor with minimal central nervous system penetration. ...
Article
Objectives: To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH-) inhibitor ASP3652 on safety and efficacy outcomes in Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). Inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors. Methods: In this adaptive, randomized, double-blind, placebo-controlled study adult male patients with moderate to severe CP/CPPS were treated for 12 weeks with an oral dose of ASP3652 (25, 75, 150 or 300mg twice daily [BID], or 300mg once daily) or placebo. A Bayesian model was used for adaptive prospective modeling of randomization, study continuation decisions and analysis of the efficacy variables. Results: The study was stopped for futility at pre-planned interim analysis when 239 patients were randomized (226 were included in the intention-to-treat set): the 25mg group showed the largest reduction of the primary endpoint NIH-CPSI total score (7.0 points), but the placebo group showed a mean reduction of 7.3 points (difference: 0.3 [95% confidence interval: -1.9 to 2.6]). Micturition outcomes improved compared to placebo in all ASP3652 groups, e.g., in the 300mg bis in die (BID, twice daily) group voiding frequency decreased by -1.10 (95% CI -2.0 to -0.2) voids/24hr vs. placebo. Safety outcomes were comparable across the treatment groups. Conclusions: ASP3652 was generally safe and well-tolerated. It did not show efficacy on pain symptoms in patients with CP/CPPS. However, results indicate that FAAH-inhibition may attenuate lower urinary tract symptoms. Dedicated studies in patients with lower urinary tract dysfunction are needed to confirm this.
... Synthetic cannabinoids comprise well over 100 different compounds with varying chemical structures that were originally developed as endocannabinoid receptor agonists for research purposes and clinical use. 1,2 Since their introduction, the recreational use of synthetic cannabinoids has become an increasing problem. 3 In 2012, synthetic cannabinoids were made illegal under the Synthetic Drug Abuse Act. 4 Despite this, recreational use has only continued to increase. ...
... Речовина CP-47,497 та гомологи були синтезовані в американській фармацевтичній компанії Pfizer Inc. Речовина HU-210 була створена в Єрусалимському університеті (HU -Hebrew University, Єврейський університет, 1988) під керівництвом професора R. Mechoulam. З часом більшість синтетичних канабіноїдів було синтезовано під керівництвом дослідників J.W. Huffman (речовина JWH) і A. Makriyannis (речовина AM) [14,15,19,22]. ...
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The publication discusses the problem of spread of spice smoking blends on the territory of the European Union and certain countries in Eastern Europe over the last decade. Focus was made on the lack of efficacy of measures on the control of smoking blends trafficking that have been implemented in the states-members of the European Union in the last 10 years. The history of the development of synthetic cannabinoids and toxicological characteristics of substances JWH, CP, HU, oleamide as the most common synthetic products with cannabinoid activity was considered. We have analyzed the biological activity and health consequences of the use of spice products according to thematic reports of research centres in the European Union and USA. The role of modern marketing strategies of spice products rollout, in particular the features of product sale via the Internet in Ukraine, was examined. We have analyzed the toxicological situation in Ukraine in recent years due to the spread of designer drugs characterized by a large-scale advertising of herbal mixtures via Internet; wide unlimited access to these products in retail locations where spice is often sold under the guise of alternative medicine or food additives and have moderately low price; widespread practice of using toxic drugs among adolescents and young people; the progressive increase in the number of overdoses and fatal poisonings in some regions of Ukraine in recent years. In this context, the key role of the state regulator was defined in the development of preventive measures against fatal effects of spice use among youth based of the experience of some countries. The authors provided suggestions for the immediate joint efforts of the authorized state bodies (Ministry of Healthcare and departmental research institutions, Ministry of Internal Affairs, Security Service of Ukraine and other relevant services) for developing national strategy and management decisions to ban spice products (and the like), or significantly limit their sales in Ukraine.
... Therefore, we assumed that this initial decrease in sucrose consumption is likely caused by an alteration of the appetite rather than to an emotional detriment, since the parallel behavioural assessment revealed an improved emotional response of OBX mice and no decline in sham animals after the administration of CBD. All the above behavioural findings reinforce the need of adequate pharmacological strategies to optimize the benefits of the treatment with CBD (McCarberg and Barkin, 2007). In order to analyse the concurrent neurochemical events that may account for the behavioural benefits of CBD, microdialysis studies in vmPFCx were performed after acute and chronic administration. ...
Article
Cannabidiol (CBD), the main non-psychotomimetic component of marihuana, exhibits anxiolytic-like properties in many behavioural tests, although its potential for treating major depression has been poorly explored. Moreover, the mechanism of action of CBD remains unclear. Herein, we have evaluated the effects of CBD following acute and chronic administration in the olfactory bulbectomy mouse model of depression (OBX), and investigated the underlying mechanism. For this purpose, we conducted behavioural (open field and sucrose preference tests) and neurochemical (microdialysis and autoradiography of 5-HT1A receptor functionality) studies following treatment with CBD. We also assayed the pharmacological antagonism of the effects of CBD to dissect out the mechanism of action. Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism.
... CB1 receptors are among the most abundant GPCRs expressed in the brain and play a significant role in the modulation of GABA and glutamate neurotransmission (27). They are densely concentrated in the cortical and subcortical regions, spinal cord in the dorsal root ganglion, and peripheral nervous system areas affecting pain from peripheral organs and tissues (28). They are responsible for most of the psychoactive components of cannabinoids like mood elevation, anxiety, panic reactions and they also induce analgesia, decrease motor function, impair memory and sense of time, and affect auditory and visual cognition (25,29,30). ...
Article
Introduction: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes. Areas covered: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain. Expert opinion: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.
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Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.
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Background Considering the extensive innervation of the pulp tissue, asymptomatic irreversible pulpitis (AIP) or “silent pulpitis” represents a confounding clinical condition. Previous studies have attributed the painless nature of AIP to the inhibition of pulpal nociceptors by local endogenous analgesics. However, there is a lack of recent information concerning its painless nature, and paradoxically, patients with dental pain are diagnosed with AIP daily worldwide. In addition, no recent review has explored the potential AIP-related mechanisms. Objective This narrative review aims to explore and update the potential mechanisms involved in the painless nature of AIP to improve our current understanding of the asymptomatic character of this clinical condition. Methods An electronic search was performed in the PubMed and Scopus databases, using as search terms “asymptomatic irreversible pulpitis,” “dental pulp,” “endogenous opioids,” “endogenous cannabinoids,” “somatostatin,” “GABA,” “bombesin,” “cortistatin,” “galanin,” and “specialized pro-resolving lipid mediators.” Results Endogenous opioids, G protein-activated inwardly rectifying K⁺ channels, endogenous cannabinoids, γ-aminobutyric acid, and neuropeptides (i.e. somatostatin, cortistatin, galanin, and bombesin) could be involved in AIP-related analgesia. Additionally, specialized pro-resolving lipid mediators, such as lipoxins, resolvins, maresins, and protectins, as well as oxytocin, phoenixin, opiorphin, and adipokines, could also be involved in this clinical condition. Conclusion This narrative review provides updated information on the potentially involved mechanisms in AIP. Nevertheless, the precise mechanisms responsible for the lack of symptoms in AIP remain to be elucidated, and further research is warranted.
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Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2–5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease’s stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients’ satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.
Article
Cannabidiol (CBD) has been used in diseases that affect the central nervous system. Its effects on the peripheral synapses are of great interest, since endocannabinoid receptors are expressed in muscles. CBD (0.3 mM) was analysed using mammalian and avian neuromuscular preparations, through myographic techniques in complementary protocols. Mammalian cells were examined by light microscopy while exogenous acetylcholine (40 µM) and potassium chloride (100 mM) were added into avian preparations, before and at the end of experiments. Pharmacological tools such as atropine (2 µM), polyethylene glycol (PEG 400, 20 µM), Ca2+ (1.8 mM), F55-6 (20 µg/mL), and nifedipine (1.3 mM) were assessed with CBD. In mice, CBD causes a facilitatory effect and paralysis, whereas in avian, paralysis. Concluding, CBD is responsible for activated or inhibited channels, for ACh release via muscarinic receptor modulation, and by the inhibition of nicotinic receptors leading to neuromuscular blockade, with no damage to striated muscle cells.
Article
Introduction: The effects of cannabidiol (CBD) on cognition has been investigated in recent years to determine the therapeutic potential of this cannabinoid for a broad gamut of medical conditions, including neuropsychiatric disorders. The aim of the present study was to perform a systematic review of studies that analyzed the effects of the acute and chronic administration of CBD on cognition in humans and animals both to assess the cognitive safety of CBD and to determine a beneficial potential of CBD on cognition. Methods: The PubMed, Web of Science, PsycINFO, and Scopus databases were searched in December of 2022 for relevant articles using the following combinations of keywords: ("cannabidiol" OR "CBD") AND ("cognition" OR "processing cognitive" OR "memory" OR "language" OR "attention" OR "executive function" OR "social cognition" OR "perceptual motor ability" OR "processing speed"). Results: Fifty-nine articles were included in the present review (36 preclinical and 23 clinical trials). CBD seems not to have any negative effect on cognitive processing in rats. The clinical trials confirmed these findings in humans. One study found that repeated dosing with CBD may improve cognitive in people who use cannabis heavily but not individuals with neuropsychiatric disorders. Considering the context of neuropsychiatric disorders in animal models, CBD seems to reverse the harm caused by the experimental paradigms, such that the performance of these animals becomes similar to that of control animals. Conclusions: The results demonstrate that the chronic and acute administration of CBD seems not to impair cognition in humans without neuropsychiatric disorders. In addition, preclinical studies report promising results regarding the effects of CBD on the cognitive processing of animals. Future double-blind, placebo-controlled, randomized clinical trials with larger, less selective samples, with standardized tests, and using different doses of CBD in outpatients are of particular interest to elucidate the cognitive effects of CBD.
Article
Purpose This study aimed to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of ASP3652, a peripherally acting inhibitor of peripheral fatty acid amide hydrolase (FAAH) after 30-, 100-, 300-, 600-, and 900-mg single and 100- and 300-mg BID multiple oral dose in Japanese patients. Methods This was a randomized, double-blind, placebo-controlled, single and multiple oral dose Phase I study in healthy, nonelderly men and elderly men and women. The study consisted of 2 parts: in the single oral dose part, 40 healthy, nonelderly men were randomized to receive placebo or ASP3652; in the multiple oral dose part, 48 enrolled nonelderly men and elderly men and women were randomized to receive placebo or ASP3652. In both parts, the investigator judged whether the individuals were healthy based on the results of physical examinations and screening. The safety profile was assessed by examining adverse events, defined as any untoward medical occurrence in an individual administered the study drug and that did not necessarily have a causal relationship with the study treatment; clinical laboratory evaluations; vital signs; the Profile of Mood States scale; and standard 12-lead ECGs and 12-lead ECGs for QT assessment. Pharmacokinetic parameters were estimated using unchanged ASP3652 concentrations in plasma and urine. Pharmacodynamic parameters were estimated using FAAH activity and plasma anandamide, oleoylethanolamide, and palmitoylethanolamide concentrations. Safety and tolerability profiles were compared with the placebo group. Findings ASP3652 was rapidly absorbed to reach Cmax in a single dose and near steady-state at approximately 3 days after the start of multiple dosing. The Cmax and AUC of ASP3652 were slightly higher than dose proportional after a single dose of ASP3652 at 30–900 mg. There was no apparent accumulation based on Cmax and AUC0–12 after multiple doses. Although no differences were found in Cmax or AUC0–12 by age in men, Cmax and AUC0–12 were slightly higher in elderly women than elderly men. FAAH activity was inhibited in a dose-dependent manner, and plasma levels of anandamide, oleoylethanolamide, and palmitoylethanolamide increased in all dose groups after single and multiple doses of ASP3652. The incidence of adverse events after multiple doses, which ranged from 44.4% to 66.7%, was similar across all treatment groups, including the placebo group. Implications Single and multiple doses of ASP3652 were well tolerated and increased endogenous cannabinoids.
Article
Cannabis, or marijuana, is comprised of many compounds with varying effects. It has become a treatment option for chronic diseases and debilitating symptoms, and evidence suggests that it has immunomodulatory and anti-inflammatory properties. Transplant centers are more frequently facing issues about cannabis, as indications and legalization expand. As of February 2020, 33 states and the District of Columbia have legalized medical cannabis and 14 recreational cannabis. Moreover, 8 states have passed legislation prohibiting the denial of transplant listing solely based on cannabis use. Studies demonstrate the potential for significant pharmacokinetic and pharmacodynamic interactions between cannabis and immunosuppression. Additionally, safety concerns include increased risk of myocardial infarction, ischemic stroke, tachyarrhythmias, malignancy, neurocognitive deficits, psychosis, other neuropsychiatric disorders, cannabis use disorder, respiratory symptoms and infection. A recent retrospective database study found a negative association between documented cannabis use disorder and graft survival, but little additional evidence exists evaluating this relationship. In the absence of robust clinical data, transplant centers need a clear, reasoned and systematic approach to cannabis. The results of our national survey unfortunately found little consensus amongst institutions. As both recreational and medicinal cannabis become more ubiquitous nationwide, transplant centers will need to develop comprehensive policies to address its use.
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Cannabidiol (CBD), a phytocannabinoid compound of Cannabis sativa, shows limited oral bioavailability due to its lipophilicity and extensive first-pass metabolism. CBD is also known for its high intra- and inter-subject absorption variability in humans. To overcome these limitations a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology incorporating CBD, as Hemp-Extract, was developed (SEDDS-CBD). The study objective was to evaluate the pharmacokinetic profile of SEDDS-CBD in a randomized, double-blind, cross-over design in 16 healthy volunteers under fasted conditions. As reference formulation, the same Hemp-Extract diluted with medium-chain triglycerides (MCT-CBD) was used. CBD dose was standardized to 25 mg. Pharmacokinetic parameters were analyzed from individual concentration-time curves. Single oral administration of SEDDS-CBD led to a 4.4-fold higher Cmax and a 2.85-/1.70-fold higher AUC0–8h/AUC0–24h compared to the reference formulation. Tmax was substantially shorter for SEDDS-CBD (1.0 h) compared to MCT-CBD (3.0 h). Subgroup analysis demonstrated a higher bioavailability in women compared to men. This difference was seen for MCT-CBD while SEDDS-CBD mitigated this gender effect. Overall, SEDDS-CBD showed a significant improvement for all determined pharmacokinetic parameters: increased CBD plasma values (Cmax), favorably enhanced bioavailability (AUC) and fast absorption (Tmax). No safety concerns were noted following either administration.
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There is increasing interest in the use of cannabinoids for disease and symptom management, but limited information available regarding their pharmacokinetics and pharmacodynamics to guide prescribers. Cannabis medicines contain a wide variety of chemical compounds, including the cannabinoids delta‐9‐tetrahydrocannabinol (THC), which is psychoactive, and the non‐psychoactive cannabidiol (CBD). Cannabis use is associated with both pathological and behavioural toxicity and accordingly, is contraindicated in the context of significant psychiatric, cardiovascular, renal or hepatic illness. The pharmacokinetics of cannabinoids and effects observed depend on the formulation and route of administration, which should be tailored to individual patient requirements. Both THC and CBD are hepatically metabolised, hence potential exists for pharmacokinetic drug interactions via inhibition or induction of enzymes or transporters. An important example is the CBD‐mediated inhibition of clobazam metabolism. Pharmacodynamic interactions may occur if cannabis is administered with other CNS depressant drugs and cardiac toxicity may occur via additive hypertension and tachycardia with sympathomimetic agents. More vulnerable populations such as older patients may benefit from the potential symptomatic and palliative benefits of cannabinoids, but are at increased risk of adverse effects. The limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing cannabis medicines using a "start low and go slow" approach, carefully observing the patient for desired and adverse effects. Further clinical studies in the actual patient populations for whom prescribing may be considered are needed to derive a better understanding of these drugs and enhance safe and optimal prescribing
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Yüzyıllardır tedavide ve keyif verici amaçla kullanılan Hint keneviri veya esrar adıyla bilinen “Cannabis sativa”, içeriğinde kannabinoidler denilen bileşenleri barındırmaktadır. Psikoaktif etkili tetrahidrokannabinol (THC), bu bitkinin temel bileşenidir. Sedasyon, kognitif disfonksiyon, kısa süreli hafızada bozulma, zaman değerlendirmesinde değişiklik gibi etkileri olan esrar bitkisi (marihuana) yıllardır uyuşturucu ve keyif verici olarak yaygın biçimde kullanılmaktadır. Son yıllarda ise laboratuvar ortamında üretilen sentetik kannabinoidler (SK), giderek artan bir biçimde kullanıma girmiştir. Bağımlılık potansiyeli oldukça yüksek olan bu bileşikler 1990'lı yıllarda John William Huffman ve arkadaşları tarafından “JWH maddeleri” adıyla sentezlenmiştir. Günümüzde “Bonzai, Spice, K2, Jamaican Gold” gibi isimlerle bilinen maddeler, sentetik kannabinoidlerin bir solventte çözülüp çeşitli bitkisel karışımlara püskürtülmesiyle elde edilmiştir. Bu maddeler sigara, pipo ya da çay şeklinde pazarlanmakta ve zehirlenme veya ölümle sonuçlanan ciddi vakalara neden olmaktadır. Kannabinoidler insan vücudunda endojen olarak da bulunur ve immün sistem, iştah, ağrı, zevk hissi, duygu durum ve hafıza gibi çeşitli fizyolojik olayların düzenlenmesinde rol oynar. Endojen kannabinoidler araşidonik asit metabolizması ürünleridir. 2-araşidonil gliserol (2-AG) ve anandamid (araşidonil etanolamid) gibi endojen kannabinoidler kannabinoid reseptörlerine (CB1 ve CB2) bağlanarak etki gösterir. Kannabinoidler kötüye kullanılan maddelerden olmasının yanı sıra çeşitli hastalıkların tedavisinde veya semptomların hafifletilmesinde de kullanılmaktadır. Günümüzde kanser kemoterapisinde bulantı ve kusmayı azaltmak, AIDS hastalarında iştahı artırmak ve kronik ağrı tedavisine yardımcı olmak amacıyla FDA tarafından onaylanmış kannabinoid analogları bulunmaktadır. Ayrıca kannabinoid sistemin regülasyonunun nörodejeneratif hastalıklarda, postmenopozal osteoporoz, kanser, obezite, diyabet, karaciğer hastalıkları, kardiyometabolik komplikasyonlar, alkol-ilaç bağımlılığı gibi hastalıklarda faydalı olabileceğini gösteren çalışmalar bulunmaktadır.
Chapter
Drogen- und Medikamentenabhängigkeit sind in allen sozialen Schichten zu finden. Suchtverlangen und Beschaffung führen oft zu delinquentem Verhalten und können in Verbindung mit den Konsumfolgeerkrankungen einen sozialen Abstieg provozieren. Ausnahmen bilden Patienten mit einer sog. niedrig dosierten Medikamentenabhängigkeit, die trotz ihrer Erkrankung häufig sozial unauffällig sind und deren Abhängigkeit nicht selten Folge einer medizinischen Behandlung ist. Die Kernsymptome von Abhängigkeitserkrankungen gehen einher mit biologischen Veränderungen bestimmter Teilstrukturen des Gehirns. Wirksame therapeutische Vorgehensweisen berücksichtigen daher immer häufiger auch biologische Erklärungsmodelle. Nur bezüglich der Opiatabhängigkeit gibt es für bestimmte Fälle gute Evidenz für eine Substitutionsbehandlung. Der Missbrauch von Substanzen ohne Abhängigkeitspotenzial betrifft z. B. Analgetika, Anabolika oder Laxanzien. Die Unterscheidung zwischen Missbrauch und Abhängigkeit erfolgt über die Kriterien der „International Classification of Diseases“ (ICD-10). Im „DIAGNOSTIC UND STATISTICAL MANUAL OF MENTAL DISORDERS“ (DSM-5) wurde diese Unterscheidung verlassen, dort werden substanzbezogene Störungen – nach Schweregraden unterteilt – als sog. Substanzkonsumstörungen operationalisiert. Das therapeutische Vorgehen bei der Behandlung eines Missbrauchs beinhaltet andere Maßnahmen als das Vorgehen bei der Behandlung einer Abhängigkeitserkrankung.
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The pharmacology of any xenobiotic is a complex set of processes that is frequently divided into two categories: pharmacokinetics and pharmacodynamics. These two processes encompass the various steps that the body takes to transform the drug to facilitate its excretion (pharmacokinetics) and the interactions of the drug with the body which result in the observed effects (pharmacodynamics). The study of these processes includes the determination of kinetic parameters to describe the rate of elimination of the drug from the body, binding affinities to describe the interaction of the drug with endogenous receptors, and the determination of enzymes that are instrumental in these processes.
Chapter
Menschen mit Drogen- und Medikamentenabhängigkeit stammen aus allen sozialen Schichten. Suchtverlangen und Beschaffung führen oft zu delinquentem Verhalten und können in Verbindung mit den Konsum folgeerkrankungen einen sozialen Abstieg provozieren. Ausnahmen sind oft Patienten mit einer sog. niedrig dosierten Medikamentenabhängigkeit. Sie sind trotz ihrer Erkrankung häufig sozial unauffällig. Hier ist die Abhängigkeitserkrankung nicht selten Folge einer medizinischen Behandlung. Funktionell bildgebende Untersuchungen haben gezeigt, dass die Kernsymptome von Abhängigkeitserkrankungen mit biologischen Veränderungen bestimmter Teilstrukturen des Gehirns einhergehen. Moderne, wirksame therapeutische Vorgehensweisen berücksichtigen daher immer häufiger biologische Erklärungsmodelle und umfassen zusätzlich Pharmakotherapie, Rückfallprophylaxe und psycho- oder soziotherapeutische Maßnahmen. Nur bei der Opiat abhängigkeit kommt in bestimmten Fällen auch eine Substitutions behandlung infrage. Der Missbrauch von Substanzen ohne Abhängigkeitspotenzial betrifft beispielsweise Analgetika, Halluzinogene, Anabo lika, aber auch Laxanzien. Die Unterscheidung zwischen Missbrauch und Abhängigkeit muss über die Kriterien der ICD-10 oder DSM-IV-TR getroffen werden. So beinhaltet das therapeutische Vorgehen bei der Behandlung eines Missbrauchs andere Maßnahmen als das Vorgehen bei der Behandlung einer Abhängigkeitserkrankung.
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Cannabis, or marijuana, has been used for centuries for both symptomatic and prophylactic treatment of migraine. It was highly esteemed as a headache remedy by the most prominent physicians of the age between 1874 and 1942, remaining part of the Western pharmacopoeia for this indication even into the mid-twentieth century. Current ethnobotanical and anecdotal references continue to refer to its efficacy for this malady, while biochemical studies of THC and anandamide have provided a scientific basis for such treatment. The author believes that controlled clinical trials of Cannabis in acute migraine treatment are warranted.
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. A central tenet underlying the use of botanical remedies is that herbs contain many active ingredients. Primary active ingredients may be enhanced by secondary compounds, which act in beneficial syn-ergy. Other herbal constituents may mitigate the side effects of dominant active ingredients. We reviewed the literature concerning medical can-nabis and its primary active ingredient, ∆ 9 -tetrahydrocannabinol (THC). Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC. Other cannabinoid and non-cannabinoid compounds in herbal cannabis or its extracts may reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activ-ity. [Article copies available for a fee from The Haworth Document Delivery Service: and: Cannabis Therapeutics in HIV/AIDS (ed: Ethan Russo) The Haworth Integrative Healing Press, an imprint of The Haworth Press, Inc., 2001, pp. 103-132. Single or multiple copies of this arti-cle are available for a fee from The Haworth Document Delivery Service [1-800-342-9678, 9:00 a.m. -5:00 p.m. (EST). E-mail address: getinfo@haworthpressinc.com].
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The human body possesses specific binding sites on the surface of many cell types for cannabi-noids, and our body produces several endocannabinoids, fatty acid derivatives that bind to these cannabinoid receptors (CB) and activate them. CB receptors and endocannabinoids together con-stitute the endocannabinoid system. Some phytocannabinoids, cannabinoids of the cannabis plant, and a multitude of synthetic cannabinoids produced in the laboratory mimic the effects of endo-cannabinoids. ∆ 9 -THC (dronabinol), the pharmacologically most active cannabinoid of the canna-bis plant, binds to both types of cannabinoid receptors that have been identified so far, the CB 1 and the CB 2 receptor. These receptors have been found in the central nervous system (brain and spinal cord) and many peripheral tissues and organs. Depending on the kind of cells, on dose and state of the body, activation of CB receptors may cause a multitude of effects including euphoria, anxiety, dry mouth, muscle relaxation, hunger and pain reduction. Besides activation of CB receptors sev-eral other approaches are under investigation to influence the cannabinoid system with therapeutic intent, including blockade of CB receptors (antagonism) and modulation of endocannabinoid con-centrations by inhibition of their degradation. Currently, several preparations that stimulate can-nabinoid receptors (dronabinol, nabilone and cannabis) and one compound that blocks the CB 1 re-ceptor (rimonabant) are used medicinally.
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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.
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To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects. A consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials with two-week treatment periods. Patients attended as outpatients, but took the CME at home. Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1). Whole-plant extracts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5-120 mg/24 hours. Measures used: Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales. At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales, administered standard measures of disability (Barthel Index), mood and cognition, and recorded adverse events. Pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were improved by CME in some patients with these symptoms. Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME. Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings.
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1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3), a potent analog of THC-11-oic acid, produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids. Therefore, CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain. To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans. Randomized, placebo-controlled, double-blind crossover trial conducted in Germany from May-September 2002. Twenty-one patients (8 women and 13 men) aged 29 to 65 years (mean, 51 years) who had a clinical presentation and examination consistent with chronic neuropathic pain (for at least 6 months) with hyperalgesia (n = 21) and allodynia (n = 7). Patients were randomized to two 7-day treatment orders in a crossover design. Two daily doses of CT-3 (four 10-mg capsules per day) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days. After a washout and baseline period of 1 week each, patients crossed over to the second 7-day treatment period. Visual analog scale (VAS) and verbal rating scale scores for pain; vital sign, hematologic and blood chemistry, and electrocardiogram measurements; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale; and adverse effects. The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence (mean [SD], -11.54 [14.16] vs 9.86 [21.43]; P =.02). Eight hours after intake of the drug, the pain scale differences between groups were less marked. No dose response was observed. Adverse effects, mainly transient dry mouth and tiredness, were reported significantly more often during CT-3 treatment (mean [SD] difference, -0.67 [0.50] for CT-3-placebo sequence vs 0.10 [0.74] for placebo-CT-3 sequence; P =.02). There were no significant differences with respect to vital signs, blood tests, electrocardiogram, Trail-Making Test, and Addiction Research Center Inventory-Marijuana scale. No carryover or period effects were observed except on the Trail-Making Test. In this preliminary study, CT-3 was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed.
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To evaluate the effect of the oral synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis. Randomised double blind placebo controlled crossover trial. Outpatient clinic, University Hospital of Aarhus, Denmark. 24 patients aged between 23 and 55 years with multiple sclerosis and central pain. Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period. Median spontaneous pain intensity (numerical rating scale) in the last week of treatment. Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change. Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.
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The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.
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In many societies, marijuana is the second most commonly smoked substance after tobacco. While delta9-tetrahydrocannabinol (THC) is unique to marijuana and nicotine to tobacco, the smoke of marijuana, like that of tobacco, consists of a toxic mixture of gases and particulates, many of which are known to be harmful to the lung. Although far fewer marijuana than tobacco cigarettes are generally smoked on a daily basis, the pulmonary consequences of marijuana smoking may be magnified by the greater deposition of smoke particulates in the lung due to the differing manner in which marijuana is smoked. Whereas THC causes modest short-term bronchodilation, regular marijuana smoking produces a number of long-term pulmonary consequences, including chronic cough and sputum, histopathologic evidence of widespread airway inflammation and injury and immunohistochemical evidence of dysregulated growth of respiratory epithelial cells, that may be precursors to lung cancer. The THC in marijuana could contribute to some of these injurious changes through its ability to augment oxidative stress, cause mitochondrial dysfunction, and inhibit apoptosis. On the other hand, physiologic, clinical or epidemiologic evidence that marijuana smoking may lead to chronic obstructive pulmonary disease or respiratory cancer is limited and inconsistent. Habitual use of marijuana is also associated with abnormalities in the structure and function of alveolar macrophages, including impairment in microbial phagocytosis and killing that is associated with defective production of immunostimulatory cytokines and nitric oxide, thereby potentially predisposing to pulmonary infection. In view of the growing interest in medicinal marijuana, further epidemiologic studies are needed to clarify the true risks of regular marijuana smoking on respiratory health.
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This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.
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The presence and function of CB2 receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB2 receptor messenger RNA and protein localization on brainstem neurons. These functional CB2 receptors in the brainstem were activated by a CB2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB1 receptors. CB2 receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.
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To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA). We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity. Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group. In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.
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To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to 12 months in the follow up study reported here. Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.
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The plant-derived cannabinoids delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) both have immunosuppressive effects; although some effects of THC are mediated by the CB2 receptor, CB2 binds CBD weakly. In examining the effects of THC and CBD on microglial proliferation, we found that these compounds potently inhibit [3H]thymidine incorporation into a murine microglial cell line with no effect on cell cycle. Treatment with THC and CBD decreased [3H]thymidine uptake into microglia, with IC50 values that match inhibition of [3H]thymidine incorporation into DNA. CBD and, less potently, THC decreased uptake of [3H]adenosine to a similar extent as [3H]thymidine in both murine microglia and RAW264.7 macrophages. Binding studies confirm that CBD binds to the equilibrative nucleoside transporter 1 with a Ki < 250 nM. Because adenosine agonists have antiinflammatory effects, and because uptake of adenosine is a primary mechanism of terminating adenosine signaling, we tested the hypothesis that CBD is immunosuppressive because it enhances endogenous adenosine signaling. In vivo treatment with a low dose of CBD decreases TNFalpha production in lipopolysaccharide-treated mice; this effect is reversed with an A2A adenosine receptor antagonist and abolished in A2A receptor knockout mice. These studies demonstrate that CBD has the ability to enhance adenosine signaling through inhibition of uptake and provide a non-cannabinoid receptor mechanism by which CBD can decrease inflammation.
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Cannabinoids have been shown to have analgesic properties in animal studies, but a potential role for these drugs in acute pain management has not been established. It was hypothesized that nabilone, an oral cannabinoid synthetic tetrahydrocannabinol analogue, decreases morphine consumption, pain scores, nausea and vomiting following major surgery. A double-blind, randomized, placebo-controlled, parallel-group pilot trial compared the effects of two different doses, 1 mg (n = 11) and 2 mg (n = 9) of nabilone, ketoprofen 50 mg (n = 11) or placebo (n = 10), given at eight-hour intervals for 24 hr. Outcomes included morphine consumption, pain scores and emesis after major surgery. Secondary outcomes included patient tolerability of the study medication. Forty-one patients (mean age 52 +/- 2 yr) undergoing gynecologic (46%), orthopedic (44%), or other (10%) surgery were recruited. Cumulative 24-hr morphine consumption was not different between the four groups, but pain scores at rest and on movement were significantly higher in the 2 mg nabilone group compared to the other groups. There were no significant differences between groups with respect to episodes of nausea and vomiting, quality of sleep, sedation, euphoria, pruritus, or the number and severity of adverse events. No serious adverse event was recorded. Contrary to the main hypothesis, high dose nabilone in the presence of morphine patient controlled analgesia is associated with an increase in pain scores in patients undergoing major surgery.
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The antinociceptive effects of various mu opioids given p.o. alone and in combination with Delta-9-tetrahydrocannabinol (Delta(9)-THC) were evaluated using the tail-flick test. Morphine preceded by Delta(9)-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED,, value when administered after Delta(9)-IHC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone acid hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, I-alpha-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Delta(9)-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta(9)-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta(9)-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta(9)-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced by an inactive dose of Delta(9)-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of mu and possibly delta opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception.
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(−)-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
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The background knowledge leading to the isolation and identification of anandamide and 2-arachidonoyl glycerol, the principal endocannabinoids is described. The structure–activity relationships of these lipid derivatives are summarized. Selected biochemical and pharmacological topics in this field are discussed, the main ones being levels of endocannabinoids in unstimulated tissue and cells, biosynthesis, release and inactivation of endocannabinoids, the effects of `entourage' compounds on the activities of anandamide and 2-arachidonoyl glycerol, their signaling mechanisms and effects in animals.
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Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-HT1A receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-HT2A and 5-HT1A response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-HT2A receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the delta9-cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-HT1A potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-HT2A, but not the 5-HT1A, receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.
Article
Various neurophysiological properties of cannabis are described in a review of the literature. The properties of the principal active cannabinoid, delta-9-tetrahydrocannabinol (delta-9-THC) are described, followed by a review of psychological and neuropsychiatric effects. Cannabis disturbs EEG, decreasing in particular REM sleep time. Cerebral atrophy is not evident, assuming no concurrent drug abuse, but cerebral perfusion is noted to decrease after THC absorption. Endocrine effects have been described in animal studies: inhibiting effects on sex hormone production and thyroid function, and a stimulating action on corticosteroid activity have been observed. These actions are thought to exert themselves at the hypothalamic level. There is also evidence of an effect on prostaglandin metabolism. At the cellular and subcellular level THC acts on membranes of neurones and synaptic vesicles, possibly affecting membrane transport systems. The morphology of the synapse is also altered. THC acts on neurone conduction, stimulating polysynaptic transmission. Various mechanisms of THC activity are considered: via specific lipoprotein receptors, via central benzodiazepine receptors and via opioid receptors. THC also exerts an effect on neurotransmitters: an increase in central cholinergic activity, a mode-rate increase in catecholaminergic activity and effects on the GABA and serotonin systems are postulated.
Article
The major finding of this analysis is that acute anti-migraine agents (e.g., ergots, sumatriptan) share high affinity for 5-HT1D receptors. This receptor appears to be present in certain intracranial blood vessels. It is also found on nerve terminals where it inhibits the release of 5-HT and other neurotransmitters. Theoretically, 5-HT1D receptor agonists may acutely inhibit the release of vasoactive and/or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of this perivascular process. In contrast, a number of prophylactic anti-migraine drugs share a relatively high affinity for 5-HT2 receptors in human brain. Although this receptor is also found in certain blood vessels, it is present throughout the nervous system. The receptor appears to mediate neuronal depolarizations at the cellular level. No hypothesis, at present, readily explains the effectiveness of prophylactic anti-migraine drugs based on this receptor. These data offer a novel approach to the analysis of anti-migraine agents. Drugs could be selected for use in clinical migraine studies based on their selectivity for a specific 5-HT receptor subtype. "Pure" drugs could be chosen which would essentially limit the number of possible sites of action for the drugs. For example, an agent which displays both high affinity and selectivity for 5-HT1D receptors could be clinically evaluated. Its effectiveness, or lack thereof, would indicate the importance of the specific 5-HT receptor site in the pathogenesis of migraine. Further attempts to determine a common mechanism of action for effective anti-migraine agents should facilitate the elucidation of the pathogenesis of this neurological syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Because a satisfactory animal model for migraine does not exist, attempts to determine a common mechanism of action for effective antimigraine agents may be of benefit in elucidating the pathogenesis of this neurologic syndrome. The present review demonstrates that the clinical data that has developed over the past 30 years may allow for the elucidation of the role of specific 5-HT receptor subtypes in the pathophysiology of migraine. A large number of both acute and prophylactic antimigraine agents share an ability to interact with 5-HT receptor subtypes in human brain. As summarized in Table 3, acute antimigraine drugs (e.g., ergots, sumatriptan) share high affinity for 5-HTID receptors and somewhat lower affinity for 5-HT1A receptors. These receptors are present in certain intracranial blood vessels. 5-HT1D receptors are also located on nerve terminals where they act to inhibit the release of 5-HT and other neurotransmitters. Theoretically, 5-HTID receptor agonists may acutely inhibit the release of vasoactive or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of this perivascular process. In addition, a number of prophylactic antimigraine drugs display a relatively high affinity for both 5-HT2 and 5-HT1C receptors in human brain. Although these receptors are also found in certain blood vessels, they are present throughout the nervous system. The receptors appear to mediate neuronal depolarizations at the cellular level. Moreover, the 5-HT2 receptor appears to play a key role in the development of inflammation in certain smooth muscle systems. Theoretically, the ability of 5-HT2 antagonists to protect perivascular inflammation may account for their efficacy in the prophylactic treatment of migraine. These data offer a novel approach to the analysis of antimigraine agents. Drugs could be selected for use in clinical migraine studies based on their selectivity for a specific 5-HT receptor subtype. For example, an agent that displays both high affinity and selectivity for 5-HT1D receptors could be clinically evaluated. Its effectiveness, or lack thereof, would indicate the importance of this specific 5-HT receptor site in the pathogenesis of migraine. Future attempts to determine a common mechanism of action for effective antimigraine agents should facilitate the elucidation of the pathogenesis of this neurologic syndrome.
Article
The effects were assessed of delta'THC (the psychoactive component of cannabis) and CBD and DMHP-CBD (the non-psychomimetic components of marijuana derivatives) on 14C labelled serotonin release from normal platelets, when incubated with patient's plasma obtained during migraine attack. A statistically significant inhibitory effect (p greater than 0.005) of 14C serotonin release was found at 10(-5)M, 10(-6)M, 10(-7)M delta'THC concentrations. Plasma of migraine patients obtained in attack-free periods revealed no significant inhibitory effect on 14C serotonin release from normal platelets using the same delta'THC concentration. CBD and DMHP-CBD had no significant inhibitory effect on 14C serotonin release from normal platelets when tested either at migraine-free period plasma or plasma obtained during migraine attack.
Article
An extract of cannabis (5 and 15 mg/kg expressed as delta 9-THC) orally administered to rats caused an elevation of the nociceptive threshold (tail-flick latency and vocalization tests). Naloxone and naltrexone (blockers of mu-type opiate receptors) as well as MR 1452 (blocker of kappa opiate receptors) did not prevent the antinociceptive effect of cannabis when used at the dose of 2 mg/kg SC; only a high dose (10 mg/kg SC) of these narcotic antagonists partially blocked cannabis antinociception. ICI 154, 129, an antagonist of delta-type opiate receptors, failed to prevent the cannabis-induced rise in nociceptive threshold when used at a dose of 2 mg/kg SC but produced a significant effect at 10 mg/kg SC. While the role of opiate receptors does not seem fundamental to cannabis antinociception, the clear-cut effectiveness shown by 6-hydroxydopamine (a neurotoxin which causes a degeneration of catecholamine-containing terminals) in reducing cannabis antinociception is indicative of a participation of catecholamines in the phenomenon.
Article
A series of the naturally occurring cannabinoids were tested for possible effects on the biosynthesis of prostaglandins. Most of the substances examined were able to inhibit in varying degrees the conversion of 8,11,14-eicosatrienoic acid to prostaglandin E1 (PGE1) when incubated with bovine seminal vesicle microsomes. The order of activity starting with the most potent was cannabinol, cannabidiolic acid, A6tetrahydrocannabinol (Δ6-THC), cannabidiol, cannabichromene and Δ1-THC; cannabicyclol showed almost no inhibitory activity. It is suggested that certain of the pharmacological actions of some of these cannabinoids may be explained by a similar effect in vivo. Olivetol, which represents a partial structure for all of the compounds tested, showed high activity, indicating that the inhibitory power of the cannabinoids resides in the aromatic portion of the molecule.
Article
Cannabichromene (CBC) is one of four major cannabinoids in Cannabis sativa L. and is the second most abundant cannabinoid in drug-type cannabis. Cannabichromene and some of its homologs, analogs, and isomers were evaluated for antiinflammatory, antibacterial, and antifungal activity. Antiinflammatory activity was evaluated by the carrageenan-induced rat paw edema and the erythrocyte membrane stabilization method. In both tests, CBC was superior to phenylbutazone. Antibacterial activity of CBC and its isomers and homologs was evaluated using gram-positive, gram-negative, and acid-fast bacteria. Antifungal activity was evaluated using yeast-like and filamentous fungi and a dermatophyte. Antibacterial activity was strong, and the antifungal activity was mild to moderate.
Article
The gastric cytoprotective effect of beta-caryophyllene, an anti-inflammatory sesquiterpene, was investigated in rats. The oral administration of beta-caryophyllene to rats significantly inhibited gastric mucosal injuries induced by necrotizing agents such as absolute ethanol and 0.6 N HCl, although it failed to prevent water immersion stress- and indomethacin-induced gastric lesions. In addition, this compound hardly affected the secretion of gastric acid and pepsin. Thus, beta-caryophyllene elicited anti-inflammatory effects without any indication of gastric mucosal damage typical of non-steroidal anti-inflammatory agents. Furthermore, this compound manifested cytoprotective effects, rendering the two-dimensional efficacious beta-caryophyllene to be a clinically safe and potentially useful agent.
Article
The influence of marijuana cannabinoids on immune function has been examined extensively over the last 25 yr. Various experimental models have been used employing drug-abusing human subjects, experimental animals exposed to marijuana smoke or injected with cannabinoids, and in vitro models employing immune cell cultures treated with various cannabinoids. For the most part, these studies suggest that cannabinoids modulate the function of T and B lymphocytes as well as NK cells and macrophages. In addition to studies examining cannabinoid effects on immune cell function, other reports have documented that these substances modulate host resistance to various infectious agents. Viruses such as herpes simplex virus and murine retrovirus have been studied as well as bacterial agents such as members of the genera Staphylococcus, Listeria, Treponema, and Legionella. These studies suggest that cannabinoids modulate host resistance, especially the secondary immune response. Finally, a third major area of host immunity and cannabinoids is that involving drug effects on the cytokine network. Employing in vivo and in vitro models, it has been determined that cannabinoids modulate the production and function of acute phase and immune cytokines as well as modulate the activity of network cells such as macrophages and T helper cells, Th1 and Th2. These results are intriguing and demonstrate that under certain conditions, cannabinoids can be immunomodulatory and enhance the disease process. However, more studies are needed to determine both the health risk of marijuana abuse and the role of the cannabinoid receptor/ligand system in immune regulation and homeostasis.
Article
High densities of cannabinoid receptors were found in the basal ganglia and hippocampus, indicating a putative functional role of cannabinoids in movement and behaviour. Anecdotal reports suggested beneficial effects of marijuana in Tourette's syndrome (TS). We therefore interviewed 64 TS patients with regard to use of marijuana and its influence on TS symptomatology. Of 17 patients (27%) who reported prior use of marijuana, 14 subjects (82%) experienced a reduction or complete remission of motor and vocal tics and an amelioration of premonitory urges and obsessive-compulsive symptoms. Our results provide more evidence that marijuana improves tics and behavioural disorders in TS. It can be speculated that cannabinoids might act through specific receptors, and that the cannabinoid system might play a major role in TS pathology.
Article
The antinociceptive effects of various mu opioids given p.o. alone and in combination with Delta-9-tetrahydrocannabinol (Delta9-THC) were evaluated using the tail-flick test. Morphine preceded by Delta9-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED50 value when administered after Delta9-THC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone and hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, l-alpha-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Delta9-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta9-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta9-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta9-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced by an inactive dose of Delta9-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of mu and possibly delta opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception.
Article
The endogenous cannabinoid anandamide was identified as an agonist for the recombinant human VR1 (hVR1) by screening a large array of bioactive substances using a FLIPR-based calcium assay. Further electrophysiological studies showed that anandamide (10 or 100 μM) and capsaicin (1 μM) produced similar inward currents in hVR1 transfected, but not in parental, HEK293 cells. These currents were abolished by capsazepine (1 μM). In the FLIPR anandamide and capsaicin were full agonists at hVR1, with pEC50 values of 5.94±0.06 (n=5) and 7.13±0.11 (n=8) respectively. The response to anandamide was inhibited by capsazepine (pKB of 7.40±0.02, n=6), but not by the cannabinoid receptor antagonists AM630 or AM281. Furthermore, pretreatment with capsaicin desensitized the anandamide-induced calcium response and vice versa. In conclusion, this study has demonstrated for the first time that anandamide acts as a full agonist at the human VR1. British Journal of Pharmacology (2000) 129, 227–230; doi:10.1038/sj.bjp.0703050
Article
Multiple sclerosis is associated with muscle stiffness, spasms, pain, and tremor. Much anecdotal evidence suggests that cannabinoids could help these symptoms. Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis. We did a randomised, placebo-controlled trial, to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity. 630 participants were treated at 33 UK centres with oral cannabis extract (n=211), Delta9-tetrahydrocannabinol (Delta9-THC; n=206), or placebo (n=213). Trial duration was 15 weeks. Our primary outcome measure was change in overall spasticity scores, using the Ashworth scale. Analysis was by intention to treat. 611 of 630 patients were followed up for the primary endpoint. We noted no treatment effect of cannabinoids on the primary outcome (p=0.40). The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 (95% CI -1.04 to 1.67), and for those taking Delta9-THC versus placebo it was 0.94 (-0.44 to 2.31). There was evidence of a treatment effect on patient-reported spasticity and pain (p=0.003), with improvement in spasticity reported in 61% (n=121, 95% CI 54.6-68.2), 60% (n=108, 52.5-66.8), and 46% (n=91, 39.0-52.9) of participants on cannabis extract, Delta9-THC, and placebo, respectively. Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale. However, though there was a degree of unmasking among the patients in the active treatment groups, objective improvement in mobility and patients' opinion of an improvement in pain suggest cannabinoids might be clinically useful.
Article
Three Cannabis Based Medicinal Extracts (CBMEs) for sublingual use became available in 2000. A total of 34 'N of 1' studies were undertaken using this novel therapy for patients with chronic, mainly neuropathic, pain and associated symptoms to explore efficacy, tolerability, safety and dosages. Three CBMEs (Delta9 Tetrahydrocannabinol (THC), Cannabidiol (CBD) and a 1:1 mixture of them both) were given over a 12-week period. After an initial open-label period, the CBMEs were used in a randomised, double-blind, placebo controlled, crossover trial. Extracts which contained THC proved most effective in symptom control. Regimens for the use of the sublingual spray emerged and a wide range of dosing requirements was observed. Side-effects were common, reflecting a learning curve for both patient and study team. These were generally acceptable and little different to those seen when other psycho-active agents are used for chronic pain. These initial experiences with CBME open the way to more detailed and extensive studies.