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Neuroprotective Antioxidants from Marijuanaa
Annals of the New York Academy of Sciences
Abstract
Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist Δ9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both a-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.
... Previous studies have revealed the presence of CB1 and CB2 receptors in various mammalian eyes, including the human retina [25][26][27][28]. Endogenous cannabinoids were found in the eye as part of an endogenous signaling system [29], and exogenous cannabinoids such as THC and various endogenous cannabinoids have been shown in vitro to be neuroprotective of cerebellar, hippocampal and neocortical neurons when challenged with toxic levels of glutamate [30][31][32][33][34][35]. The neuroprotective effects of cannabinoids on RGCs following glutamate toxicity have not been determined in vitro or in vivo. ...
... Our in vivo test of a cannabinoid agonist to protect against glutamate excitotoxicity correlates with several in vitro studies on the efficacy of these agents. These studies all found that cannabinoids provided neuroprotection of cultured cortical, cerebellar, and hippocampal neurons [30][31][32][33][34][35]. The cannabinoid agonist WIN 55,212-2 has been found to bind the CB1 and CB2 receptors [54] to elicit the presently demonstrated neuroprotective effect [34]. ...
... The cannabinoid agonist WIN 55,212-2 has been found to bind the CB1 and CB2 receptors [54] to elicit the presently demonstrated neuroprotective effect [34]. Some studies have demonstrated neuroprotective actions by cannabinoids independent of CB1 or CB2 receptors [31,34], suggesting a novel receptor. Others have proposed that the cannabinoid protection results from decreasing the release of glutamate presynaptically [35]. ...
Cannabinoid and glutamatergic signaling systems in the human retina coexist and greatly influence one another. Under glaucomatous conditions, excess levels of glutamate accrete in the retinal ganglion cell layer. The present study tests the putative neuroprotective effect mediated by cannabinoids at the CB1 and CB2 receptors. In the first experiment, mice were given intravitreal injections of 160 nmol NMDA in one eye and saline in the paired eye. In the second experiment, both eyes were given NMDA, while one of the two was additionally given the cannabinoid agonist WIN 55,212-2. Ten days later, animals were perfused and the retinae were dissected as wholemounts and stained with cresyl violet. Quantitative analysis revealed that 70% of the neurons in the retinal ganglion cell layer exposed to NMDA underwent cell death. The addition of the cannabinoid CB1/CB2 agonist doubled the number of neurons surviving the NMDA treatment. These data provide evidence that cannabinoids, either exogenous or endogenous, may be harnessed to provide protection from neurodegenerative diseases, including glaucoma, and from glutamate-induced, and potentially other forms of neurotoxicity, under chronic or acute conditions.
... Alternative pharmacological agents include phytocannabidiol (CBD), an active compound of the Cannabis sativa plant (marijuana), which showed neuroprotective effects in mouse models of several neurodegenerative diseases, including PD (Hampson et al., 1998;Hampson et al., 2000;Lastres-Becker et al., 2005;Garcia et al., 2011;Ruiz-Valdepenas et al., 2011; Frontiers in Cell and Developmental Biology frontiersin.org 04 Pacher et al., 2020). ...
... Another compound found in the C. sativa plant, Tetrahydrocannabinol (THC), has been shown to reduce NMDA, AMPA, and kainate receptor-mediated neurotoxicity (Hampson et al., 2000). An endogenous cannabinoid receptor agonist with similar pharmacological effects as THC is anandamide (AEA, the major psychoactive component of marijuana) that directly inhibits currents through homomeric GluA1 and GluA3 receptors at rather high concentrations, with IC 50 values of 161 and 143 μM, respectively, and heteromeric GluA1/3 and GluA2/3 receptors, with the similar IC 50 values of 148 and 241 μM, respectively (Akinshola et al., 1999a;Akinshola et al., 1999b). ...
Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission and are implicated in various neurological disorders. In this review, we discuss the role of the two fastest iGluRs subtypes, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, in the pathogenesis and treatment of Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis. Although both AMPA and kainate receptors represent promising therapeutic targets for the treatment of these diseases, many of their antagonists show adverse side effects. Further studies of factors affecting the selective subunit expression and trafficking of AMPA and kainate receptors, and a reasonable approach to their regulation by the recently identified novel compounds remain promising directions for pharmacological research.
... Low concentration of THC lowered total glycogen synthase kinase-3 beta (GSK-3β) and pGSK-3β, and augmented mitochondrial function (Cao et al., 2014). THC has also been shown to act as a neuroprotective antioxidant (Hampson et al., 1998(Hampson et al., , 2000Russo, 2011Russo, , 2019. ...
... CBD has neuroprotective properties via protection against neurotoxicity by inhibiting adenosine uptake (Carrier et al., 2006), reduction of glutamate toxicity (Hampson et al., 1998(Hampson et al., , 2000, and rescue of mitochondrial ferritin and epigenetic modulation of mitochondrial deoxyribonucleic acid (mDNA) (da Silva et al., 2018). CBD and CBDV have also been found to prevent oxytosis (Schubert et al., 2019), and CBDA was effective in preventing rotenone-induced neurotoxicity, however, this effect was likely due to decarboxylated CBDA (producing CBD), as CBD also showed neuroprotection against rotenone (Echeverry et al., 2020). ...
Alzheimer's disease (AD) is the most common form of dementia, and currently there is no cure. New therapeutic strategies that have the potential to address the complex pathophysiology of AD are urgently required; medicinal cannabis offers this possibility. Several potential leads can be extracted from Cannabis sativa (cannabis) that can target AD pathophysiology and alleviate symptoms, making it a prime candidate for AD drug discovery research. To date, most cannabis and AD research has focused on the major cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), paying little attention to other plant constituents with therapeutic properties for AD. This chapter will highlight emerging evidence on the therapeutic potential of medicinal cannabis going beyond CBD and THC to discuss cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabinoid acids, and other cannabinoid homologs, terpenes, and flavonoids that may have relevance to AD therapy. Further, the entourage effect, clinical implications, and directions for future research will be discussed.
... CBD also demonstrated antioxidant properties in an in vitro study with higher potency than THC [258]. Moreover, its antioxidant properties against glutamate neurotoxicity were demonstrated in neuronal cultures, with a better protective profile than the antioxidants ascorbate and tocopherol [269]. ...
... This possibility, however, was not investigated in the referred studies [169,172]. Moreover, considering reactive oxygen species (ROS) can trigger NLRP3 inflammasome activation [80,[105][106][107][108] and CBD has antioxidant properties [258][259][260]269]. Moreover, decreasing ROS production could be another mechanism by which CBD attenuates NLRP3 inflammasome activation. ...
Many psychiatric patients do not respond to conventional therapy. There is a vast effort to investigate possible mechanisms involved in treatment resistance, trying to provide better treatment options, and several data points toward a possible involvement of inflammatory mechanisms. Microglia, glial and resident immune cells, are involved in complex responses in the brain, orchestrating homeostatic functions, such as synaptic pruning and maintaining neuronal activity. In contrast, microglia play a major role in neuroinflammation, neurodegeneration, and cell death. Increasing evidence implicate microglia dysfunction in neuropsychiatric disorders. The mechanisms are still unclear, but one pathway in microglia has received increased attention in the last 8 years: the NLRP3 inflammasome pathway. Stress response and inflammation, including microglia activation, can be attenuated by Cannabidiol (CBD). CBD has antidepressant, anti-stress, antipsychotic, anti-inflammatory, and other properties. CBD effects are mediated by direct or indirect modulation of many receptors, enzymes, and other targets. This review will highlight some findings for neuroinflammation and microglia involvement in stress-related psychiatric disorders, particularly addressing the NLRP3 inflammasome pathway. Moreover, we will discuss evidence and mechanisms for CBD effects in psychiatric disorders and animal models and address its potential effects in stress response via neuroinflammation and NLRP3 inflammasome modulation.
... CBD has a low binding affinity towards CB1 with the capacity to antagonize CB1 at nM levels [12]. THC and its analogs have been shown to reduce glutamate toxicity by activating the cannabinoid receptors and reducing the influx of calcium through voltage-sensitive calcium channels [15,16]. We have recently reported on the radical scavenging activity of THC and CBD in the absence of SH-SY5Y cells using UV-Vis assays based on the colorimetric reactions between reactive oxygen species (ROS) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and hypochlorous acid (HOCl) [17]. ...
... CBD has a low binding affinity towards CB 1 with the capacity to antagonize CB 1 at nM levels [12]. THC and its analogs have been shown to reduce glutamate toxicity by activating the cannabinoid receptors and reducing the influx of calcium through voltage-sensitive calcium channels [15,16]. We have recently reported on the radical scavenging activity of THC and CBD in the absence of SH-SY5Y cells using UV-Vis assays based on the colorimetric reactions between reactive oxygen species (ROS) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and hypochlorous acid (HOCl) [17]. ...
In this proof-of-concept study, the antioxidant activity of phytocannabinoids, namely cannabidiol (CBD) and Δ9- tetrahydrocannabinol (THC), were investigated using an in vitro system of differentiated human neuronal SY-SH5Y cells. The oxidative stress was induced by hydrogen peroxide, as reactive oxygen species (ROS). Alzheimer’s disease (AD)-like pathological conditions were mimicked in vitro by treating the differentiated neuronal cells with amyloid-β1–42 (Aβ1–42) in the presence of Cu(II). We showed that THC had a high potency to combat oxidative stress in both in vitro models, while CBD did not show a remarkable antioxidant activity. The cannabis extracts also exhibited a significant antioxidant activity, which depended on the ratio of the THC and CBD. However, our results did not suggest any antagonist effect of the CBD on the antioxidant activity of THC. The effect of cannabis extracts on the cell viability of differentiated human neuronal SY-SH5Y cells was also investigated, which emphasized the differences between the bioactivity of cannabis extracts due to their composition. Our preliminary results demonstrated that cannabis extracts and phytocannabinoids have a promising potential as antioxidants, which can be further investigated to develop novel pharmaceuticals targeting oxidative stress therapy.
... Cannabidiol effects in ischemic stroke have been studied mainly in mice and rats with middle cerebral artery occlusion (Table 4). In this model of stroke, CBD administered both pre-and/or post-ischemia reduced infarct volume [50,53,[120][121][122] (but not in newborn rats [123]) and improved impaired neurological and/or neurobehavioral functions [50,[120][121][122][123][124]. CBD increased cerebral blood flow during the occlusion [50,53], which is consistent with the meta-analysis by Sultan et al. [24] that indicated increased CBF in mouse models of stroke after CBD administration. ...
... Cannabidiol effects in ischemic stroke have been studied mainly in mice and rats with middle cerebral artery occlusion (Table 4). In this model of stroke, CBD administered both pre-and/or post-ischemia reduced infarct volume [50,53,[120][121][122] (but not in newborn rats [123]) and improved impaired neurological and/or neurobehavioral functions [50,[120][121][122][123][124]. CBD increased cerebral blood flow during the occlusion [50,53], which is consistent with the meta-analysis by Sultan et al. [24] that indicated increased CBF in mouse models of stroke after CBD administration. ...
Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we reviewed the influence of CBD on this system in health and disease to determine the potential risk of cardiovascular side effects during CBD use for medical and wellness purposes and to elucidate its therapeutic potential in cardiovascular diseases. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. Although CBD has been found to exhibit vasodilatory and antioxidant properties in hypertension, it has not affected blood pressure in hypertensive animals. Hypotensive action of CBD has been mainly revealed under stress conditions. Many positive effects of CBD have been observed in experimental models of heart diseases (myocardial infarction, cardiomyopathy, myocarditis), stroke, neonatal hypoxic ischemic encephalopathy, sepsis-related encephalitis, cardiovascular complications of diabetes, and ischemia/reperfusion injures of liver and kidneys. In these pathological conditions CBD decreased organ damage and dysfunction, oxidative and nitrative stress, inflammatory processes and apoptosis, among others. Nevertheless, further clinical research is needed to recommend the use of CBD in the treatment of cardiovascular diseases.
... Generally, different Cannabis extracts present different proportions between CBD and THC, which may modify pharmacological and psychological effects (Potter et al., 2008). In that context, CBD has been shown to be a promising compound due to its hypnotic (Carlini and Cunha, 1981;Monti, 1977;Pickens, 1981), antiinflammatory (Costa et al., 2004;Esposito et al., 2011), antioxidants (Hampson et al., 1998(Hampson et al., , 2000, antipsychotic (Zuardi et al., 1991;2006) and neuroprotective (Hampson et al., 1998(Hampson et al., , 2000Iuvone et al., 2004) properties. Additionally, CBD presents low toxicity, high tolerability and the lack of psychoactive effects (Bergamaschi et al., 2011;Carlini and Cunha, 1981;Cunha et al., 1980), supporting its safe pharmacological use. ...
... Generally, different Cannabis extracts present different proportions between CBD and THC, which may modify pharmacological and psychological effects (Potter et al., 2008). In that context, CBD has been shown to be a promising compound due to its hypnotic (Carlini and Cunha, 1981;Monti, 1977;Pickens, 1981), antiinflammatory (Costa et al., 2004;Esposito et al., 2011), antioxidants (Hampson et al., 1998(Hampson et al., , 2000, antipsychotic (Zuardi et al., 1991;2006) and neuroprotective (Hampson et al., 1998(Hampson et al., , 2000Iuvone et al., 2004) properties. Additionally, CBD presents low toxicity, high tolerability and the lack of psychoactive effects (Bergamaschi et al., 2011;Carlini and Cunha, 1981;Cunha et al., 1980), supporting its safe pharmacological use. ...
Epilepsy is a neurological disorder characterized by the presence of seizures and neuropsychiatric comorbidities. Despite the number of antiepileptic drugs, one-third of patients did not have their seizures under control, leading to pharmacoresistance epilepsy. Cannabis sativa has been used since ancient times in Medicine for the treatment of many diseases, including convulsive seizures. In this context, Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been a promising compound for treating epilepsies due to its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. In this review, we summarize evidence of the CBD anticonvulsant activities present in a great diversity of animal models. Special attention was given to behavioral CBD effects and its translation to human epilepsies. CBD anticonvulsant effects are associated with a great variety of mechanisms of action such as endocannabinoid and calcium signaling. CBD has shown effectiveness in the clinical scenario for epilepsies, but its effects on epilepsy-related comorbidities are scarce even in basic research. More detailed and complex behavioral evaluation about CBD effects on seizures and epilepsy-related comorbidities are required.
... CBD has been shown to reduce oxidative stress by scavenging free radicals and modulating the activity of antioxidant enzymes [8]. Additionally, it protects against oxidative damage in various cell types, including neurons, which is beneficial for neurodegenerative disorders like Alzheimer's and Parkinson's diseases [9][10][11][12]. The antioxidant properties of the phytocannabinoids and their ability to prevent low-density lipoprotein (LDL) oxidation have also been previously reported [13]. ...
In recent years, extensive research has focused on cannabidiol (CBD), a well-studied non-psychoactive component of the plant-derived cannabinoids. CBD has shown significant therapeutic potential for treating various diseases and disorders, including antioxidants and anti-inflammatory effects. Due to the promising therapeutic effect of CBD in a wide variety of diseases, synthetic derivatization of this compound has attracted the attention of drug discovery in both industry and academia. In the current research, we focused on the derivatization of CBD by introducing Schiff base moieties, particularly (thio)-semicarbazide and aminoguanidine motifs, at the 3-position of the olivetolic ring. We have designed, synthesized, and characterized new derivatives based on CBD’s framework, specifically aminoguanylhydrazone- and (thio)-semicarbazones-CBD-aldehyde compounds. Their antioxidant potential was assessed using FRAP and DPPH assays, alongside an evaluation of their effect on LDL oxidation induced by Cu2+ and AAPH. Our findings suggest that incorporating the thiosemicarbazide motif into the CBD framework produces a potent antioxidant, warranting further investigation.
... In the glutamatergic-based mechanism there is the involvement of cannabinoid receptors in the reduction of reactive oxygen species (ROS), while THC (1) and CBD (2) seem to reduce toxicity independently of these receptors. 26 A possible anti-inflammatory activity was also suggested despite the complexity and multifactorial aspects of this condition since some studies identified that CBD (2) could effectively suppress TNF production. Regarding cannabinoid receptors, both anticonvulsant and anti-inflammatory activities seemed to be stereospecific, once (+)-CBD and its analogues favorably bind to CB1 and CB2 receptors, as opposed to (-)-CBD (2) that could not bind to either of them. ...
Cannabidiol is a metabolite present in Cannabis with several pharmacological properties, including neuroprotection, anti-convulsive, antimicrobial, antinociceptive, and anti-inflammatory. Although these activities are promising for drug development and clinical uses, the neuroprotective action is the most investigated, while the anti-inflammatory and antinociceptive mechanisms are not fully known. Therefore, this brief review aims to report the knowledge advances over the last 3 decades regarding the anti-inflammatory and anti-nociceptive/analgesic properties of cannabidiol and its derivatives or analogues designed as novel drug candidates. Recent studies of the mechanisms of action underlying the anti-inflammatory effects of cannabidiol have revealed its interaction with different inflammatory mediators, including cannabinoid receptor 1 and cyclooxygenase 2, among others. On the other hand, there is a lack of information related to the analgesic activity of cannabidiol, with some reports pointing out the involvement only of transient receptor potential vanilloid receptors. In addition, several cannabidiol derivatives and structural analogues with anti-inflammatory and antinociceptive activities have been described, but their mechanisms of action have not yet been fully elucidated. Therefore, it is clear that greater efforts are still needed to unravel the mechanisms involved in such activities of great interest in drug discovery.
... The absorption spectrum of CBD (220-280 nm) is within the UVC-UVB light spectrum, 4,20 indicating that CBD could function as a photoprotective agent, preventing the interaction of UVC and UVB radiation with the skin. In addition, the antioxidant activity of CBD 21,22 prevents free radical damage associated with UVR (ultraviolet radiation). ...
The thermodynamic characteristics, antioxidant potential, and photoprotective benefits of full‐spectrum cannabidiol (FS‐CBD) against UVB‐induced cellular death were examined in this study. In silico analysis of CBD showed antioxidant capacity via proton donation and UV absorption at 209.09, 254.73, and 276.95 nm, according to the HAT and SPLET methodologies. FS‐CBD protected against UVB‐induced bacterial death for 30 min. FS‐CBD protected against UVB‐induced cell death by 42% (1.5 μg/mL) and 35% (3.5 μg/mL) in an in vitro keratinocyte cell model. An in vivo acute irradiated CD‐1 et/et mouse model (UVB‐irradiated for 5 min) presented very low photoprotection when FS‐CBD was applied cutaneously, as determined by histological analyses. In vivo skin samples showed that FS‐CBD regulated inflammatory responses by inhibiting the inflammatory markers TGF‐β1 and NLRP3. The docking analysis showed that the CBD molecule had a high affinity for TGF‐β1 and NLRP3, indicating that protection against inflammation might be mediated by blocking these proinflammatory molecules. This result was corroborated by the docking interactions between CBD and TGF‐β1 and NLRP3, which resulted in a high affinity and inhibition of both proteins The present work suggested a FS‐CBD moderate photoprotective agent against UVB light‐induced skin damage and that this effect is partially mediated by its anti‐inflammatory activity.
... At higher concentrations, CBD can activate the PPAR-γ receptors and vanilloid receptors (TRPV1 and TRPV2), contributing to its antioxidant effects. Research studies have underscored CBD's efficacy as a potent antioxidant, suggesting its promising role in various pathological conditions characterized by oxidative stress [42]. ...
Phytocannabinoids, a diverse group of naturally occurring compounds extracted from the Cannabis plant, have attracted interest due to their potential pharmacological effects and medicinal uses. This comprehensive review presents the intricate pharmacological profiles of phytocannabinoids while exploring the diverse impacts these substances have on biological systems. From the more than one hundred cannabinoids which were identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids. CBD is a non-psychoactive compound, which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions. THC, known for its psychoactive effects, possesses analgesic and antiemetic properties, contributing to its therapeutic potential. In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN). The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways. The complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches and lays the groundwork for further developments in the field of cannabinoid-based medicine. This review summarizes the state of the field, points out information gaps, and emphasizes the need for more studies to fully realize the therapeutic potential of phytocannabinoids.
... CBD is also an adenosine receptor (AR) agonist [71], which promotes adenosine-mediated signal transduction, prevents oxidative stress, and exerts antiinflammatory, anti-epileptic, and anti-anxiety effects. Crucially, CBD exerts anti-inflammatory, neuroprotective, and anti-cancer activity in a peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent manner [72][73][74][75][76][77][78]. In terms of anti-inflammatory effects, CBD suppresses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-induced inflammation through a PPAR-γ-dependent signaling inhibition [79]. ...
Background
The NLRP3 inflammasome is a vital player in the emergence of inflammation. The priming and activation of the NLRP3 inflammasome is a major trigger for inflammation which is a defense response against adverse stimuli. However, the excessive activation of the NLRP3 inflammasome can lead to the development of various inflammatory diseases. Cannabidiol, as the second-most abundant component in cannabis, has a variety of pharmacological properties, particularly anti-inflammation. Unlike tetrahydrocannabinol, cannabidiol has a lower affinity for cannabinoid receptors, which may be the reason why it is not psychoactive. Notably, the mechanism by which cannabidiol exerts its anti-inflammatory effect is still unclear.
Methods
We have performed a literature review based on published original and review articles encompassing the NLRP3 inflammasome and cannabidiol in inflammation from central databases, including PubMed and Web of Science.
Results and conclusions
In this review, we first summarize the composition and activation process of the NLRP3 inflammasome. Then, we list possible molecular mechanisms of action of cannabidiol. Next, we explain the role of the NLRP3 inflammasome and the anti-inflammatory effect of cannabidiol in inflammatory disorders. Finally, we emphasize the capacity of cannabidiol to suppress inflammation by blocking the NLRP3 signaling pathway, which indicates that cannabidiol is a quite promising anti-inflammatory compound.
... Cannabidiol (CBD) is a metabolite of tetrahydrocannabinol, with potential antioxidant, immunosuppressive and anti-inflammatory properties (Pubchem 2015). Hampson et al. (2000) reported that the antioxidant activity of cannabidiol found in hempseed was superior to α-tocopherol and ascorbate. ...
Hemp seed cake (HSC) (Cannabis sativa L.) is a rich source of polyunsaturated fatty acids, high-quality proteins and essential amino acids. The aim of this study was to evaluate the effects of dietary inclusion of HSC on growth performance, meat quality traits, fatty acids profile and oxidative status, and intestinal morphology in slow-growing broilers. A total of 180 male slow-growing broilers were randomly assigned to one of three dietary treatments containing different levels of HSC: 0 (HSC0), 5 (HSC5) or 10% (HSC10). Birds were slaughtered at 49 days of age: breast and thigh muscles were analysed and duodenum mucosa histomorphological features were evaluated. Regardless the level of HSC inclusion, no differences among groups were found for performance and meat quality traits. The thigh and breast fatty acid profile were significantly improved in both HSC groups, with an increase of the long chain fatty acids of n-3 series and decrease of n-6/n-3 ratio. The HSC diets lowered the MDA concentration and lipid hydroperoxides in breast meat. Histomorphometrical analysis revealed a significant increase in villus height, surface area and villus/crypt ratio, with a decrease of crypt depth, suggesting that dietary supplementation with HSC may boost intestinal health status in poultry. In conclusion, dietary HSC did not affect performance, carcass traits and meat quality, while it positively influenced the lipid profile of meat, and improved the oxidative status and gut health, thus representing a valuable and sustainable alternative ingredient in broiler diet.
... Therapeutic potential of the cannabinoid and endocannabinoid system after hypoxia-ischemia Several studies have proposed the involvement of the cannabinoid and endocannabinoid systems in a variety of activities, including the modulation of calcium homeostasis and excitability, regulation of immune and inflammatory responses (Klein, 2005), activation of cytoprotective signalling pathways (Pacher et al., 2006), and modulation of synaptic plasticity, excitatory glutamatergic transmissions (Freund et al., 2003) and their hypothermic and antioxidant properties (Hampson et al., 2000), although the precise neuroprotective mechanisms of cannabis are not fully understood. In this context, the cannabinoid and endocannabinoid system may additionally serve as a crucial neuroprotective mechanism in both acute and chronic neuronal hypoxic-ischaemic brain injury. ...
Neonatal hypoxic-ischaemic events, which can result in long-term neurological impairments or even cell death, are among the most significant causes of brain injury during neurodevelopment. The complexity of neonatal hypoxic-ischaemic pathophysiology and cellular pathways make it difficult to treat brain damage; hence, the development of new neuroprotective medicines is of great interest. Recently, numerous neuroprotective medicines have been developed to treat brain injuries and improve long-term outcomes based on comprehensive knowledge of the mechanisms that underlie neuronal plasticity following hypoxic-ischaemic brain injury. In this context, understanding of the medicinal potential of cannabinoids and the endocannabinoid system has recently increased. The endocannabinoid system plays a vital neuromodulatory role in numerous brain regions, ensuring appropriate control of neuronal activity. Its natural neuroprotection against adult brain injury or acute brain injury also clearly demonstrate the role of endocannabinoid signalling in modulating neuronal activity in the adult brain. The goal of this review is to examine how cannabinoid-derived compounds can be used to treat neonatal hypoxic-ischaemic brain injury and to assess the critical function of the endocannabinoid system and its potential for use as a new neuroprotective treatment for neonatal hypoxic-ischaemic brain injury.
... From this observation, it can be concluded that CBD per se does not affect body temperature. This conclusion is consistent with the observations of other researchers [73]. ...
The study aimed to explore in vivo the influence of cannabidiol (CBD) on the development of alcohol tolerance in rats. Rats were treated with ethanol (3.0 g/kg, i.p.) and CBD (20 mg/kg, p.o.) for nine successive days, and rectal body temperature, sedation (sleeping time), and blood alcohol concentration (BAC) were measured. In the prefrontal cortex, hippocampus, and striatum, the cannabinoid (CB1R and CB2R) and dopaminergic (DRD1, DRD2, DRD4, DRD5) receptors’ mRNA level changes were analyzed using the quantitative RT-PCR method. CBD inhibited the development of tolerance to the hypothermic and sedative action of alcohol, coupled with BAC elevation. On a molecular level, the most pronounced effects of the CBD + ethanol interaction in the striatum were observed, where CBD reversed the downregulation of CB2R gene transcription caused by ethanol. For CB1R, DRD1, and DRD2 mRNAs, the CBD + ethanol interaction produced opposite effects than for CB2R ones. In turn, for the transcription of genes encoding dopaminergic receptors, the most potent effect of alcohol as CBD occurred in the hippocampus. However, the combined CBD and alcohol administration showed the same effect for each substance administered separately. Since tolerance is considered a prelude to drug addiction, obtained results allow us to emphasize the thesis that CBD can inhibit the development of alcohol dependence in rats.
... The C. sativa possesses broad ranges of therapeutic potential against nerve disorders, Tourette's syndrome, pain, inflammation, multiple sclerosis, nausea and vomiting, colitis, sleep disorders, schizophrenia, Alzheimer's and Parkinson's disease (Allan et al., 2018;Bonini et al., 2018;Hasenoehrl et al., 2017;Hill et al., 2012;Mastinu et al., 2021;Premoli et al., 2019;Rice and Cameron, 2018;Whiting et al., 2015). The cannabinoids also showed pharmacological activities such as anticancer, antibacterial, antidepressant, antifungal, antioxidant, anticonvulsive, immunosuppressive properties and antierythemic effects (Al Khoury et al., 2021Hampson et al., 2000Kopustinskiene et al., 2022;Marsicano et al., 20022). Recently, it has also been demonstrated that high CBD/low THC-rich C. sativa extracts suppress the expression of host entry proteins (ACE2 and TMPRSS2) of SARS-CoV-2 (Wang et al., 2022). ...
Cannabis sativa L., an industrially important plant, is a source of medicinally important cannabidiol (CBD) and Δ9-tetrahydrocannabinol (D9-THC). C. sativa is mainly a dioecious plant. However, rarely monoecious plants with hermaphrodite inflorescence were also reported naturally. The monoecious C. sativa plant research is still inadequate compared to dioecious plants. The present study aims to evaluate four monoecious C. sativa accessions (CH-1, CH-2, CH-3 and CH-4) for organ-specific (leaves, male flowers, and female flowers) distribution of trichomes, histochemical localization phytocannabinoids in trichomes, and phytocannabinoids content and antioxidant potential. Results showed that morphological traits differed in all the accessions (p < 0.05). The phytocannabinoids are produced in capitate sessile and capitate stalked glands. The highest density of phytocannabinoids synthesizing glands was found in female flowers (46.67–57.01 mm-2), followed by male flowers (30.73–33.98 mm-2) and leaves (12.37–23.64 mm-2) in different monoecious accessions. The female flower produces the maximum content of total phytocannabinoids. In the same way, the female flower shows the highest free radical scavenging activity and total antioxidant capacity compared to other studied plant parts. In conclusion, the CH-1 accession is superior to the other in terms of morphological characters, phytocannabinoids synthesizing glands and cannabinoids content. Moreover, the levels of phytocannabinoids are higher in female flowers than the male flowers and leaves. The approach towards monoecious accession with higher cannabinoid content has enormous potential for industrial applications.
... Cannabidiol (CBD), a passive (i.e., non-psychoactive) ingredient in cannabis (Burstein 2015), has previously been shown to have antioxidant and anti-inflammatory properties (Gallily et al. 2018;Atalay et al. 2019), therefore possibly reducing inflammation in certain pathologies mentioned above. However, whether the same anti-inflammatory properties are embodied by cannabis more broadly (Hampson et al. 2000;Marsicano et al. 2002;Centonze et al. 2007) will be important to identify in future studies. ...
Rationale and objectives
Cannabis use is often associated with the use of other psychoactive substances, which is subsequently linked to an increased risk for addiction. While there is a growing body of neuroimaging literature investigating the cognitive effect of long-term cannabis use, very little is known about the potential additive effects of cannabis polysubstance use.
Methods
Fifty-six adults composed of 18 polysubstance users (i.e., cannabis plus at least one other illicit substance), 19 cannabis-only users, and 19 nonusers completed a visuospatial attention task while undergoing magnetoencephalography. A data-driven approach was used to identify oscillatory neural responses, which were imaged using a beamforming approach. The resulting cortical regions were probed for group differences and used as seeds for whole-brain connectivity analysis.
Results
Participants exhibited robust theta, alpha, beta, and gamma responses during visuospatial processing. Statistical analyses indicated that the cannabis-only group had weaker occipital theta relative to the nonusers, and that both polysubstance and cannabis-only users had reduced spontaneous gamma in the occipital cortices during the pre-stimulus baseline period relative to nonusers. Finally, functional connectivity analyses revealed that polysubstance users had sharply reduced beta connectivity between occipital and prefrontal, as well as occipital and left temporal cortices.
Conclusions
Cannabis use should be considered in a polysubstance context, as our correlational design suggests differences in functional connectivity among those who reported cannabis-only versus polysubstance use in occipital to prefrontal pathways critical to visuospatial processing and attention function. Future work should distinguish the effect of different polysubstance combinations and use more causal designs.
... CBD has showed anti-inflammatory [17,18], immunomodulatory [19], and neuroprotective [20] effects. Regarding the latter, CBD's anti-oxidant properties [17,21,22] seems to reduce apoptosis and favors neuroprotective effects and cell viability [23,24], effects that can be therapeutically explored. ...
The use of Cannabis for medicinal purposes has been documented since ancient times, where one of its principal cannabinoids extracted from Cannabis sativa, cannabidiol (CBD), has emerged over the last few years as a promising molecule with anti-seizure potential. Here, we present an overview of recent literature pointing out CBD’s pharmacological profile (solubility, metabolism, drug-drug interactions, etc.,), CBD’s interactions with multiple molecular targets as well as advances in preclinical research concerning its anti-seizure effect on both acute seizure models and chronic models of epilepsy. We also highlight the recent attention that has been given to other natural cannabinoids and to synthetic derivatives of CBD as possible compounds with therapeutic anti-seizure potential. All the scientific research reviewed here encourages to continue to investigate the probable therapeutic efficacy of CBD and its related compounds not only in epilepsy but also and specially in drug-resistant epilepsy, since there is a dire need for new and effective drugs to treat this disease.
... Birkaç çalışma, CB2 reseptörlerinin uyarılmasının migroglial aktivasyonu azalttığını ve transgenik farelerde Ab düzeylerini düşürdüğünü göstermiştir (201). ...
... It is also used for the treatment of several skin conditions, including psoriasis, atopic dermatitis, skin cancer, and hair growth disorders [19][20][21]. CBD has also demonstrated anti-inflammatory [22,23], anti-oxidative and wound healing effects [24][25][26][27]. CBG acts as the precursor molecule for the most abundant phytocannabinoids. ...
In this study, drug carrier nanoparticles comprised of Pluronic-F127 and cannabidiol (CBD) or cannabigerol (CBG) were developed, and their wound healing action was studied. They were further incorporated in 3D printed films based on sodium alginate. The prepared films were characterized morphologically and physicochemically and used to evaluate the drug release profiles of the nanoparticles. Additional studies on their water loss rate, water retention capacity, and 3D-printing shape fidelity were performed. Nanoparticles were characterized physicochemically and for their drug loading performance. They were further assessed for their cytotoxicity (MTT Assay) and wound healing action (Cell Scratch Assay). The in vitro wound-healing study showed that the nanoparticles successfully enhanced wound healing in the first 6 h of application, but in the following 6 h they had an adverse effect. MTT assay studies revealed that in the first 24 h, a concentration of 0.1 mg/mL nanoparticles resulted in satisfactory cell viability, whereas CBG nanoparticles were safe even at 48 h. However, in higher concentrations and after a threshold of 24 h, the cell viability was significantly decreased. The results also presented mono-disperse nano-sized particles with diameters smaller than 200 nm with excellent release profiles and enhanced thermal stability. Their entrapment efficiency and drug loading properties were higher than 97%. The release profiles of the active pharmaceutical ingredients from the films revealed a complete release within 24 h. The fabricated 3D-printed films hold promise for wound healing applications; however, more studies are needed to further elucidate their mechanism of action.
... THC and CBD protected rat neuronal cell cultures against hydroperoxide-induced oxidative damage (EC 50 of 2-4 µM) at a degree comparable to that of ascorbate and tocopherol [40]. Moreover, both cannabinoids were effective as direct antioxidants, protecting rat cortical neuron cultures against the damage of toxic levels of the neurotransmitter glutamate [61]. THC and CBD, at submicromolar concentrations, prevented the oxidative cell death of B lymphoblastoid cells and fibroblasts in serum-deprived medium, via direct antioxidant action [62]. ...
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 neuroprotective activity of CBD has been attributed in part to its anti-oxidative activity [190,191]. Based on its immunomodulatory activities, CBD has been implicated in the treatment of various autoimmune diseases [14,21], and its anti-nociceptive activity was found to be beneficial in relieving chronic pain [192]. In addition, CBD has potential uses in psychiatry due to its neuromodulatory activities in the brain that control recognition, emotional and behavioral responses [111,193,194]. ...
Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
... [9] Tetrahydrocannabinol and its analogs have been shown to reduce glutamate toxicity by activating cannabinoid receptors and decreasing calcium flow through voltage-sensitive calcium channel cavities. [10] However, while many cannabinoids have been shown to have neuroprotective effects in various models of neurotoxicity, the mechanisms are not fully understood. The most important thing that is currently being understood is how the positive feedback produced by the ECS via receptors in response to oxidative stress will produce results in various situations. ...
Cannabis sativa L. subspecies sativa is a subspecies of the genus Cannabis (Cannabaceae), also known as industrial hemp. It is a herbaceous and double-jawed plant. Tetrahydrocannabinol (THC), a psychoactive compound found in cannabis plants, and the non-psychoactive cannabidiol (CBD) are essential compounds in industry and medicine. These compounds are very similar to endocannabinoids, which are found in the human body. As a result, both compounds have the potential to interact with the body's endocannabinoid system. They exhibit chemical activity in areas affected by oxidative stress, such as the cardiovascular system, muscle development, liver and lung function, reproductive function, metabolism, neurological activities, and cell aging. Since the human body's free radical and antioxidant levels are destabilized, antioxidants fail to neutralize free radicals, resulting in oxidative damage, i.e. a stress effect. This balance in the body can be influenced by compounds like THC and CBD acting on cellular receptors. Thus, the occurrence of various diseases is observed. This review examined the effect of the active substances in the cannabis plant on oxidative stress and the diseases that develop as a result of this stressful situation.
... In vitro and in vivo research done gives a preliminary insight of Cannabis in modulating immune system, as a bronchodilator and in stopping the entry, replication of SARS-CoV-2. [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] The base of the formulation Cow-Ghee itself enhances Ojas (immune booster), [33] conductive to Rasa dhatu (blood plasma) and Sukra dhatu (tissues of reproductive system) [81] commonly consumed for its properties viz-Jwaraghna (antipyretic), Dipana (appetiser), [33] Bala (strength promoting), Cakshushya (wholesome for eyes), Visha hara (removes toxins from body). [32] Ghee in general has Swarya (Voice promoting), Ayushya (longevity), Vayahsthapana (anti-ageing) properties and acts as Rakshoghna (ward off various infectious microorganisms). ...
Covid-19 is an infectious disease caused by airborne virus SARS-CoV-2 was declared as global pandemic by WHO on 11th March 2020. Medical community is facing challenges in developing anti-viral medicines and vaccines, as various mutations in novel corona virus are causing hurdles in formulating an effective remedy. Environment is crowded with many microorganisms including pathogens like virus, bacteria, fungi, parasites etc. Hence immunomodulation (redirecting immunity to natural course) is the best way to tackle such pandemic situations. Ayurveda, the Indian system of medicine is the oldest science known to mankind has quite a few medicines and therapies to improve immune system. Vijaya (Cannabis sativa Linn.) is the one of the Divyaushadhi (celestial plant) mentioned in Ayurveda having Rasayana (Rejuvenative), Vyavayi (fast diffusing) and Yogavahi (synergetic) attributes. On the basis of Ayurvedic principles we made an attempt to interpret the immune modulating aspect of a rare Cannabis formulation Vijaya Ghrita, presumed to be liposomal medication that has swift bio-enhancing ability. Ayurvedic properties of the ingredients of Vijaya Ghrita found in classical texts could treat most of the symptoms of Covid-19 disease and the contemporary scientific researches of Cannabis phytochemicals on Covid-19 have shown significant results in reducing the pro-inflammatory cytokine storm, also to certain range halt the entry, replication of SARS-CoV-2.
... The potent anti-inflammatory and immunomodulatory effects of CBD, combined with its low toxicity, make cannabis an upand-coming therapeutic candidate for various inflammatory diseases and associated pain disorders (Esposito et al. 2013). Additionally, previous studies showed the higher protection and effectiveness of CBD than vitamin E, C, and a-tocopherol (Hampson et al. 2006). Such protective effect of CBD is mainly mediated by scavenging free radicals, regulating oxidative stress markers (Atalay et al. 2019). ...
Aluminum phosphide (AlP) poisoning is common in many countries responsible for high mortality. The heart is the main target organ in AlP poisoning. Several studies have reported the beneficial effects of cannabidiol (CBD) in reducing heart injuries. This study aimed to investigate the possible protective effect of CBD on cardiac toxicity caused by AlP poisoning. Study groups included almond oil, normal saline, sole CBD (100 µg/kg), AlP (11.5 mg/kg), and four groups of AlP + CBD (following AlP gavage, CBD administrated at doses of 5, 25, 50, and 100 μg/kg via intravenous (iv) injection). Thirty minutes after AlP treatment, an electronic cardiovascular device (PowerLab) was used to record electrocardiographic (ECG) changes, heart rate (HR), and blood pressure (BP) for three hours. Cardiac tissue was examined for the activities of mitochondrial complexes, ADP/ATP ratio, the release of cytochrome C, mitochondrial membrane potential (MMP), apoptosis, oxidative stress parameter, and cardiac biomarkers at 12 and 24 hours time points. AlP administration caused abnormal ECG, decreased HR, and BP. AlP also significantly reduced mitochondrial complex I and IV activity and ADP/ATP ratio. The level of cytochrome C release, apoptosis, oxidative stress, and cardiac biomarkers was considerably increased by AlP, which was compensated following CBD administration. CBD was able to improve hemodynamic function to some extent in AlP poisoned rats. CBD restored ATP levels and mitochondrial function and decreased oxidative damage and thus, prevented the heart cells from entering the apoptotic stage. Further clinical trials are needed to explore any possible benefits of CBD in AlP-poisoned patients.
... Despite having some shreds of evidence in the previous studies [46,100,101], the complex functions of cannabinoids relate to the defensive role toward biotic and abiotic stresses are not clear. Among the cannabinoids, THC and CBD were most discussed for having their antioxidant properties [102]. Earlier, THC, THCA, CBD, and CBDA were predicted as stress indicators along with some other secondary metabolites in the hemp plant under controlled drought stress [100]. ...
Abstract: Hemp adaptability through physiological and biochemical changes was studied under 10 LED light spectra and natural light in a controlled aeroponic system. Light treatments were imposed on 25 days aged seedlings for 16 h daily (300 µmol m −2 s −1) for 20 days. Plant accumulated highest Cannabidiol (CBD) in R7:B2:G1 light treatment, with relatively higher photosynthetic rate and lower reactive oxygen species, total phenol content, total flavonoid content, DPPH radical scavenging capacity , and antioxidant enzymatic activities. Tetrahydrocannabinol (THC) also accumulated at a higher level in white, R8:B2, and R7:B2:G1 light with less evidence of stress-modulated substances. These results indicated that CBD and THC have no or little relation with light-mediated abiotic stress in hemp plants. On the contrary, Tetrahydrocannabinolic acid (THCA) was accumulated higher in R6:B2:G1:FR1 and R5:B2:W2:FR1 light treatment along with lower photosynthetic rate and higher reactive oxygen species , total phenol content, total flavonoid content, DPPH radical scavenging capacity, and antioxidant enzymatic activities. However, Cannabidiolic acid (CBDA) was accumulated higher in R6:B2:G1:FR1 light treatment with higher stress-modulated substances and lower physiological traits. CBDA was also accumulated higher in R8:B2 and R7:B2:G1 light treatments with less evidence of stress-modulated substances. Besides, Greenlight influenced CBD and CBDA synthesis where FR and UV-A (along with green) play a positive and negative role in this process. Overall, the results indicated that the treatment R7:B2:G1 enhanced the medicinal cannabinoids most, and the role of THCA as a stress marker is more decisive in the hemp plant than in other cannabinoids under attributed light-mediated stress.
... The assertion of potential therapeutic actions of CBD is based on pre-clinical data, limited clinical data and ongoing human clinical trials. Preclinical studies show that CBD has antioxidant [27,28] anti-inflammatory [27], anti-convulsant [29,30], neuroprotective [31], and anti-cancer properties [32]. CBD also shows potential as a therapeutic agent in cardiovascular [33], neurological, and neuropsychiatric disorders [26]. ...
Cannabidiol (CBD), the major non-intoxicating constituent of Cannabis sativa, has gained recent attention due to its putative therapeutic uses for a wide variety of diseases. CBD was discovered in the 1940s and its structure fully characterized in the 1960s. However, for many years most research efforts related to cannabis derived chemicals have focused on D9-tetrahydrocannabinol (THC). In contrast to THC, the lack of intoxicating psychoactivity associated with CBD highlights the potential of this cannabinoid for clinical drug development. This review details in vitro and in vivo studies of CBD related to the eye, the therapeutic potential of cannabidiol for various ocular conditions, and molecular targets and mechanisms for CBD-induced ocular effects. In addition, challenges of CBD applications for clinical ocular therapeutics and future directions are discussed.
... In a model of Alzheimer's disease-related neuroinflammation (intrahippocampal injection of the human amyloid-β in mice), CB1 agonists showed promising effects against neuronal tau hyperphosphorylation and behavioral impairments (36). Additionally, cannabinoids inhibit acetylcholinesterase and β amyloid aggregation, while agonism on CB1 and 2 receptors results in a significant increase of β amyloid clearance across the blood-brain barrier (37)(38)(39). Casajeros et al. (2013) noted that nabiximols reduced tangling of tau proteins in mice, improving dopamine metabolism, glial function and oxidative stress, as well as reduction in anxiety and self-injury (40). ...
Both phytocannabinoids (Δ9-tetrahydrocannabinol, cannabidiol) and synthetic derivatives (nabilone, dronabinol) showed therapeutic benefits in some neurological disorders. Cannabis inhalation was reported to attenuate several symptoms (rigidity, bradykinesia, tremor) in Parkinson’s disease. A significant reduction in monthly seizures in patients with epilepsy has been noted for cannabidiol, while administration of Δ9-tetrahydrocannabinol resulted in benefits on psychomotor agitation in patients suffering from Alzheimer’s disease. Although there are clinical studies supporting the use of cannabis preparations as adjuvant therapy in neurological disorders, more investigations are needed to assess their safety and efficacy.
... The antioxidant effect of CBD, evaluated in rat cortical neuron cultures, was not affected by the presence of 500 nmol/L of the selective CB 1 cannabinoid receptor antagonist SR-141716A in an in vitro preparation of ischemic injury and was higher than the effect of other antioxidants such as α-tocopherol and ascorbate in AMPA/kainate receptor toxicity assays. 12 In agreement with these findings, Hacke et al, 13 reported that the antioxidant activity of THC and CBD in pure and mixed solutions was comparable to that of well-known antioxidants such as ascorbic acid (AA), resveratrol (Resv), and (-)-epigallocatechin-3-gallate (EGCG). ...
Cannabidiol (CBD) is the second most abundant component of the Cannabis plant and is known to have effects distinct from Δ9 -tetrahydrocannabinol (THC). Many studies that examined the behavioral effects of CBD concluded that it lacks the psychotomimetic effects attributed to THC. However, CBD was shown to have a broad spectrum of effects on several conditions such as anxiety, inflammation, neuropathic pain, and epilepsy. It is currently thought that CBD engages different targets and hence CBD's effects are thought to be due to multiple molecular mechanisms of action. A well-accepted set of targets include GPCRs and ion channels, with the serotonin 5-HT1A receptor and the transient receptor potential cation channel TRPV1 channel being the two main targets. CBD has also been thought to target G protein-coupled receptors (GPCRs) such as cannabinoid and opioid receptors. Other studies have suggested a role for additional GPCRs and ion channels as targets of CBD. Currently, the clinical efficacy of CBD is not completely understood. Evidence derived from randomized clinical trials, in vitro and in vivo models and real-world observations support the use of CBD as a drug treatment option for anxiety, neuropathy, and many other conditions. Hence an understanding of the current status of the field as it relates to the targets for CBD is of great interest so, in this review, we include findings from recent studies that highlight these main targets.
... During many pathological conditions and diseases processes like age-related inflammatory and autoimmune diseases [7], asthma, atherosclerosis, cancer, chronic obstructive pulmonary disease, hypertension, ischemia/perfusion, diabetes, and HIV dementia [8], the cells of the body accumulate high levels of toxic reactive oxygen species (R.O.S.)/free radicals in comparison to antioxidants [9]. This imbalance can cause significant damage to cell structures [9]. ...
The Cannabis plant (Cannabis sativa L.) produces an estimated 545 chemical compounds of different biogenetic classes. In addition to economic value, many of these phytochemicals have medicinal and physiological activity. The plant is most popularly known for its two most prominent and most studied secondary metabolites— Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD). Both Δ9-THC and CBD have a wide therapeutic window across many ailments and form part of a class of secondary metabolites called cannabinoids—of which approximately over 104 exist. This review will focus on non-cannabinoid metabolites of Cannabis sativa that also have therapeutic potential, some of which share medicinal properties similar to those of cannabinoids. The most notable of these non-cannabinoid phytochemicals are flavonoids and terpenes. We will also discuss future directions in cannabis research and development of cannabis-based pharmaceuticals. Caflanone, a flavonoid molecule with selective activity against the human viruses including the coronavirus SARS-COV2, and certain cancers, is one of the most promising non-cannabinoid molecules that is being advanced into clinical trials. As validated by thousands of years of the use of cannabis for medicinal purposes, vast anecdotal evidence abounds on the medicinal benefits of the plant. These benefits are attributed to the many phytochemicals in this plant, including non-cannabinoids. The most promising non-cannabinoids with potential to alleviate global disease burdens are discussed.
... During many pathological conditions and diseases processes like age-related inflammatory and autoimmune diseases [7], asthma, atherosclerosis, cancer, chronic obstructive pulmonary disease, hypertension, ischemia/perfusion, diabetes, and HIV dementia [8], the cells of the body accumulate high levels of toxic reactive oxygen species (R.O.S.)/free radicals in comparison to antioxidants [9]. This imbalance can cause significant damage to cell structures [9]. ...
The Cannabis plant (Cannabis sativa L.) produces an estimated 545 chemical compounds of different biogenetic classes. In addition to economic value, many of these phytochemicals have medicinal and physiological activity. The plant is most popularly known for its two most prominent and most studied secondary metabolites— Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD). Both Δ9-THC and CBD have a wide therapeutic window across many ailments and form part of a class of secondary metabolites called cannabinoids—of which approximately over 104 exist. This review will focus on non-cannabinoid metabolites of Cannabis sativa that also have therapeutic potential, some of which share medicinal properties similar to those of cannabinoids. The most notable of these non-cannabinoid phytochemicals are flavonoids and terpenes. We will also discuss future directions in cannabis research and development of cannabis-based pharmaceuticals. Caflanone, a flavonoid molecule with selective activity against the human viruses including the coronavirus SARS-COV2, and certain cancers, is one of the most promising non-cannabinoid molecules that is being advanced into clinical trials. As validated by thousands of years of the use of cannabis for medicinal purposes, vast anecdotal evidence abounds on the medicinal benefits of the plant. These benefits are attributed to the many phytochemicals in this plant, including non-cannabinoids. The most promising non-cannabinoids with potential to alleviate global disease burdens are discussed.
... Despite having some shreds of evidence in the previous studies 45,88,89 , the complex functions of cannabinoids relate to the defensive role toward biotic and abiotic stresses are not clear. Among the cannabinoids, THC and CBD were most discussed for having their antioxidant properties 90 . Earlier increasing of THC, THCA, CBD, and CBDA were predicted as stress indicators along with some other secondary metabolites in hemp plant under controlled drought stress 89 . ...
Hemp adaptability through physiological and biochemical changes was studied under 10 LED light spectra and natural light in a controlled aeroponic system. Light treatments were imposed on 25 days aged seedlings for 16 hours daily (300 µmol m-2s-1) for 20 days. Plant accumulated highest Cannabidiol (CBD) in R7:B2:G1 light treatment, with relatively higher photosynthetic rate and lower reactive oxygen species, total phenol content, total flavonoid content, DPPH radical scavenging capacity, and antioxidant enzymatic activities. Tetrahydrocannabinol (THC) also accumulated higher in white, R8:B2, and R7:B2:G1 light with less evidence of stress modulated substances. These results indicated that CBD and THC have no or little relation with light-mediated abiotic stress in hemp plants. On the contrary, Tetrahydrocannabinolic acid (THCA) was accumulated higher in R6:B2:G1:FR1 and R5:B2:W2:FR1 light treatment along with lower photosynthetic rate and higher reactive oxygen species, total phenol content, total flavonoid content, DPPH radical scavenging capacity, and antioxidant enzymatic activities. However, Cannabidiolic acid (CBDA) was accumulated higher in R6:B2:G1:FR1 light treatment with higher stress modulated substances and lower physiological traits. CBDA was also accumulated higher in R8:B2 and R7:B2:G1 light treatments with less evidence of stress modulated substances. Besides, Greenlight influenced in CBD and CBDA synthesis where FR and UV-A (along with green) play a positive and negative role in this process, respectively. These results indicate that the role of THCA as a stress marker is more decisive in hemp plant than other cannabinoids under attributed light-mediated stress.
... Beside antioxidant activities (e.g. Hampson et al. 1998Hampson et al. /2000 one common feature in cannabis anticancer activity is that the cytotoxic and apoptotic activity observed in several cancer cell lines in vitro surpass the effect in healthy tissues. This is reported for THC (e.g. ...
Cannabis is used as a co-medication by patients with cancer or chronic inflammatory diseases. Anti-inflammatory effects of Δ9-tetrahydrocannabinol (THC) and other cannabinoids are frequently linked to the modulation of the Nuclear Factor kappaB (NF-KB). Advantages of using whole plant preparations have also been reported. The composition of preparations such as traditional hydroethanolic cannabis extracts (CE) varies due to the type of plant and preparation. This dissertation aimed to contribute insights into chemical standardisation and pharmacological profiling as part of a European Project developing CE medicines. The chemical profile of CE from different starting materials was determined using HPLC and 1H-NMR. Their pharmacological properties were measured as the ability to modulate the activation of NF-KB in IL-6 reporter gene stably transfected HeLa cells, to induce in vitro cytotoxicity in cancer cell lines (MTT-assay) and to activate caspase 3/7. The effect of pure cannabinoids and their combinations with plant phenolics and classical anti-inflammatory/cytotoxic drugs was also investigated. The HPLC/NMR profiles showed cannabinoid dominance even in polar extracts and a substantial portion of cannabinoid acids depending on CE age and storage. Markers for standardisation indicating plant type, solvent and stability -such as the ratio between neutral and carboxylated cannabinoids- are proposed. CE toxicity correlated with the total cannabinoid but not necessarily the THC content. Also all main pure phytocannabinoids proved to be equally toxic. Some CE were more toxic than pure phytocannabinoids, other CE reduced the effects of the compounds alone. In most cases toxicity correlated with the effect on NF-KB activation and also with the caspase 3/7 activation indicating apoptotic signalling. It appears also that the NF-KB activity of cannabinoids/CE is neither CB1 nor CB2 receptor dependent. The results show that there is a strong link between NF-KB and the toxic effect of cannabis in cancer cell lines. The in vitro effect of CE can differ from that of pure cannabinoids and is more influenced by factors other than the chemotype. Thus standardised CE of plants with predominantly non-psychotropic cannabinoids such as cannabidiol or cannabigerol may be as useful as traditional THC-type derived CE for the co-treatment in cancer and inflammatory diseases.
... Tetrahydrocannabinol (THC) is the major cannabinoid present in hempseed. These cannabinoids are potent lipophilic antioxidants and has been used for various therapeutic purposes from ancient times (Hampson et al. 2000). It is also a rich source of vitamin E. ...
... Although the risks associated with THC use in adolescence have been a topic of significant debate, substantial evidence has suggested that THC is a potent antioxidant with neuroprotective properties Hampson et al., 2000). In this study, RmTBI affected 4/6 of the behaviours examined, with therapeutic administration of THC following RmTBI producing beneficial outcomes in 3 of these measures. ...
The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serve as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-Tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague Dawley rats were randomly assigned to receive Δ9-Tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens, and prefrontal cortex, were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-Tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinoladministration following RmTBI was beneficial to 3 of the 6 behavioral outcomes affected by injury (reducing anxiety and depressive like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt, and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-Tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-Tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.
... Many studies on experimental animal models provide evidence that the brain is susceptible to alcohol toxicity, especially in the cerebral cortex and hippocampus [37][38][39][40][41]. Alcohol enters the nervous system and increases intracellular ROS, leading to apoptosis of hippocampal neurons, which in turn leads to cognitive and memory impairment and neurodegenerative diseases, such as alcoholic-associated dementia [42][43][44][45]. Earlier studies have shown that the main cause of alcoholic learning and memory impairments is damage to the hippocampus by ROS [43,46,47]. Therefore, exploring the mechanism of learning and memory impairment induced by apoptosis of hippocampal neurons with alcohol, and understanding the relationship among ROS, mitochondrial, antioxidant system, and neuronal cell apoptosis, can provide potential therapeutic targets for alcoholic brain damage. ...
Excessive alcohol intake can significantly reduce cognitive function and cause irreversible learning and memory disorders. The brain is particularly vulnerable to alcohol-induced ROS damage; the hippocampus is one of the most sensitive areas of the brain for alcohol neurotoxicity. In the present study, we observed significant increasing of intracellular ROS accumulations in Peroxiredoxin II (Prx II) knockdown HT22 cells, which were induced by alcohol treatments. We also found that the level of ROS in mitochondrial was also increased, resulting in a decrease in the mitochondrial membrane potential. The phosphorylation of GSK3β (Ser9) and anti-apoptotic protein Bcl2 expression levels were significantly downregulated in Prx II knockdown HT22 cells, which suggests that Prx II knockdown HT22 cells were more susceptible to alcohol-induced apoptosis. Scavenging the alcohol-induced ROS with NAC significantly decreased the intracellular ROS levels, as well as the phosphorylation level of GSK3β in Prx II knockdown HT22 cells. Moreover, NAC treatment also dramatically restored the mitochondrial membrane potential and the cellular apoptosis in Prx II knockdown HT22 cells. Our findings suggest that Prx II plays a crucial role in alcohol-induced neuronal cell apoptosis by regulating the cellular ROS levels, especially through regulating the ROS-dependent mitochondrial membrane potential. Consequently, Prx II may be a therapeutic target molecule for alcohol-induced neuronal cell death, which is closely related to ROS-dependent mitochondria dysfunction.
The partial legalization of cannabis in Germany in 2024 will affect both medical and recreational use of cannabis. Tetrahydrocannabinol (THC), the main psychoactive component of the cannabis plant, influences heart rate and blood pressure through the endocannabinoid system. Acute and chronic use can pose cardiovascular risks. There is evidence of a link between cannabis use and cardiovascular events such as stroke and myocardial infarction, although studies show conflicting results. The non-psychoactive cannabidiol (CBD) could have anti-inflammatory and antioxidant effects. Smoking cannabis poses additional cardiovascular risks similar to tobacco. Given these risks, cardiologists should routinely ask their patients about possible cannabis use and inform them about the potential cardiovascular dangers. The article also highlights the psychiatric risks of cannabis use, including dependence and psychosis, and emphasizes the need for interdisciplinary collaboration between cardiologists and psychiatrists to effectively manage cannabis-related health problems.
Synaptic plasticity, including long‐term potentiation (LTP) and long‐term depression (LTD), is an essential phenomenon in memory formation as well as maintenance along with many other cognitive functions, such as those needed for coping with external stimuli. Synaptic plasticity consists of gradual changes in the biochemistry and morphology of pre‐ and postsynaptic neurons, particularly in the hippocampus. Consuming marijuana as a primary source of exocannabinoids immediately impairs attention and working memory‐related tasks. Evidence regarding the effects of cannabinoids on LTP and memory is contradictory. While cannabinoids can affect a variety of specific cannabinoid receptors (CBRs) and nonspecific receptors throughout the body and brain, they exert miscellaneous systemic and local cerebral effects. Given the increasing use of cannabis, mainly among the young population, plus its potential adverse long‐term effects on learning and memory processes, it could be a future global health challenge. Indeed, the impact of cannabinoids on memory is multifactorial and depends on the dosage, timing, formula, and route of consumption, plus the background complex interaction of the endocannabinoids system with other cerebral networks. Herein, we review how exogenously administrated organic cannabinoids, CBRs agonists or antagonists, and endocannabinoids can affect LTP and synaptic plasticity through various receptors in interaction with other cerebral pathways and primary neurotransmitters.
The aim of the present study was to assess the effects of different levels of hempseed (HS) on growth performance, immunity and gut health in broiler chickens. A total of 192 Hubbard broiler chicks were divided into four groups and fed HS as follow: control (HS0), HS 10% (HS-10), HS 15% (HS-15) and HS 20% (HS-20). The study on HS supplementation in broilers revealed no significant impacts on feed intake during the starter (p = .2294) and finisher phases (p = .2294), or overall (p = .0944), though numerical increases were noted with higher HS levels. Body weight gain showed no significant influence in the starter and finisher phases, with overall weight gain also not significantly different (p = .0944), but numerically higher with increased HS. Feed conversion ratio was unaffected in the starter (p = .6986) and finisher phases (p = .6425), and overall (p = .2218). Dressing percentage (p = .1062) and mortality (p = .1631) were not significantly altered, but HS-20 had the highest dressing percentage and lowest mortality numerically. White blood cell counts increased significantly (p = .0377), especially in HS-15 and HS-20 groups. IgM and IgG production was higher in HS-20 on day 28 (p = .021). Gut pH (p > .05) and intestinal histomorphology (p > .05) were not significantly affected, although villus height increased numerically with higher HS levels. These results suggest potential benefits of HS, especially at higher inclusion levels. In conclusion, the obtained results indicated that HS incorporation into the diet of broilers did not affect the growth performance and gut health; however, the immune responses were significantly higher at 15 and 20% levels.
Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers. Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.
Cannabidiol (CBD) appears to possess some neuroprotective properties, but experimental data are still inconsistent. Therefore, this in vitro study aimed to compare the effects of CBD in a wide range of concentrations on oxidative stress and excitotoxic-related cell damage. Results showed that low concentrations of CBD ameliorated the H2O2-evoked cell damage of primary cortical neuronal cell culture. However, higher concentrations of CBD alone (5–25 μM) decreased the viability of cortical neurons in a concentration-dependent manner and aggravated the toxic effects of hydrogen peroxide (H2O2). Neuroprotection mediated by CBD in primary neurons against H2O2 was not associated with a direct influence on ROS production nor inhibition of caspase-3, but we found protective effects of CBD at the level of mitochondrial membrane potential and DNA fragmentation. However, CBD had no protective effect on the glutamate-induced cell damage of cortical neurons, and in higher concentrations, it enhanced the toxic effects of this cell-damaging factor. Likewise, CBD, depending on its concentration, at least did not affect or even enhance cortical cellular damage exposed to oxygen–glucose deprivation (OGD). Finally, we showed that CBD in submicromolar or low micromolar concentrations significantly protected human neuronal-like SH-SY5Y cells against H2O2- and 6-hydroxydopamine (6-OHDA)-induced cell damage. Our data indicate that CBD has a dual effect on oxidative stress-induced neuronal death-in low concentrations, it is neuroprotective, but in higher ones, it may display neurotoxic activity. On the other hand, in excitotoxic-related models, CBD was ineffective or enhanced cell damage. Our data support the notion that the neuroprotective effects of CBD strongly depend on its concentration and experimental model of neuronal death.
The medicinal properties of cannabis and cannabinoid-derivative are entirely investigated and known. In addition, the identification of psychotropic plant cannabinoids has led to more studies regarding the cannabinoid system and its therapeutic features in the treatment and management of clinical symptoms of neuroinflammatory disorders, such as multiple sclerosis (MS), Parkinsons disease (PD), and Alzheimers disease (AD). In fact, cannabinoid agonists are able to control and regulate inflammatory responses. In contrast to the cannabinoid receptor type 1 (CB1) and its unwanted adverse effects, the cannabinoid receptor type 2 (CB2) and its ligands hold promise for new and effective therapeutic approaches. So far, some successes have been achieved in this field. This review will discuss an outline of the endocannabinoid system's involvement in neuroinflammatory disorders. Moreover, the pharmacological efficacy of different natural and synthetic preparations of phytocannabinoids acting on cannabinoid receptors, particularly in MS, PD, and AD, will be updated. Also, the reasons for targeting CB2 for neurodegeneration will be explained.
Palliative care teams are often consulted to assist in treating persistent dementia-related behavioral issues. Delta-9-tetrahydrocannabinol (THC) offers an alternative to traditional antipsychotic drugs in the long-term management of dementia with behavioral change. We present the case of an 85-year-old man with dementia with Lewy bodies with worsening aggression refractory to antipsychotic management. Multiple regimens of antipsychotics failed both in the outpatient and inpatient settings. After exhausting other options and in the setting of worsening agitation, a tincture of THC was prescribed. After starting THC tincture, the patient's behavior rapidly improved, and he was discharged home to the care of his spouse. The challenges of prescribing and obtaining THC are discussed.
PurposeCannabis use has reportedly increased in type 2 diabetic users as a possible co-treatment for associated pain and inflammation. Both cannabis and metformin (an anti-diabetic drug) have a limited number of studies completed on their effect on male reproductive parameters in a diabetic model. This study determined if cannabis and metformin administration alter various reproductive parameters in diabetic male rats.Methods
Male Wistar rats (n = 35) were fed on a high fat diet and injected with streptozotocin (30 mg/kg rat) to induce a type-2 diabetic model. Treatment groups received cannabis based on Delta-9-Tetrahydrocannabinol (THC) concentrations of 1.25, 2.5 and 5 mg/kg per rat and metformin (50 mg/kg) every alternate day for 10 weeks. Organ weight; serum testosterone levels and sperm count, motility, lipid peroxidation, citrate synthase and lactate dehydrogenase activities were measured.ResultsCannabis treatment induced a significant concentration dependent decrease in sperm motility at 5 mg/kg rat THC (P = 0.009) administration. Metformin significantly (P = 0.035) increased sperm counts and lactate dehydrogenase activity (P = 0.002). Both cannabis and metformin negatively affected testosterone concentrations.Conclusions
Cannabis needs to be used cautiously as an alternative treatment in diabetic males based on the negative effects observed for the various reproductive parameters in this diabetic rat model.
Previous studies have demonstrated that phosphine gas (PH3) released from aluminium phosphide (AlP) can inhibit cytochrome oxidase in cardiac mitochondria and induce generation of free radicals, oxidative stress, alteration in antioxidant defense system and cardiotoxicity. Available evidence suggests that cannabinoids have protective effects in the reduction of oxidative stress, mitochondrial and cardiovascular damages. The objective of this study was to evaluate the effect of trans-Δ-9-tetrahydrocannabinol (THC) on AlP-induced toxicity in isolated cardiomyocytes and cardiac mitochondria. Rat heart isolated cardiomyocytes and mitochondria were cotreated with different concentrations of THC (10, 50 and 100 μM) and IC50 of AlP, then cellular and mitochondrial toxicity parameters were assayed. Treatment with AlP alone increased the cytotoxicity, depletion of cellular glutathione (GSH), mitochondrial reactive oxygen species (ROS) generation, lipid oxidation, mitochondria membrane potential (ΔΨm) collapse and mitochondrial swelling, when compared to control group. However, incubation with THC (10, 50 and 100 μM) attenuated the AlP-induced changes in all these parameters in a THC concentration-dependent manner. Interestingly, the obtained results showed remarkably significant protective effects of THC by attenuation the different parameters of cytotoxicity, mitochondrial toxicity and oxidative stress induced by ALP in isolated cardiomyocytes and cardiac mitochondria. It is the first report showing the protective effects of THC against AlP-induced toxicity, and these effects are related to antioxidant potential and inhibition of mitochondria permeability transition (MPT) pore. Based on these results, it was hypothesized that THC may be used as a potential therapeutic agent for the treatment of AlP-induced mitochondrial dysfunction and cardiotoxicity.
Cannabis is the most widely used illicit drug worldwide. Evidence indicated negative impact for cannabis on the brain. Animal research and in vitro studies using delta-9-THC (THC) or cannabis extracts with high THC content provided evidence for a detrimental effect on neuronal integrity with DNA damage, cell shrinkage, atrophy and apoptosis. The mechanisms by which herbal cannabis affects brain structure and function are not clear but impaired mitochondrial functioning, reduced glucose availability and inhibition of brain energetic metabolism by cannabis have been shown. Clinical studies investigating the effects of cannabis in humans found raised serum levels of proinflammatory cytokines in chronic cannabis users. Human studies also indicated increased oxidative stress biomarkers and reduced antioxidants in blood of chronic cannabis users. Preclinical data on the effect of cannabis or THC on oxidative stress, however, were less conclusive in that cannabis might increase or attenuate oxidative stress and neurotoxicity. The aim of this review is to summarize the evidence from animal and clinical studies pertaining to the toxic effects of cannabis and its main psychoactive ingredient THC on the brain and possible mechanisms involved.
The cannabis plant (Cannabis sativa L.) produces an estimated 545 chemical compounds of different biogenetic classes. In addition to economic value, many of these phytochemicals have medicinal and physiological activity. The plant is most popularly known for its two most-prominent and most-studied secondary metabolites—Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Both Δ9-THC and CBD have a wide therapeutic window across many ailments and form part of a class of secondary metabolites called cannabinoids—of which approximately over 104 exist. This review will focus on non-cannabinoid metabolites of Cannabis sativa that also have therapeutic potential, some of which share medicinal properties similar to those of cannabinoids. The most notable of these non-cannabinoid phytochemicals are flavonoids and terpenes. We will also discuss future directions in cannabis research and development of cannabis-based pharmaceuticals. Caflanone, a flavonoid molecule with selective activity against the human viruses including the coronavirus OC43 (HCov-OC43) that is responsible for COVID-19, and certain cancers, is one of the most promising non-cannabinoid molecules that is being advanced into clinical trials. As validated by thousands of years of the use of cannabis for medicinal purposes, vast anecdotal evidence abounds on the medicinal benefits of the plant. These benefits are attributed to the many phytochemicals in this plant, including non-cannabinoids. The most promising non-cannabinoids with potential to alleviate global disease burdens are discussed.
The aberrant accumulation of disease-specific protein aggregates accompanying cognitive decline is a pathological hallmark of age-associated neurological disorders, also termed as proteinopathies, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Along with oxidative stress and neuroinflammation, disruption in protein homeostasis (proteostasis), a network that constitutes protein surveillance system, plays a pivotal role in the pathobiology of these dementia disorders. Cannabidiol, a non-psychotropic phytocannabinoid of Cannabis sativa, is known for its pleiotropic neuropharmacological effects on the central nervous system, including the ability to abate oxidative stress, neuroinflammation, and protein misfolding. Over the past years, compelling evidence has documented disease-modifying role of cannabidiol in various preclinical and clinical models of neurological disorders, suggesting the potential therapeutic implications of cannabidiol in these disorders. Because of its putative role in the proteostasis network in particular, cannabidiol could be a potent modulator for reversing not only age-associated neurodegeneration but also other protein misfolding disorders. However, the current understanding is insufficient to underpin this proposition. In this review, we discuss the potentiality of cannabidiol as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing roles in the neurodegenerative disorders. We anticipate that the current effort will advance our knowledge on the implication of CBD in proteostasis network, opening up a new therapeutic window for ageing proteinopathies.
The aims of this work were to summarize the nutritional value of the milk thistle seed cakes and hempseed cakes and describe the influence on selected performance parameters, metabolism and animal health from inclusion of these non-traditional feeds into diets. It seems more appropriate to apply the extract of the bioactive substances complex to the livestock diets than addition of expellers or other forms of plants processing. The seed expellers, etc. mostly worsened the chickens' performance parameters with higher doses in diets, while most of the work using the extract yields had positive results on animal performance.
The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive
role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates
were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced.
These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the
concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
The antinociceptive effects of various cannabinoids, alone and in combination with opiates, were evaluated in antinociceptive tests in mice. The cannabinoids tested produce marked antinociceptive effects after i.t. administration to mice. The rank order of potency for the drugs using the tail-flick test was levonantradol greater than CP-55,940 = CP-56,667 greater than 11-hydroxy-delta 9-THC greater than delta 9-THC greater than delta 8-THC; dextronantradol was inactive at a dose of 25 micrograms/mouse. Respective ED50 values in the tail-flick test were 0.4, 12.3, 4.2, 15, 45 and 72 micrograms/mouse. Although pretreatment with morphine somewhat enhanced the effects of delta 9-THC, pretreatment of the mice with naloxone (1 mg/kg s.c. or 1 micrograms/mouse i.t.) failed to block the antinociceptive effects of the cannabinoids, indicating that the cannabinoid-induced antinociception does not occur due to direct interaction with the opiate receptor. Pretreatment of mice with 3.13 micrograms/mouse and 6.25 micrograms/mouse of delta 9-THC shifted the ED50 of morphine to 0.15 and 0.05 micrograms/mouse, respectively (a 4-and a 12-fold shift). The shifts in the dose-response curve of the morphine were parallel. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of the combination of 6.25 micrograms of delta 9-THC with morphine. The AD50 for naloxone blockade of the drug combination was 0.24 (0.06-0.94) mg/kg s.c. and the pA2 was 7.7 (6.7-8.9). The pA2 for naloxone blockade of the dimethylsulfoxide-morphine combination was 6.9 (5.7-8.1).(ABSTRACT TRUNCATED AT 250 WORDS)
In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.
Like all pharmacologic agents known, N-methyl-D-aspartate (NMDA) antagonist compounds have side effects. It is expected that neuroactive molecules have effects, including side effects, in the central nervous system (CNS). With NMDA antagonists in rodents, these side effects are remarkably focal in the cingulate and retrosplenial cortex. The salient features of NMDA antagonist neurotoxicity which should be underscored are hypermetabolism, lactate accumulation, neuronal vacuolization in aldehyde fixed material, and neuronal death in older rodents. The scope of this phenomenon must urgently be determined in non-rodent species, specifically primates. This is important from both a regulatory and neurotherapeutic point of view, since effective molecules having potential in human disease states may also have NMDA antagonist properties.
The amino acid L-glutamate is a neurotransmitter that mediates fast neuronal excitation in a majority of synapses in the central nervous system. Glutamate stimulates both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. While activation of NMDA receptors has been implicated in a variety of neurophysiologic processes, excessive NMDA receptor stimulation (excitotoxicity) is thought to be primarily responsible for neuronal injury in a wide variety of acute neurological disorders including hypoxia-ischemia, seizures, and trauma. Very little is known about endogenous molecules and mechanisms capable of modulating excitotoxic neuronal death. Saturated N-acylethanolamides like palmitoylethanolamide accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation. Here we report that palmitoylethanolamide, but not the cognate N-acylamide anandamide (the ethanolamide of arachidonic acid), protects cultured mouse cerebellar granule cells against glutamate toxicity in a delayed postagonist paradigm. Palmitoylethanolamide reduced this injury in a concentration-dependent manner and was maximally effective when added 15-min postglutamate. Cannabinoids, which like palmitoylethanolamide are functionally active at the peripheral cannabinoid receptor CB2 on mast cells, also prevented neuron loss in this delayed postglutamate model. Furthermore, the neuroprotective effects of palmitoylethanolamide, as well as that of the active cannabinoids, were efficiently antagonized by the candidate central cannabinoid receptor (CB1) agonist anandamide. Analogous pharmacological behaviors have been observed for palmitoylethanolamide (ALI-Amides) in downmodulating mast cell activation. Cerebellar granule cells expressed mRNA for CB1 and CB2 by in situ hybridization, while two cannabinoid binding sites were detected in cerebellar membranes. The results suggest that (i) non-CB1 cannabinoid receptors control, upon agonist binding, the downstream consequences of an excitotoxic stimulus; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for CB2-like receptors on granule cells; and (iii) activation of such receptors may serve to downmodulate deleterious cellular processes following pathological events or noxious stimuli in both the nervous and immune systems.
The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
Anandamide is an endogenous ligand of cannabinoid receptors that induces pharmacological responses in animals similar to those of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Typical pharmacological effects of cannabinoids include disruption of pain, memory formation, and motor coordination, systems that all depend on NMDA receptor mediated neurotransmission. We investigated whether anandamide can influence NMDA receptor activity by examining NMDA-induced calcium flux (ΔCa2+NMDA) in rat brain slices. The presence of anandamide reduced ΔCa2+NMDA and the inhibition was disrupted by cannabinoid receptor antagonist, pertussis toxin treatment, and agatoxin (a calcium channel inhibitor). Whereas these treatments prevented anandamide inhibiting ΔCa2+NMDA, they also revealed another, underlying mechanism by which anandamide influences ΔCa2+NMDA. In the presence of cannabinoid receptor antagonist, anandamide potentiated ΔCa2+NMDA in cortical, cerebellar, and hippocampal slices. Anandamide (but not THC) also augmented NMDA-stimulated currents in Xenopus oocytes expressing cloned NMDA receptors, suggesting a capacity to directly modulate NMDA receptor activity. In a similar manner, anandamide enhanced neurotransmission across NMDA receptor-dependent synapses in hippocampus in a manner that was not mimicked by THC and was unaffected by cannabinoid receptor antagonist. These data demonstrate that anandamide can modulate NMDA receptor activity in addition to its role as a cannabinoid receptor ligand.
Glutamate kills sensitive neurons through several steps downstream to receptor activation: increased free Ca2+ levels, activation of various enzymes and accumulation of reactive oxygen species (ROS). We have evaluated in a well established model of neuronal cultures the neuroprotective effects of blocking these mechanisms, either singularly or by combining multiple enzyme inhibition and/or ROS scavenging. In vitro cultures of cerebellar granule cells were exposed to a toxic concentration of glutamate (100 μM for 15 min in the absence of Mg2+) combined with several pharmacological treatments. Inhibition of nitric oxide synthase (NOS) and phospholipase A2 (PLA2) were effective in decreasing cell death and the combined treatments showed some degree of additivity. By contrast, inhibition of xanthine oxidase (XO) with allopurinol was uneffective. Antioxidants (in particular vitamin E or vitamin E analogs), protected neurons up to more than 50%. A synergistic effect was demonstrated by the combination of vitamin E and C. On the other hand, antioxidants did not increase the protection granted by enzyme inhibitors, suggesting that they act downstream to NOS and PLA2. In conclusion, NOS and PLA2 activated by Ca2+ influx give rise to reactive oxygen species whose deleterious action can be counteracted either by inhibiting these enzymes or by scavenging the excess of free radicals produced by them. Finally, a moderate protection was obtained by blocking protein synthesis with cycloheximide, suggesting a partial contribution of apoptotic mechanisms to the excitotoxic cell death.
This study examines the ability of (+)-(3S,4S)-7-hydroxy-Δ6-tetrahydrocannabinol-1,1-dimethylheptyl (HU-211), a non-competitive NMDA receptor antagonist to: (1) rescue neurons in culture from injury evoked by sodium nitroprusside, hydrogen peroxide (H2O2) and oxygen glucose deprivation; and (2) scavenge reactive oxygen species in vitro. Qualitative and quantitative assessments of cell survival have indicated that: (1) Neuronal cell injury produced following deprivation of oxygen and glucose was significantly attenuated by 5 μM HU-211. (2) Glial and neuronal cell damage induced by sodium nitroprusside was markedly ameliorated by 10 μM HU-211. (3) HU-211 reduced protein oxidation initiated by gamma irradiation, and scavenged peroxyl radicals. (4) HU-211 carries an oxidation potential of 550 mV. These findings suggest that HU-211 holds a unique position among putative neuroprotectant agents in that it combines NMDA receptor antagonistic activity and free radical scavenging abilities in a single molecule.
Based on encouraging preliminary findings, cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, was evaluated for symptomatic efficacy and safety in 15 neuroleptic-free patients with Huntington's Disease (HD). The effects of oral CBD (10 mg/kg/day for 6 weeks) and placebo (sesame oil for 6 weeks) were ascertained weekly under a double-blind, randomized cross-over design. A comparison of the effects of CBD and placebo on chorea severity and other therapeutic outcome variables, and on a Cannabis side effect inventory, clinical lab tests and other safety outcome variables, indicated no significant (p greater than 0.05) or clinically important differences. Correspondingly, plasma levels of CBD were assayed by GC/MS, and the weekly levels (mean range of 5.9 to 11.2 ng/ml) did not differ significantly over the 6 weeks of CBD administration. In summary, CBD, at an average daily dose of about 700 mg/day for 6 weeks, was neither symptomatically effective nor toxic, relative to placebo, in neuroleptic-free patients with HD.
The widely used antioxidant butylated hydroxytoluene (BHT, 2,6-di-tert-butyl-4-methylphenol) produces acute pulmonary toxicity in mice, and also enhances the multiplicity of lung tumors in mice when chronically administered following a single dose of a carcinogen such as urethane. Evidence strongly indicates that the pulmonary effects of BHT are caused by one or more of its reactive metabolites, particularly the hydroperoxide or quinone methide products. The former, BHT-OOH (2,6-di-tert-butyl-4-hydroperoxy-4-methylcyclohexa-2,5-dienone+ ++), is later converted to free radicals by cytochrome P-450, and evidence implicating this pathway in BHT-OOH-induced cytotoxicity has been obtained using isolated rat hepatocytes. Pulmonary microsomes from mice effectively hydroxylate BHT to BHT-BuOH [6-tert-butyl-2-(hydroxy-tert-butyl)-4-methylphenol]; this metabolite was several-fold more effective than BHT as a lung tumor promoter, substantially more pneumotoxic than BHT in vivo, and more toxic to isolated rat hepatocytes and mouse bronchiolar Clara cells in vitro. These effects may be a result of oxidation of BHT-BuOH to the corresponding quinone methide, which is a highly electrophilic. The tumor promoting effects of BHT in mouse lung may be a result of selective cytotoxicity or altered signal transduction caused by radical-generating hydroperoxide and/or electrophilic quinone methide metabolites.
The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
Male and female C3H mice were fed a diet containing 0.5% or 0.05% of the antioxidant butylated hydroxytoluene (BHT). After 10 months, male but not female animals had a significantly increased incidence of liver tumors compared to animals kept on a BHT-free control diet. In a second experiment, male BALB/c mice were treated subcutaneously with the carcinogens dimethylhydrazine (DMH) or intrarectally with methylnitrosourea (MNU). A diet containing 0.5% BHT significantly increased the incidence of colon tumors in DMH treated animals but had no effect in mice given MNU. It is concluded that the effect of BHT on tumor development depends on strain and target organ examined and possibly also on the chemical carcinogen used.
Marihuana inhalation was accompanied by increased heart rate and decreased intraocular and blood pressure in 18 subjects with heterogenous glaucomas. The hypotensive effects appeared in 60 to 90 minutes as the decrease in intraocular pressure (IOP) appeared to follow the decrease in blood pressure. In addition to any local effect, the mechanism of lowered to any local effect, the mechanism of lowered IOP may also involve the decreased pressure perfusing the ciliary body vasculature as a result of the peripheral vasodilatory properties of marihuana. Postural hypotension, tachycardia, palpitations, and alterations in mental status occurred with such frequency as to mitigate against the routine used in the general glaucoma population. Our data indicate that further research should be directed to local means of delivering the ocular hypotensive cannabinoid to the glaucomatous eye.
Delta-8-tetrahydrocannabinol (delta-8-THC), a cannabinoid with lower psychotropic potency than the main Cannabis constituent, delta-9-tetrahydrocannabinol (delta-9-THC), was administered (18 mg/m2 in edible oil, p.o.) to eight children, aged 3-13 years with various hematologic cancers, treated with different antineoplastic drugs for up to 8 months. The total number of treatments with delta-8-THC so far is 480. The THC treatment started two hours before each antineoplastic treatment and was continued every 6 hrs for 24 hours. Vomiting was completely prevented. The side effects observed were negligible.
The neuronal damage induced by systemic administration of kainic acid reproduces the cellular and regional pattern of damage produced by repeated seizures. The ability of kainic acid to induce lipid peroxidation, and the ability of free radical inhibitors to prevent ischaemically-induced cell death, has led us to examine the possible role of free radicals in kainate-induced injury. Ascorbic acid was able to reduce kainate-induced damage of the rat hippocampus, measured by means of the gliotic marker ligand [3H]PK11195. Ascorbate was significantly effective at doses of 30 mg kg-1 and above, with total protection against kainate at 50 mg kg-1. Histologically, ascorbate at 50 mg kg-1 was able to prevent kainate-induced neuronal loss in the hippocampal CA1 and CA3a cell layers. The antioxidant was also effective when administered simultaneously with, or 1 h before the kainate. Protection was also obtained by allopurinol, 175 mg kg-1 and by oxypurinol, 40 mg kg-1. Ascorbate did not modify synaptically evoked potentials or long-term potentiation in hippocampal slices, ruling out any blocking activity at glutamate receptors. It is concluded that the neuronal damage produced by systemically administered kainate involves the formation of free radicals.
Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predominately located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent (K(1/2) = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (omega-conotoxin-GVIA-sensitive) and P/Q-type (omega-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.
Anandamide is an endogenous ligand of cannabinoid receptors that induces pharmacological responses in animals similar to those of cannabinoids such as delta9-tetrahydrocannabinol (THC). Typical pharmacological effects of cannabinoids include disruption of pain, memory formation, and motor coordination, systems that all depend on NMDA receptor mediated neurotransmission. We investigated whether anandamide can influence NMDA receptor activity by examining NMDA-induced calcium flux (deltaCa2+NMDA) in rat brain slices. The presence of anandamide reduced deltaCa2+NMDA and the inhibition was disrupted by cannabinoid receptor antagonist, pertussis toxin treatment, and agatoxin (a calcium channel inhibitor). Whereas these treatments prevented anandamide inhibiting deltaCa2+NMDA, they also revealed another, underlying mechanism by which anandamide influences deltaCa2+NMDA. In the presence of cannabinoid receptor antagonist, anandamide potentiated deltaCa2+NMDA in cortical, cerebellar, and hippocampal slices. Anandamide (but not THC) also augmented NMDA-stimulated currents in Xenopus oocytes expressing cloned NMDA receptors, suggesting a capacity to directly modulate NMDA receptor activity. In a similar manner, anandamide enhanced neurotransmission across NMDA receptor-dependent synapses in hippocampus in a manner that was not mimicked by THC and was unaffected by cannabinoid receptor antagonist. These data demonstrate that anandamide can modulate NMDA receptor activity in addition to its role as a cannabinoid receptor ligand.