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Neuroprotective Antioxidants from Marijuanaa
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.
... 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.
... The effects of THC include analgesia, muscle relaxation, antiemetic and psychotropic effects [23]. CBD, in contrast, is psychoinactive and may not have activity at these receptors, though the effects of CBD are documented to be largely anxiolytic, antipsychotic and even neuroprotective [24,25]. It does agonize 5-HT1A receptors, transient receptor potential vanilloid type 1 receptors and downregulates adenosine A2A receptors [1]. ...
... Another modality that may contribute to pain relief is the attentional distraction that cannabis provides which perhaps may markedly reduce awareness of the pain itself. The combination of analgesic, anti-inflammatory, affective and even possibly the antioxidant properties of cannabis needs to be further explored [25]. ...
With the opioid epidemic reaching new heights in the USA, it has become critical to find suitable alternatives to opioids. Cannabis, an antinociceptive, is a strong contender to help patients reduce their opioid usage. A growing literature has been examining the complex effects cannabis has on pain relief and on opioid usage; whether it is a substitute for opioids or increases their use. This review explores the studies that compare cannabis-opioid interactions and presents some challenges of cannabis research and usage. The practical clinical pharmacology of cannabis as an analgesic, including the route of administration, safety and pharmacokinetics, are discussed to address the concerns, as well as possible solutions, of cannabis as a pain reliever.
... 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.
... 14,15 Available evidence suggests there are multiple neuroprotective properties of cannabinoids. [16][17][18][19][20] Ligands at the CB 1 cannabis receptors reduce presynaptic neurotransmitter release, including glutamate. [21][22][23] As excessive glutamate in the synapse can lead to oxidative stress and damage to neurons promoting neurodegeneration, this is considered a therapeutic mechanism for cannabinoids in dementia. ...
Background:
In 2016, the global number of individuals living with dementia was 43.8 million, representing a 117% increase from 1990-mainly due to increases in aging and population growth. Up to 90% of individuals with dementia experience neuropsychiatric symptoms (NPS). However, the limitations of current treatments for NPS have drivent he search for safer pharmacotherapies-including cannabinoids.
Aim:
To assess the efficacy and acceptability of cannabinoids for the treatment of NPS in individuals with dementia.
Design:
Systematic review and meta-analysis of clinical trials.
Setting and participants:
Of 6,902 papers, 9 were eligible (n = 205, 44% female, 78 ± 7 years, 85% Alzheimer disease). Trials were in North America and Europe and explored tetrahydrocannabinol (n = 3), dronabinol (n = 5), or nabilone (n = 1).
Measurement:
Titles/abstracts were independently screened by one reviewer and reviewed by a second. Full-text screening was by two reviewers with discrepancies resolved via a third reviewer. We extracted data on the standardized mean difference (SMD) for several NPS instruments, trial completion, and adverse events. Data were pooled using random-effects models.
Findings:
Cannabinoids led to significant improvements across NPS instruments, including the Cohen Mansfield Agitation Inventory (SMD = -0.80; 95% confidence interval [CI], -1.45 to -0.16), the Neuropsychiatric Inventory (SMD = -0.61; CI, -1.07 to -0.15), and nocturnal actigraphy (SMD = -1.05; CI, -1.56 to -0.54h). Cannabinoids were well-tolerated, with an overall trial completion rate of 93% (193/205) and no serious treatment-related adverse events. Treatment efficacy was associated with baseline dementia severity and dose, but not dementia subtype, age, or sex. The overall study quality was rated as low.
Conclusions:
There is preliminary evidence for the efficacy and tolerability of cannabinoids as treatments for NPS. Population-based studies are needed to characterize their real-world effectiveness and acceptability.
... Tetrahydrocannabinol, cannabidiol, α-pinene, myrecene, linalool, limonene, trans-βocimene, α-terpinolene, trans-caryophyllene, α-humulene and caryophyllene-oxide Hampson et al. (2000) 5. Jawaid et al. (2013Jawaid et al. ( , 2015 38. ...
Free radicals are the byproducts of physiological aerobic cellular metabolism. Intrinsic antioxidant system plays its pivotal function in prevention of any loss due to free radicals. Though, incorporation or excess production of free radicals from environment to living system or imbalanced defense mechanism of antioxidant system leads to severe consequences like neuro-degeneration. Sensory or functional loss occurs in neural cells in neurodegenerative diseases. Besides numerous other genetic or environmental factors, oxidative stress is the major cause which leads to damage of neurons and production of neurodegenative diseases. However, oxygen is vital for existence, excessive reactive oxygen species production and imbalanced metabolism leads to a variety of diseases such as aging, Parkinson’s disease, Alzheimer’s disease, and many other neurodegenative diseases. Free radicals toxicity contributes to DNA and proteins damage, tissue damage, inflammation and consequent cellular apoptosis. Neuroprotection is a broad term commonly used to refer therapeutic strategies that can prevent, delay or even reverse neuronal damage. Since thousands of years, lots of medicinal plants have been used in a group of herbal preparations of Ayurveda (Indian traditional health care system) named Rasayana because of the antioxidant principles present in it, responsible for their medicinal use in neurodegenerative diseases. This work constitutes a literature review on natural products contain antioxidant principles used in the treatment of neurodegenerative disease.
... From all the natural constituents of the cannabis plant, CBD, a non-psychoactive cannabinoid (Loewe, 1946;Pertwee, 2009), is being widely studied given its high therapeutic value. CBD has been shown, both in humans and rodents, to have antiseizure (Jones et al., 2010;Pamplona and Coan, 2017;Perucca, 2017;Zaheer et al., 2018), antiinflammatory (Malfait et al., 2000;Nagarkatti et al., 2009;Petrosino et al., 2018), antioxidant (Hampson et al., 2000), and anti-psychotic properties (Zuardi et al., 1991(Zuardi et al., , 2012Iseger and Bossong, 2015), to have neuroprotective effects (Iuvone et al., 2009;Fernández-Ruiz et al., 2013), to reduce nausea (Parker et al., 2011;Mersiades et al., 2018) and to work as an anxiolytic and anti-depressive drug (de Mello Schier et al., 2014;Blessing et al., 2015;Zuardi et al., 2017). Furthermore, CBD is known to potentiate the clinical efficacy of 9 -THC, increasing the durability of its beneficial effects, while preventing its psychoactive effects (Russo and Guy, 2006;Solymosi and Kofalvi, 2017). ...
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene, being one of the leading causes of mental disability in females. Mutations in the MECP2 gene are responsible for 95% of the diagnosed RTT cases and the mechanisms through which these mutations relate with symptomatology are still elusive. Children with RTT present a period of apparent normal development followed by a rapid regression in speech and behavior and a progressive deterioration of motor abilities. Epilepsy is one of the most common symptoms in RTT, occurring in 60 to 80% of RTT cases, being associated with worsening of other symptoms. At this point, no cure for RTT is available and there is a pressing need for the discovery of new drug candidates to treat its severe symptoms. However, despite being a rare disease, in the last decade research in RTT has grown exponentially. New and exciting evidence has been gathered and the etiopathogenesis of this complex, severe and untreatable disease is slowly being unfolded. Advances in gene editing techniques have prompted cure-oriented research in RTT. Nonetheless, at this point, finding a cure is a distant reality, highlighting the importance of further investigating the basic pathological mechanisms of this disease. In this review, we focus our attention in some of the newest evidence on RTT clinical and preclinical research, evaluating their impact in RTT symptomatology control, and pinpointing possible directions for future research.
... Cannabidiol has been shown to have antioxidant, antibacterial, anti-inflammatory and immune stimulating effects (Hampson et al. 1998;Straus 2001). Tetrahydrocannabinol is a potent lipophilic antioxidant with appetitestimulating properties (Hampson et al. 2000;Koch 2001). ...
The aim of the study was to evaluate the effect of feeding hempseed expellers in a feed mixture on the quality indicators of broiler chicken’s meat. One hundred and fifty Ross 308 hybrid cockerels were used in the present study. The control group (HS0) was fed without hempseed expellers; the other two groups received diets containing 50 g·kg ⁻¹ and 150 g·kg ⁻¹ of hempseed expellers (HS5 and HS15, respectively). The birds were slaughtered at the age of 37 days, and samples of breast and thigh muscles were collected for determination of proximate chemical composition and technological properties, and sensory analyses. Feeding with hempseed expellers influenced the colour of meat with a significant difference observed for a* (redness) and b* (yellowness) values in the HS15 group. The colour of breast meat in HS15 group is more intense compared to HS5 and HS0 groups. Breast meat was evaluated as the best in terms of odour for HS15 group compared to HS0. The colour of thigh meat was better rated in the HSE supplemented groups compared to the controls. In conclusion, dietary supplementation with hempseed expellers appears to affect the colour and odour of broiler chicken’s meat which is positive for the consumers. Including hempseed cakes can be recommended as a component of broiler chicken’s feed.
... Over 80 cannabinoids have been identified in cannabis (ElSohly and Slade, 2005), and some of them could potentially exacerbate or counteract the effects observed in this study. For example, cannabidiol has neuroprotective properties via anti-oxidative effects (Hampson et al., 2000), and cannabivarin, another cannabinoid, may be a weak cannabinoid receptor antagonist (Pertwee, 2008). Moreover, the ratio of cannabinoids in cannabis preparations has varied widely over the years and across locations of preparation (Botticelli, , 2017ElSohly et al., 2016). ...
Cannabis is the most commonly used illicit drug among pregnant women, and rates are likely to increase given recent legalization. In addition, half of pregnant women who report consuming cannabis also report drinking alcohol. However, little is known about the consequences of prenatal cannabis alone or in combination with alcohol, particularly with cannabis products that are continually increasing in potency of the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (THC). The current study investigated the effects of early exposure to cannabinoids during the brain growth spurt on early physical and motor development alone (Experiment 1) or in combination with alcohol (Experiment 2). In Experiment 1, Sprague-Dawley rat pups were exposed to a cannabinoid receptor agonist (CP-55,940 [CP]; 0.1, 0.25, 0.4 mg/kg/day), the drug vehicle, or a saline control from postnatal days (PD) 4–9. In Experiment 2, rat pups were exposed to CP (0.4 mg/kg/day) or the vehicle, and were additionally intubated with alcohol (11.9% v/v; 5.25 g/kg/day) or received a sham intubation. Subjects in both experiments were tested on a motor development task (PD 12–20) and a motor coordination task during adolescence (PD 30–32). Both developmental cannabinoid and alcohol exposure separately decreased body growth throughout development, and combined exposure exacerbated these effects, although only alcohol exposure induced long-term body weight reductions. Developmental cannabinoid exposure advanced early motor development, whereas alcohol exposure delayed development, and subjects given combined exposure did not differ from controls on some measures. Alcohol exposure impaired motor coordination later in life. In contrast, cannabinoid exposure, by itself, did not significantly affect long-term motor coordination, but did exacerbate alcohol-related impairments in motor coordination among females. These results suggest that cannabinoid exposure may not only alter development by itself, but may exacerbate alcohol's teratogenic effects in specific behavioral domains. These findings have important implications not only for individuals affected by prenatal exposure, but also for establishing public policy for women regarding cannabis use during pregnancy.
... Although the mechanism behind these effects remains unclear, the function of CBD may be related to its action as an antagonist/inverse agonist of CB1 receptors ( Thomas et al., 2007) or as a positive allosteric modulator of 5HT1A receptors (Rock et al., 2012). An attribute of CBD is that possess neuroprotective and anti-inflammatory effects ( Hampson et al., 2000). A preclinical study revealed that tetrahydrocannabinol (THC) and cannabidiol (CBD) clearly have anticonvulsant properties in animal models of acute seizures and epilepsy ( Wallace et al., 2002;Jones et al., 2010). ...
The aim of this review was to know the effect, properties and mechanism of action of essential oils in order to enhance their use as a treatment and adjuvant in some neurodegenerative pathologies and others associated to stress and human behavior, based on clinical trials and descriptive research. Some studies suggest that essential oils have been widely used in various applications, mainly in the pharmaceutical, cosmetic, food and agricultural industries since middle age. At the same time, based on human and animal studies has been established the effects of some essential oils about their behavior in the treatment of depression, anxiety, schizophrenic, sleep disorders in the regulation of mood modulating several neurotransmitters such as serotonin, noradrenaline, dopamine, glutamate, and gamma-aminobutyric acid also in some degenerative diseases such as Parkinson's or Alzheimer, as well as in the associated behaviors in depressive disorders, Autism spectrum disorder, ADHD, drugs addictions, people with stress and sleep disorders. It is necessary to know. RESUMEN Esta revisión tiene como objetivo conocer el efecto, propiedades y mecanismo de acción de los aceites esenciales para potenciar su uso como tratamiento y coadyuvante en algunas patologías neurodegenerativas y otras asociadas al estrés y al comportamiento humano, basado en ensayos clínicos y trabajos descriptivos. Algunos estudios sugieren que desde la edad media, los aceites esenciales han sido ampliamente utilizados en diversas aplicaciones, principalmente en las industrias farmacéutica, cosmética, alimentaria y agrícola. Al mismo tiempo, a partir de estudios en humanos y animales se han establecido los efectos de algunos aceites esenciales sobre el comportamiento en el tratamiento de la depresión, ansiedad, esquizofrenia, trastornos del sueño y en en la regulación del estado de ánimo modulando varios neurotransmisores: serotonina, noradrenalina, dopamina, glutamato y ácido gamma-aminobutírico; también en algunas enfermedades degenerativas como el Parkinson o el Alzheimer, así como en los comportamientos asociados en los trastornos depresivos, trastornos del espectro autista, trastorno de déficit de atención con hiperactividad (TDAH) , adicciones a las drogas, personas con estrés y trastornos del sueño.
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.
Despite many advances made in the field of interventional pain management in the past decades, pharmacological therapy often remains the core of the spine pain multimodal treatment. It represents an indispensable therapeutic tool, especially when more interventional methods either failed or are not indicated. This chapter is devoted to describing both neurobiological basis and clinical utility of pharmacological agents used to treat chronic spinal pain. Opioid analgesics have been the mainstay for treatment of pain for centuries. Although opioids may be very useful in treating severe pain conditions, the gravity of their side effects and recently recognized “opioid epidemic” lead to imposing much stricter control of their utilization. NSAIDs (nonsteroidal anti-inflammatory drugs) probably remain the most widely used class of drugs to treat chronic spinal pain because of their ability to reduce pain and inflammation. Centrally acting muscle relaxants are a diverse group of medications with different mechanisms of actions that may be used as an adjuvant treatment, especially when spinal pain is associated with painful muscle spasms. Some antidepressants [tricyclic antidepressants (TCAs) and selective norepinephrine reuptake inhibitors (SNRIs)] have demonstrated their efficacy in treatment of spinal neuropathic pain. Select anticonvulsants, such as gabapentinoids, are also widely used to treat such pain. Topical medications of different classes may have an advantage of exhibiting analgesia without significant systemic absorption. Although there is still insufficient evidence to recommend cannabinoids for spine pain treatment, we discuss this emerging medication class because it has been already used to treat certain pain conditions.
Background
Cardiac disease is accounted as the leading cause of worldwide morbidity and mortality, mainly in association with induction of inflammation and oxidative stress. The disease is characterized by the overproduction of reactive oxygen and/or nitrogen species (ROS/RNS), and reduced antioxidant capacity. Cannabidiol (CBD) is a non-psychoactive ingredient of marijuana that reported to be safe and well tolerated in patients. Due to its pleiotropic effect, CBD has been shown to exert cytoprotective effects. This study intended to clarify the mechanisms and the potential role of CBD regarding cardiac injuries treatment.
Methods
A systematic literature search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, in the electronic databases including PubMed, Web of Science, Scopus, and Embase up to July 2018 using predefined search terms in the titles and abstracts by two independent investigators. Accordingly, a set of pre-specified inclusion and exclusion criteria were considered and 8 articles were ultimately included in this study.
Results
Our findings obviously demonstrate that CBD has multi-functional protective assets to improve cardiac injuries; preliminary through scavenging of free radicals, and reduction of oxidative stress, apoptosis, and inflammation.
Conclusion
CBD can protect against cardiac injuries, mainly through its anti-oxidant, anti-inflammatory, and anti-apoptotic effects on the basis of non-clinical studies.
Herein, we report the antioxidant activity of cannabidiol (CBD) and Δ9- tetrahydrocannabinol (THC) in pure and mixed solutions at different ratios, as well as of six different Cannabis sativa extracts containing various proportions of CBD and THC by using spectrophotometric (reducing power assay, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), hypochlorous acid (HOCl) scavenging assays) and electrochemical methods (cyclic voltammetry and differential pulse voltammetry). The isolated cannabinoids, the different stochiometric ratios of CBD and THC, and the natural extracts proved to have remarkable antioxidant properties in all the methods employed in this work. The antioxidant activity of CBD and THC were compared against the well-defined antioxidants such as ascorbic acid (AA), resveratrol (RES) and (-)-epigallocatechin-3-gallate (EGCG). A clear evidence of the synergistic and antagonistic effects between CBD and THC regarding to their antioxidant activities was observed. Moreover, a good correlation was obtained between the optical and electrochemical methods, which proved that the reported experimental procedures can easily be adapted to determine the antioxidant activity of extracts from various Cannabis sativa species and related compounds.
Migraine is a disabling neurovascular disorder with few targeted, tolerable and effective treatments. Phytomedicines, or plant-based medicinal formulations, hold great promise in the identification of novel therapeutic targets in migraine. Many patients also turn toward herbal and plant-based therapies for the treatment of their migraines as clinical and preclinical evidence of efficacy increases. Patients seek effective and tolerable treatments instead of or in addition to current conventional pharmacologic therapies. We review some phytomedicines potentially useful for migraine treatment—feverfew (Tanacetum parthenium), butterbur (Petasites hybridus), marijuana (Cannabis spp.), Saint John’s Wort (Hypericum perforatum) and the Damask rose (Rosa × damascena)—with respect to their mechanisms of action and evidence for treatment of migraine. The evidence for feverfew is mixed; butterbur is effective with potential risks of hepatotoxicity related to preparation; marijuana has not been shown to be effective in migraine treatment, and data are scant; Saint John’s Wort shows relevant physiological activity but is a hepatic enzyme inducer and lacks clinical studies for this purpose; the Damask rose when used in topical preparations did not show efficacy in one clinical trial. Other plant preparations have been considered for migraine treatment but most without blinded randomized, placebo-controlled trial evidence.
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.