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Antibacterial activity of delta9-tetrahydrocannabinol and cannabidiol

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Abstract

The minimum inhibiting concentrations (MIC) of delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) for staphylococci and streptococci in broth are in the range of 1-5 mug/ml. In the same range, both compounds are also bactericidal. In media containing 4% serum or 5% blood the antibacterial activity is strongly reduced (MIC 50 mug/ml). Gram-negative bacteria are resistant to THC and CBD.

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... In the last years, the nonpsychoactive cannabinoid CBD, very common in certain strains of cannabis, has gained clinical relevance. Besides psychoactivity, cannabis have shown antinociceptive [45], anticonvulsant [46], immunosuppressive [47], antiemetic [48], appetite stimulation [49] and antimicrobial [50,51] properties. These effects result from either cannabinoid receptor activation or eCBs-metabolic enzyme competition. ...
... Like THC, CBD presents neuroprotective effects and displays potent antioxidant [57] and antimicrobial [51] properties. CBD, in contrast to THC, may activate the TRPV1 receptor [58] and inhibit both FAAH activity and AEA reuptake [59]. ...
Article
Although cannabis use is increasing in general population, their prevalence among young adults is remarkably high. In recent years, their medical use gained a renewed interest. However, it can underline the reputation of cannabis being a harmless drug. Between cannabinoids, uniquely found on the cannabis plant, Δ9-tetrahydrocannabinol (THC) is the well-studied compound. It is responsible for the psychoactive effects via central cannabinoid receptors. Nevertheless, cannabinoids interact with other chemical signalling systems such as the hypothalamic-pituitary-gonadal axis. THC indirectly decreases gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus. The consequences are diverse, and several key hormones are affected. THC disturbs important reproductive events like folliculogenesis, ovulation and sperm maturation and function. Although generally accepted that cannabinoid consumption impacts male and female fertility, prevailing evidence remains largely on pre-clinical studies. Here, we introduce cannabinoids and the endocannabinoid system, and we review the most prominent clinical evidence about cannabis consumption in reproductive potential and teratogenicity.
... Since cannabinoids are phenolics, their antibacterial activity is not surprising; however, their potency and the activity against multidrug-resistant bacterial strains are remarkable. Data on the antibiotic activity of CBC [75], CBG [76], CBD [77], and D 9 -THC [77] have been obtained, and C. sativa preparations have been investigated as topical antiseptic agents. More recently, the potential of the major cannabinoids to address antibiotic resistance to methicillin-resistant Staphylococcus aureus (MRSA) has been investigated [78]. ...
... Since cannabinoids are phenolics, their antibacterial activity is not surprising; however, their potency and the activity against multidrug-resistant bacterial strains are remarkable. Data on the antibiotic activity of CBC [75], CBG [76], CBD [77], and D 9 -THC [77] have been obtained, and C. sativa preparations have been investigated as topical antiseptic agents. More recently, the potential of the major cannabinoids to address antibiotic resistance to methicillin-resistant Staphylococcus aureus (MRSA) has been investigated [78]. ...
Chapter
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Cannabinoids, a class of meroterpenoids derived from the alkylation of an olivetol-like alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. This class includes over a hundred members belonging to several structural types, mainly differing by the constitution of their terpenoid moiety. The biomedical relevance of cannabinoids transcends the psychotropic properties of Δ9-THC since, because of their anti-inflammatory, analgesic, and antibacterial activity, they show potential in various fields of medicine, addressing unmet needs like the symptomatic mitigation of multiple sclerosis and the treatment of MRSA infections. Research on cannabinoid activities has yielded to the discovery of an entire new class of human receptors, called cannabinoid (CB) receptors, and of their endogenous agonists, collectively named endocannabinoids (EC). Since its discovery in the early 1990s, the EC system has increasingly emerged as a key signaling system involved in a plethora of physiological and pathological functions in mammals. This chapter will provide an overview on this multi-faceted class of natural products.
... The Cannabis sativa extracts used show a variety of antimicrobial potentiality against multidrug resistant bacterial isolates tested. Van et al., (1976) Escherichia coli, Bacillus subtilis, S. aureus, Pseudomonas aeruginosa, A. niger, and Candida albicans screened using appropriate solvent extracts showed some activity. But this is generally, pronounced against Gram-positive bacteria and moderate to no activity against Gram-negative and fungi. ...
... Cannabidiol (CBD), the main non-psychoactive ingredient of the Cannabis sativa plant, has antimicrobial affects against a variety of bacteria (Appendino et al., 2008;Van Klingeren and Ten Ham, 1976) and a documented bactericidal activity against MRSA (Blaskovich et al., 2021). We have previously shown that CBD, acts as an antibiotic adjuvant in combination with the antibiotic bacitracin (BAC) (Wassmann et al., 2020). ...
Article
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Emergence of antibiotic resistant bacteria is evolving at an alarming pace; therefore, we must start turning to alternative approaches. One of these, could be the use of antibiotic adjuvants that enhances the effect of antibiotics towards resistant bacteria. A novel antibiotic adjuvant is cannabidiol (CBD), which we have previously shown can enhance the effect of bacitracin (BAC). BAC targets cell wall synthesis by inhibiting dephosphorylation of the lipid carrier undecaprenyl pyrophosphate prior to recycling across the membrane. However, the mechanism underlying this CBD mediated potentiation of BAC has remained unknown. To explore this, we examined resistance to CBD in Staphylococcus aureus through daily exposures to CBD. By subsequent whole genome sequencing, we observed multiple genes to be mutated, including the farE/farR system encoding a fatty acid efflux pump (FarE) and its regulator (FarR). Importantly, recreation of mutations in these genes showed decreased susceptibility towards the combination of CBD and BAC. Furthermore, we searched the Nebraska Transposon Mutant Library for CBD susceptible strains and identified menH encoding a protein participating in menaquinone biosynthesis. Strains containing deletions in this and other menaquinone related genes showed increased susceptibility towards CBD, while addition of exogenous menaquinone reversed the effect and reduced susceptible towards CBD. These results suggest that CBD potentiates BAC by redirecting the isoprenoid precursor isopentenyl pyrophosphate towards production of menaquinone rather than the lipid carrier undecaprenyl pyrophosphate, which dephosphorylation is inhibited by BAC. This in turn might decrease the level of undecaprenyl pyrophosphate thus enhancing the effect of BAC. Our study illustrates how antibiotic adjuvants may apply to enhance efficacy of antimicrobial compounds.
... This observation can show that CHD, delta-8-THC, and delta-9 THC can be a further target for antituberculosis drug development. The three studied main active ingredients of cannabis are reported for bactericidal activity for some grampositive bacteria [11]. However, there is still no report on mycobacteria. ...
Article
Background Cannabis is presently legalized in several countries owing to its medicinal property. The antibacterial properties of active ingredients of cannabis have been mentioned. Their usefulness in the management of tuberculosis is very interesting. Materials and methods The authors performed a bioinformatics analysis to assess the possibility of important active ingredients of cannabis. Results Based on the present analysis, it can be seen that the studied active ingredients of cannabis can effectively pass through the cell wall of Mycobacterium tuberculosis, indicating the possibility of further pharmacological actions. Conclusion The active ingredients of cannabis are the possible new targets for further antituberculosis drug development.
... Staphylococci and Streptococci in broth are in the range of 1-5 μg/ml (Klingeren and Ham, 1976 ...
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Plantmaterials are important for animaland human health care and also important for microbial controlling program. This present study has been attempt to determine the antibacterial activity of Cannabis sativa leaf extract to some selective pathogenicbacterial strains such as Staphylococcus aureus, Escherichia coli,Pseudomunas aeruginosa, Enterococcusfaecalis, Salmonella typhi and Klebsiella by using leaf Ethanol extract and Hot water extract. Antibacterial activity of Cannabis Sativa was evaluated by well diffusion methods.The highest zone of inhibition produced by Ethanol extract. The leaf of Cannabis Sativa exerted pronounced antibacterial activity (24.1mm) against Staphylococcus aureus, (10.3mm) against Pseudomonas aeruginosa, (22.2mm) against Escherichia coli, (18.1mm) against Enterococcus faecalis respectively and inactive against the two strainsSalmonella typhi and Klebsiella.The minimum inhibitory effect of C. sativa leaf extract is due to certain compounds present in the C.sativa.Further research should be done to identify the compounds responsible for its activity which can be used as medicines to control a wide range of disease in the world.
... When tested individually, the major cannabinoids CBG, CBD, CBC, Δ 9 -THC, and CBN display antibiotic activity against methicillin-resistant Staphylococcus aureus [54]. Δ 9 -THC and CBD exhibit bactericidal effect against Gram-positive staphylococci and streptococci in the 1-5 μg/ml range, but not against Gram-negative bacteria [55]. This ...
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Phytocannabinoids are bioactive natural products found in some flowering plants, liverworts, and fungi that can be beneficial for the treatment of human ailments such as pain, anxiety, and cachexia. Targeted biosynthesis of cannabinoids with desirable properties requires identification of the underlying genes and their expression in a suitable heterologous host. We provide an overview of the structural classification of phytocannabinoids based on their decorated resorcinol core and the bioactivities of naturally occurring cannabinoids, and we review current knowledge of phytocannabinoid biosynthesis in Cannabis, Rhododendron, and Radula species. We also highlight the potential in planta roles of phytocannabinoids and the opportunity for synthetic biology approaches based on combinatorial biochemistry and protein engineering to produce cannabinoid derivatives with improved properties.
... Hemp contains many classes of resinous compounds, such as terpenes, terpenols, cannabinoids and dihydrostilbenes. Cannabinoids have been reported to exhibit antimicrobial activity against bacteria and fungi (Klingeren and Ham, 1976;McPartland, 1984). Hemp oil also contains important terpenes, such as α-pinene, β-pinene, limonene, α-selinene, β-caryophyllene and β-humulene (Romano and Hazekamp, 2013). ...
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The effects of unconventional oils high in polyunsaturated fatty acids (PUFAs) (blackberry, blueberry, raspberry, pomegranate, black seed and hemp oils) on in vitro rumen fermentation and methane (CH4) production were examined in a 24-h batch culture experiment. Treatments consisted of a control (no oil supplement), a control plus corn oil, or a control plus the unconventional oils. Oils were added to rumen cultures at 500 mg L-1 (equivalent to 3.3 g oil.kg-1 of dietary dry matter (DM)). After 24 h of incubation, CH4 production was not different between the control and the corn oil treatment. Of the six unconventional oils tested, only the hemp and blueberry oils reduced CH4 production by 10-16% relative to that of the control and corn oil treatments. Dry matter degradability and total volatile fatty acids (VFAs) were not affected by the addition of oils. Except for a reduction in the acetate concentration with the raspberry and hemp oils, all tested unconventional oils had no effects on fermentation and the VFA profile relative to those of the control. In conclusion, our results showed that hemp and blueberry oils were moderately effective in reducing rumen CH4 formation without compromising rumen fermentation and digestibility.
... In relation to antibiotic activity, cannabinoids including CBD, have been widely studied for their anti-bacterial activity ( Wasim et al., 1995;Bass et al., 1996;Appendino et al., 2008;Hernández-Cervantes et al., 2017). For example, C. sativa extracts have previously been shown to have microbicidal activity on various Gram-positive bacteria, including several strains of S. aureus, as well as some Gram-negative bacteria ( Wasim et al., 1995;Elphick, 2007;Nissen et al., 2010), with the minimum inhibitory concentrations (MIC) for the main phytocannabinoids, such as CBD, being in the 0.5-5 µM range, which is similar to many modern antibiotics (Van Klingeren and Ten Ham, 1976;Appendino et al., 2008). How precisely CBD may be working as an anti-bacterial agent is still not entirely clear ( Appendino et al., 2008), particularly in the light of a plethora of targets for CBD (Ibeas Bih et al., 2015;Hernández- Cervantes et al., 2017), while structure-activity studies indicate that the ability of plant-derived phenolic compounds to interact with membranes and the existence of electrophilic functional groups are important (Miklasinska-Majdanik et al., 2018). ...
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Membrane vesicles (MVs) released from bacteria participate in cell communication and host-pathogen interactions. Roles for MVs in antibiotic resistance are gaining increased attention and in this study we investigated if known anti-bacterial effects of cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, could be in part attributed to effects on bacterial MV release. We found that CBD is a strong inhibitor of MV release from Gram-negative bacteria (E. coli VCS257), while inhibitory effect on MV release from Gram-positive bacteria (S. aureus subsp. aureus Rosenbach) was negligible. When used in combination with selected antibiotics, CBD significantly increased the bactericidal action of several antibiotics in the Gram-negative bacteria. In addition, CBD increased antibiotic effects of kanamycin in the Gram-positive bacteria, without affecting MV release. CBD furthermore changed protein profiles of E. coli MVs after 1 h treatment. Our findings indicate that CBD may pose as a putative adjuvant agent for tailored co-application with selected antibiotics, depending on bacterial species, to increase antibiotic activity, including via MV inhibition, and help reduce antibiotic resistance.
... In relation to antibiotic activity, cannabinoids including CBD, have been widely studied for their anti-bacterial activity (Wasim et al., 1995;Bass et al., 1996;Appendino et al., 2008;Hernández-Cervantes et al., 2017). For example, C. sativa extracts have previously been shown to have microbicidal activity on various Gram-positive bacteria, including several strains of S. aureus, as well as some Gram-negative bacteria (Wasim et al., 1995;Elphick, 2007;Nissen et al., 2010), with the minimum inhibitory concentrations (MIC) for the main phytocannabinoids, such as CBD, being in the 0.5-5 µM range, which is similar to many modern antibiotics (Van Klingeren and Ten Ham, 1976;Appendino et al., 2008). How precisely CBD may be working as an anti-bacterial agent is still not entirely clear (Appendino et al., 2008), particularly in the light of a plethora of targets for CBD (Ibeas Bih et al., 2015;Hernández-Cervantes et al., 2017), while structure-activity studies indicate that the ability of plant-derived phenolic compounds to interact with membranes and the existence of electrophilic functional groups are important (Miklasinska-Majdanik et al., 2018). ...
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Membrane vesicles (MVs) released from bacteria participate in cell communication and host-pathogen interactions. Roles for MVs in antibiotic resistance are gaining increased attention and in this study we investigated if known anti-bacterial effects of cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, could be in part attributed to effects on bacterial MV release. We found that CBD is a strong inhibitor of MV release from Gram-negative bacteria (E. coli VCS257), while inhibitory effect on MV release from Gram-positive bacteria (S. aureus subsp. aureus Rosenbach) was negligible. When used in combination with selected antibiotics, CBD significantly increased the bactericidal action of several antibiotics in the Gram-negative bacteria. In addition, CBD increased antibiotic effects of kanamycin in the Gram-positive bacteria, without affecting MV release. CBD furthermore changed protein profiles of E. coli MVs after 1 h treatment. Our findings indicate that CBD may pose as a putative adjuvant agent for tailored co-application with selected antibiotics, depending on bacterial species, to increase antibiotic activity, including via MV inhibition, and help reduce antibiotic resistance. https://www.frontiersin.org/articles/10.3389/fcimb.2019.00324/abstract
... Groups of both 10 and 20 individuals treated with 0.2 mg/L THC had higher survival and hatching rates than control groups. Because THC has antimicrobial properties, the lower dosage of THC could have kept the microbial burden lower for embryos, improving health, survival, and hatching rates (van Kilngeren et al. 1976;Appendino et al., 2008) (ZFIN.com). In the present study, embryos in groups of 20 treated with 0.2 mg/L THC and 0.6 mg/L THC had higher hatching rates than control and 2 mg/L THC treated groups (Table 4). ...
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Hyperekplexia is a neurological disorder affecting infants and can be characterized by excessive startle reactions in response to unexpected stimuli. This disease can be modeled in zebrafish in the bandoneon (beo) mutant, where the glrbbmutation results in glycine receptor (GLYR) loss of function glycine receptors and ultimately, improper inhibitory signaling. Though hyperekplexia is a glycinergic-based signaling disorder, disease symptoms are often alleviated with GABA-agonistic benzodiazepines. Exogenous cannabinoids also modulate GABAergic signaling, and THC, one of the natural compounds that prompted the discovery of the endocannabinoid system mimics the effects of endogenous cannabinoids at endocannabinoid and non-cannabinoid sites in the central nervous system. These cannabinoids also have therapeutic effects in animal models of seizures and epilepsy, leading to the aims of the present study to examine the developmental and behavioral influences of THC on wild-type (WT) and bandoneon (beo) embryos and to compare these effects to those observed after exposure to Lorazepam, a common benzodiazepine used to mitigate spasticity in hyperekplexics. Since both THC and Lorazepam restore balanced signaling, we hypothesized that THC would alleviate spasticity and Lorazepam would serve as a positive control inbeoembryos. We assessed embryonic growth parameters at 24, 48, 72, 96, and 120 hours post fertilization (hpf) following THC (0.2, 0.6, 2.0 and 5.0 mg/L) and Lorazepam (0.02 and 0.2 mg/L) exposure at 0-1hpf in WT and beoembryos. In WT and beoembryos, survival and hatching rates were inversely proportional to THC concentration confirming that THC exposure slows development and can impact survivorship. Morphological anomalies, however, increased with higher THC concentrations. We then assessed embryonic behavior using the innate escape response essential to survival at 24, 48, 72, 96, and 120 hpf following THC (0.2 and 2.0 mg/L) and Lorazepam (0.2 and 0.02 mg/L) exposure. Impacts on escape behavior varied, and when dosed with Lorazepam and THC, individuals displayed similar response times to controls at 24, 96, and 120 hpf. Significant differences in escape behavior times were measured at 48 and 72 hpf, specifically during the coil to relax phase of the escape response. During this time, beocontrol individuals were significantly different than 0.2 mg/L Lorazepam (p<0.0003 and p<0.0001 respectively) and 0.2 mg/L THC (p<0.0014 and p<0.0021 respectively). 0.2 mg/L THC was significantly different from 0.2 mg/L Lorazepam during the coil to relax phase of the escape response at 48 and 72 hpf (p<0.0014 and p<0.0002 respectively) and the total response time at 72 hpf (p<0.0201). These data suggest that THC exposure can deleteriously affect development and the establishment of neural circuits essential to survival, but can also alleviate spasticity symptoms depending on developmental stage and concentration.
... Staphylococci and Streptococci in broth are in the range of 1-5 μg/ml (Klingeren and Ham, 1976 ...
... Staphylococci and Streptococci in broth are in the range of 1-5 μg/ml (Klingeren and Ham, 1976 ...
... As early as 1952, cannabis extracts have been documented to possess antibacterial activity (Krejci 1952;Ferenczy et al. 1958;Radosevic et al. 1962;Turner et al. 1980). Subsequently, individual cannabinoids were analyzed, revealing that a number of cannabinoids are potent antibiotics (Gal and Vajda 1970;Farkas and Andrassy 1976;Van Klingeren and Ten Ham 1976;ElSohley et al. 1982), and even against antibiotic resistant strains (Appendino et al. 2008). Interestingly, this activity, described against methicillin resistant Staphylococcus aureus (MRSA), was not strongly linked to the nature of the prenyl moiety as CBD, CBC, CBG, and THC were all quite active. ...
Chapter
Of the many medicinal plants with therapeutic potential, Cannabis sativa is, by far, the most promising in the near future for large scale utilization. However, the inherent chemical variability of plant based medicines must be addressed, before cannabis can be incorporated into modern medical practices. This chemical variability can only be controlled and potentially optimized if the underlying causes of the production of therapeutic compounds in cannabis is adequately understood. Many of the medically useful compounds produced by plants are the result of the plant stress response. Although not completely clear, there is a significant body of evidence suggesting a similar role for cannabinoids. Cannabinoids are implicating in both, biotic and abiotic stresses, including thermal, nutrient, and water stress, photoradiation, as well as bacterial and fungal pathogens. This chapter will explore the possible ecological roles of cannabinoids in cannabis and the potential utilization of these roles via biotic or abiotic elicitors.
... Antibacterial and antiviral actions. Antibacterial actions have been demonstrated for CBD, CBG and THC (Van Klingeren and Ten Ham 1976). Incubation with THC reduced the infectious potency of herpes simplex viruses (Lancz et al. 1991). ...
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... Over 60 cannabinoids such as cannabidiol, cannabinol, delta 9-tetrahydrocannbinol, tetrahydrocannbivarin, tetrahydrocannbinolic acid, etc. have been identified (McPartland, 1997). Delta 9-tetrahydrocannbinol and other cannabinoids have proven activity against bacteria and fungi (Klingeren and Ham, 1976;McPartland, 1984), their activity against nematodes is not yet established. Cannabis also contains volatile compounds, such as terpenes, ketones, methyl ketones, esters, limonene and several pinenes (Ross and ElSohly, 1996) and are powerful insect repellents (Kashyap et al., 1991). ...
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Because of being costly and pernicious to the environment and human health, the use of nematicides has become prohibitive in many countries and the management of plant parasitic nematodes using antagonistic plants can be a very attractive alternative. In the present studies the effectiveness of aqueous extracts of Cannabis sativa and Zanthoxylum alatum was assessed on hatching, mortality and infectivity of Meloidogyne incognita at different concentrations viz. S, S:1, S:5, S:10, S:25, S:50 and S:100. Both the plants had significant effects on juvenile mortality and hatching inhibition in a dose-dependent manner. Mortality and hatching inhibition caused by C. sativa were significantly higher than that of Z. alatum. Time duration also affected mortality and hatching inhibition significantly. Significant inhibition in invasion of M. incognita juveniles on cucumber cv. Royal Sluis was observed by different treatments with extracts. M. incognita juveniles exposed to ‘S’ extracts of C. sativa and Z. alatum for 24 and 48 h caused no infection. Exposure for 12 and 6 h caused more than 95 and 90% reductions in infectivity of M. incognita juveniles respectively. Similarly, soil drench and root dip treatments also caused significant reductions in infection. Reduction in infectivity was found to be significantly higher with extracts of C. sativa as compared to Z. alatum and decreased in a dose-responsive manner. The results of the studies showed that the extracts of test plants, commonly found locally, possess high potentials for the control of root-knot nematodes and could be the possible replacement for synthetic nematicides.
... Much effort has been focused on determining the distribution, nature and practical use of plant derived substances that have nematode-antagonistic activity. Naturally occurring nematicidal compounds towards M. incognita include pyrrolizidine alkaloids (Kinghorn and Smolenski, 1981), trans-anethole (Oka et al., 2000b), p-anisaldehyde, trans-cinnamaldehyde, 2-furaldehyde and benzaldehyde (Oka, 2001). In the present study, the nematicidal principles/properties of C. sativa might be due to presence of cannabinoids. ...
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a b s t r a c t In view of the recently increased interest in developing plant origin nematicides as a surrogate to chemical nematicides, the present study was carried out to assess the nematicidal potential of two antagonistic plants Cannabis sativa L. (Cannabaceae) and Zanthoxylum alatum Roxb. (Rutaceae) against the most devastating root-knot nematode, Meloidogyne incognita responsible for colossal yield losses in cucumber. The leaves of C. sativa and Z. alatum were incorporated in the soil at the rate of 0, 2, 4, 6, 8, 10 and 20 g per kg of soil. After decomposition, cucumber (cv. Royal Sluis) seeds were sown and inoculated with 2000 s stage juveniles of M. incognita ten days after emergence. Data on growth variables and nematode infestations were recorded after six weeks of inoculation. Both the plants significantly reduced nematode infestations and enhanced plant growth criteria compared to the untreated check. The reductions in number of galls, egg masses, nematode fecundity and build up caused by C. sativa were significantly higher as compared to Z. alatum. Maximum reductions in these variables were recorded with 20 g dosage. The addition of C. sativa and Z. alatum to the soil as organic amendment can work very well as nematicides and can be successfully used for controlling root-knot nematodes replacing tradi-tional chemical treatments and avoiding environmental pollution.
... CBD reportedly has little or no effect on the immune system (reviewed byKlein et al. 1998), although the mouse arthritis study byMalfait et al. (2000)showed CBD decreases the production of tumor necrosis factor (TNF) and Interferon-gamma (IFN-γ), which are two immunomodulatory cytokines described later. CBD actually kills bacteria and fungi, with greater potency than THC (Klingeren and Ham 1976;ElSohly et al. 1982;McPartland 1984). Thus, cannabis may have less microbial contamination than other herbs, an important consideration for immunocompromised individuals (McPartland and Pruitt 1997). ...
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. A central tenet underlying the use of botanical remedies is that herbs contain many active ingredients. Primary active ingredients may be enhanced by secondary compounds, which act in beneficial syn-ergy. Other herbal constituents may mitigate the side effects of dominant active ingredients. We reviewed the literature concerning medical can-nabis and its primary active ingredient, ∆ 9 -tetrahydrocannabinol (THC). Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC. Other cannabinoid and non-cannabinoid compounds in herbal cannabis or its extracts may reduce THC-induced anxiety, cholinergic deficits, and immunosuppression. Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activ-ity. [Article copies available for a fee from The Haworth Document Delivery Service: and: Cannabis Therapeutics in HIV/AIDS (ed: Ethan Russo) The Haworth Integrative Healing Press, an imprint of The Haworth Press, Inc., 2001, pp. 103-132. Single or multiple copies of this arti-cle are available for a fee from The Haworth Document Delivery Service [1-800-342-9678, 9:00 a.m. -5:00 p.m. (EST). E-mail address: getinfo@haworthpressinc.com].
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Multidrug-resistant (MDR) Gram-negative pathogens remain an unmet public health threat. In recent times, increased rates of resistance have been reported not only to commonly used antibiotics, but also to the last-resort antibiotics, such as polymyxins. More worryingly, despite the current trends in resistance, there is a lack of new antibiotics in the drug-discovery pipeline. Hence, it is imperative that new strategies are developed to preserve the clinical efficacy of the current antibiotics, particularly the last-line agents. Combining conventional antibiotics such as polymyxins with non-antibiotics (or adjuvants), has emerged as a novel and effective strategy against otherwise untreatable MDR pathogens. This review explores the available literature detailing the latest polymyxin/non-antibiotic combinations, their mechanisms of action, and potential avenues to advance their clinical application.
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Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.
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Novel antimicrobial drugs are urgently needed to counteract the increasing occurrence of bacterial resistance. Extracts of Cannabis sativa have been used for the treatment of several diseases since ancient times. However, its phytocannabinoid constituents are predominantly associated with psychotropic effects and medical applications far beyond the treatment of infections. It has been demonstrated that several cannabinoids show potent antimicrobial activity against primarily Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). As first in vivo efficacy has been demonstrated recently, it is time to discuss whether cannabinoids are promising antimicrobial drug candidates or overhyped intoxicants with benefits.
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The cannabinoid cannabidiol (CBD) is characterised in this study as a helper compound against resistant bacteria. CBD potentiates the effect of bacitracin (BAC) against Gram-positive bacteria (Staphylococcus species, Listeria monocytogenes, and Enterococcus faecalis) but appears ineffective against Gram-negative bacteria. CBD reduced the MIC value of BAC by at least 64-fold and the combination yielded an FIC index of 0.5 or below in most Gram-positive bacteria tested. Morphological changes in S. aureus as a result of the combination of CBD and BAC included several septa formations during cell division along with membrane irregularities. Analysis of the muropeptide composition of treated S. aureus indicated no changes in the cell wall composition. However, CBD and BAC treated bacteria did show a decreased rate of autolysis. The bacteria further showed a decreased membrane potential upon treatment with CBD; yet, they did not show any further decrease upon combination treatment. Noticeably, expression of a major cell division regulator gene, ezrA, was reduced two-fold upon combination treatment emphasising the impact of the combination on cell division. Based on these observations, the combination of CBD and BAC is suggested to be a putative novel treatment in clinical settings for treatment of infections with antibiotic resistant Gram-positive bacteria.
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The spread of antimicrobial resistance continues to be a priority health concern worldwide, necessitating exploration of alternative therapies. Cannabis sativa has long been known to contain antibacterial cannabinoids, but their potential to address antibiotic resistance has only been superficially investigated. Here, we show that cannabinoids exhibit antibacterial activity against MRSA, inhibit its ability to form biofilms and eradicate stationary phase cells persistent to antibiotics. We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic infection model caused by MRSA. We also show that cannabinoids are effective against Gram-negative organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane. Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for cannabinoids.
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Cannabis microbial testing presents unique challenges. Unlike food testing, cannabis testing has to consider various routes of administration beyond just oral administration. Cannabis flowers produce high concentrations of antimicrobial cannabinoids and terpenoids and thus represent a different matrix than traditional foods 1, 2. In 2018, it is estimated that 50% of cannabis is consumed via vaporizing or smoking oils and flowers while the other half is consumed in Marijuana Infused Products or MIPs. Transdermal patches, salves and suppositories all present unique microbial safety considerations. Since the most harmful cannabis microbes are endophytes (live in side the plant), culture based plating system fail to adequately survey the microbial risks. The pros and cons of DNA based methods and culture based methods are discussed.
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The anti-cancer effect of the plant-derived cannabinoid, cannabidiol, has been widely demonstrated both in vivo and in vitro. However, this body of preclinical work has not been translated into clinical use. Key issues around this failure can be related to narrow dose effects, the cell model used and incomplete efficacy. A model of acute lymphoblastic disease, the Jurkat T cell line, has been used extensively to study the cannabinoid system in the immune system and cannabinoid-induced apoptosis. Using these cells, this study sought to investigate the outcome of those remaining viable cells post-treatment with cannabidiol, both in terms of cell size and tracking any subsequent recovery. The phosphorylation status of the mammalian Target of Rapamycin (mTOR) signaling pathway and the downstream target ribosomal protein S6, were measured. The ability of cannabidiol to exert its effect on cell viability was also evaluated in physiological oxygen conditions. Cannabidiol reduced cell viability incompletely, and slowed the cell cycle with fewer cells in the G2/M phase of the cell cycle. Cannabidiol reduced phosphorylation of mTOR, PKB and S6 pathways related to survival and cell size. The remaining population of viable cells that were cultured in nutrient rich conditions post-treatment were able to proliferate, but did not recover to control cell numbers. However, the proportion of viable cells that were gated as small, increased in response to cannabidiol and normally sized cells decreased. This proportion of small cells persisted in the recovery period and did not return to basal levels. Finally, cells grown in 12% oxygen (physiological normoxia) were more resistant to cannabidiol. In conclusion, these results indicate that cannabidiol causes a reduction in cell size, which persists post-treatment. However, resistance to cannabidiol under physiological normoxia for these cells would imply that cannabidiol may not be useful in the clinic as an anti-leukemic agent.
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With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Δ(9)-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.
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This article summarizes current knowledge about the medicinal value of cannabis and its principal psychoactive ingredient, delta 9-tetrahydrocannabinol (THC), particularly in the control of nausea and vomiting, in glaucoma, and in reduction of spasticity in multiple sclerosis. The major issues in the controversy about marijuana and medicine, primarily moral and ethical, are discussed.
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Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.
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The rate and extent of glass binding of Δ9 -tetrahydrocannabinol in aqueous solution depend on the surface area and pretreatment of glass and the concentration of the drug. A total of 20 and 40% at 0.1 and 0.05 μg/ml, respectively, was bound to 50-ml volumetric flasks but could be minimized by silyl pretreatment of the glass. The drug rapidly diffused into plastics, and 70–97% was taken up by the rubber closures used for plasma vials. These bindings precluded classical methods of solubility determination, so spectral and particle-size counting determinations, which observed those concentrations at which true solution was terminated, were used. The aqueous solubility was a linear function of both the ethanol concentration (increasing) at constant ionic strength and the square root of the ionic strength (decreasing) at constant ethanol concentration. The salting-out coefficient was of high magnitude and typical solubilities were 2.8 mg/liter in water and 0.77 mg/liter in 0.15 M NaCl at 23°. The bindings also precluded the use of the classical methods of equilibrium dialysis and ultrafiltration to determine the protein binding of tetrahydrocannabinol. A method of variable plasma concentrations was devised, so protein binding was determined from the pseudoplasma concentrations of the drug after the separation of the pseudoplasma from the red blood cells added to form pseudoblood with known concentrations of Δ9 -tetrahydrocannabinol. This use of the competition between the high partitioning of drug between red blood cells with plasma water (D = 12.5) and the binding to plasma protein permitted an estimate of 97% binding which was not drug concentration dependent. The spectrophotometric pKa' of Δ9 -tetrahydrocannabinol was 10.6. Δ9 -Tetrahydrocannabinol degraded readily in acid solutions. Subsequent to a rapid loss, the kinetics appeared to be first-order and specific hydrogen-ion catalyzed. Concomitantly, small amounts of Δ8 -tetrahydrocannabinol were produced, as were two GLC observable products, P2 and P3, and the rate of their appearance appeared to parallel the rate of Δ9 -tetrahydrocannabinol degradation. A peak, P1, also appeared almost instantaneously but did not parallel drug degradation.
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Δ1-Tetrahydrocannabinol-3H is almost completely metabolized to more polar metabolites after intravenous (i.v.) injection in the rabbit. About 35 per cent of the dose is excreted in the urine during the first 24 hr as compared to only 10 per cent in the faeces. A considerable amount (4–10 per cent) of the radioactivity excreted in the 24-hr urine is extractable with ether and upon acidification of the urine the extractable amount increases four times or more. At least three major metabolites of Δ1-THC-3H are excreted in the urine. The half-life of radioactivity in blood after i.v. injection of Δ1-tetrahydrocannabinol-3H ranged from 7 to 16 min. The compound is rapidly metabolized and 30 min after i.v. administration of †1-tetrahydrocannabinol-3H, only 3–4 per cent of the radioactivity in the blood is due to unchanged compound. The blood level of an ether-soluble metabolite reaches its maximum 0.5–2 hr after injection. Thus, the formation of a pharmacologically active metabolite cannot be excluded at present. The distribution of radioactivity in tissues largely reflect the elimination of Δ1-tetrahydrocannabinol-3H through liver and kidneys. Brain and spinal cord show the lowest activity levels of all the investigated tissues. Three days after administration high levels of radioactivity still persist in body fat and spleen.