No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Beyond Cannabis: Plants and the Endocannabinoid System
Abstract
Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review.
... Scientists believe that the ECS evolved in primitive animals approximately 600 million years ago and it has been called one of the most significant medical findings in the 20 th century (Russo, 2016a). It is an important system of the human body and understanding its functions is central to understanding how and why cannabis can be both an effective medicine and a recreational pleasure. ...
... arachidonoyl glycerol (2-AG) (McPartland & Russo, 2014;Mechoulam, Fride, & Di Marzo, 1998). Endocannabinoids act as transmitters and AEA and 2-AG bind to and activate multiple receptors including CB 1, CB 2, and TRPV1 (Russo, 2016a). ...
... Endo means within, in this case, the body, so unlike THC, which is a phytocannabinoid, endogenous cannabinoids are naturally produced by human cells (Russo, 2016a). Endocannabinoids appear to be made on-demand within the body and used only when needed -nor are they stored in the body for later (Russo, 2016a). ...
Contents at a glance
At a time when cannabis legalisation is spreading across an increasing number of jurisdictions globally, this book cuts across the noise and presents a factual account of issues faced by regulators in the real-world context of Colorado. It can be read as an evidence-based handbook for regulators and should be a first port of call for anyone interested in the legalisation of cannabis.
In January 2014, Colorado implemented a commercial cannabis market for pleasure - the first jurisdiction globally to implement a regulated, adult-use cannabis supply chain from seed-to-sale. It was reported as an historic occasion that presaged a grand social and economic experiment in drug legalisation.
Including analysis of hundreds of pages of government documents, almost 1000 media articles, and interviews in the field with over 30 senior government officials, industry executives, and front-line public health representatives, this book is the definitive account of real-world cannabis policy implementation.
The cannabis academic public health literature is examined prodigiously including its potential for harm and benefit together with alternative regulatory approaches. The book also features a number of papers published in academic journals based on the PhD research of the author. The commodification of cannabis vs the craft approach together with the entanglement of the medical and recreational markets are two of many topical themes discussed in detail.
Multiple recommendations relevant for other jurisdictions considering the legalisation of cannabis are presented. Recognising the limitations of harm reduction approaches that cannot conceptually conceive beneficial aspects of cannabis consumption, a new framework, the spectrum of wellness is proposed as an alternative in Appendix 1 of the book.
... This is why it's critical to consume an Omega-3 to Omega-6 ratio of 1:1. The usual American diet is far too high in Omega-6 fatty acids (1:10) [45]. Hemp seeds, walnuts, chia seeds, flax seeds, and their oil; eggs, yogurt, sardines, and anchovies (seafood) are some worthy sources of omega-3 to encourage balance with omega-6 [45]. ...
... The usual American diet is far too high in Omega-6 fatty acids (1:10) [45]. Hemp seeds, walnuts, chia seeds, flax seeds, and their oil; eggs, yogurt, sardines, and anchovies (seafood) are some worthy sources of omega-3 to encourage balance with omega-6 [45]. ...
... Interestingly, this trend in higher combined effectiveness extended to WIN 55,212-2, a highly potent synthetic analogue of THC. Researchers showed that melanoma cell lines have reduced viability when exposed to a combination of CBD and THC and were more effective than those exposed to only THC [166]. ...
... However, terpenoid related synergistic interaction is not a result of TRPA1 or TRPA2 modulation [172] nor through direct binding interactions to CR 1 and 2 [166]. Knowledge of the mechanisms by which terpenoids and other polyphenols interact within the ECS are limited. ...
Melanoma is deadly, physically impairing, and has ongoing treatment deficiencies. Current treatment regimens include surgery, targeted kinase inhibitors, immunotherapy, and combined approaches. Each of these treatments face pitfalls, with diminutive five-year survival in patients with advanced metastatic invasion of lymph and secondary organ tissues. Polyphenolic compounds, including cannabinoids, terpenoids, and flavonoids; both natural and synthetic, have emerging evidence of nutraceutical, cosmetic and pharmacological potential, including specific anti-cancer, anti-inflammatory, and palliative utility. Cannabis sativa is a wellspring of medicinal compounds whose direct and adjunctive application may offer considerable relief for melanoma suffers worldwide. This review aims to address the diverse applications of C. sativa’s biocompounds in the scope of melanoma and suggest it as a strong candidate for ongoing pharmacological evaluation.
... Indeed, in recent years there have been numerous attempts to find phytocannabinoids in other plants. 20 Alas, so far the results are not satisfactory enough, as the revealed compounds have only low or moderate affinities toward CB1, unsatisfactory intrinsic activity and their pharmacological relevance has not been fully determined. 20 Therefore, there is a huge potential in finding new non-Cannabis phytocannabinoids with a more favorable pharmacological profile. ...
... 20 Alas, so far the results are not satisfactory enough, as the revealed compounds have only low or moderate affinities toward CB1, unsatisfactory intrinsic activity and their pharmacological relevance has not been fully determined. 20 Therefore, there is a huge potential in finding new non-Cannabis phytocannabinoids with a more favorable pharmacological profile. ...
Cannabinoid receptor type 1 (CB1) is an important modulator of many key physiological functions and thus a compelling molecular target. However, safe CB1 targeting is a non-trivial task. In recent years, there has been a surge of data indicating that drugs successfully used in the clinic for years (e.g. paracetamol) show CB1 activity. Moreover, there is a lot of promise in finding CB1 ligands in plants other than Cannabis sativa. In this study, we searched for possible CB1 activity among already existing drugs, their metabolites, phytochemicals, and natural-like molecules. We conducted two iterations of virtual screening, verifying the results with in vitro binding and functional assays. The in silico procedure consisted of a wide range of structure- and ligand-based methods, including docking, molecular dynamics, and quantitative structure-activity relationship (QSAR). As a result, we identified travoprost and ginkgetin as CB1 ligands, which provides a starting point for future research on the impact of their metabolites or preparations on the endocannabinoid system. Moreover, we found five natural-like compounds with submicromolar or low micromolar affinity to CB1, including one mixed partial agonist/antagonist viable for hit-to-lead phase. Finally, the computational procedure established in this work will be of use for future screening campaigns for novel CB1 ligands.
... 3 Research on the compound languished thereafter for decades, and CBG was passed over for testing in the 1970s in pioneering human bioassay experiments. 4 Although it is a common misconception that phytocannabinoids occur in Nature solely in the cannabis plant, CBG was previously extracted from Helichrysum umbraculigerum 5,6 in 1979. This botanical medicine is known to be used by South African healers, 7,8 with species of the genus employed for headaches, menstrual pain, and wound dressings, even smoked for treatment of pain. ...
... Conditions are listed in order of the % who endorsed use for the condition. 6 RUSSO ET AL. ...
Introduction: Cannabigerol (CBG), and its precursor before decarboxylation, cannabigerolic acid is sometimes labeled the "mother of all cannabinoids." The purpose of the present study was to investigate reasons for use and self-reported therapeutic effects in CBG-predominant cannabis users. Usage patterns and adverse effects, including withdrawal symptoms were also explored. Methods: Cannabidiol-predominant cannabis users were recruited online to complete an online survey assessing CBG use patterns, conditions treated with CBG-predominant cannabis (containing >50% CBG), perceived efficacy, associated adverse events, and withdrawal symptoms. One hundred twenty-seven eligible participants (U.S. residents ages 21+ who reported using CBG-predominant cannabis in the past 6 months) completed the survey. Results: Most of the samples (n=65; 51.2%) reported use of CBG-predominant products solely for medical purposes (n=46; 36.2% reported use for medical and recreational purposes; n=8; 6.3% reported recreational use only, and n=8 were missing). The most common conditions the complete sample reported using CBG to treat were anxiety (51.2%), chronic pain (40.9%), depression (33.1%), and insomnia/disturbed sleep (30.7%). Efficacy was highly rated, with the majority reporting their conditions were "very much improved" or "much improved" by CBG. Furthermore, 73.9% claimed superiority of CBG-predominant cannabis over conventional medicines for chronic pain, 80% for depression, 73% for insomnia, and 78.3% for anxiety. Forty-four percent of CBG-predominant cannabis users reported no adverse events, with 16.5% noting dry mouth, 15% sleepiness, 11.8% increased appetite, and 8.7% dry eyes. Around 84.3% reported no withdrawal symptoms, with sleep difficulties representing the most frequently endorsed withdrawal symptom (endorsed by two respondents). Conclusions: This is the first patient survey of CBG-predominant cannabis use to date, and the first to document self-reported efficacy of CBG-predominant products, particularly for anxiety, chronic pain, depression, and insomnia. Most respondents reported greater efficacy of CBG-predominant cannabis over conventional pharmacotherapy, with a benign adverse event profile and negligible withdrawal symptoms. This study establishes that humans are employing CBG and suggests that CBG-predominant cannabis-based medicines should be studied in randomized controlled trials.
... Cannabis hemp and drug types also differ in their relative yield of cannabidiolic acid (CBDA) and 9-tetrahydrocannabinolic acid (THCA), the two most abundant and studied of at least 100 unique secondary metabolites known as cannabinoids (8). After decarboxylation, their bioactive forms (the well-known CBD and psychoactive THC) bind to endocannabinoid receptors in an animal's central nervous system, eliciting a broad range of effects, some of which may alleviate symptoms of neurological disorders (9)(10)(11)(12)(13)(14). Hemp cultivated for fiber typically produces higher concentrations of CBDA than THCA, whereas marijuana contains very high amounts of THCA and much higher overall levels of cannabinoids. ...
... S1; see Materials and Methods). We characterized the genetic relationships among all Cannabis accessions using maximum likelihood (ML) phylogeny (rooted on Humulus lupulus), as well as admixture and principal component analysis (PCA; Fig. 1 13 landraces, and 20 cultivars). The third group (Drug-type feral, group C) contains at its base 3 feral samples collected in southern China, 11 feral plants collected in India and Pakistan south of the Himalayas, and one drug cultivar from India. ...
Cannabis sativa has long been an important source of fiber extracted from hemp and both medicinal and recreational drugs based on cannabinoid compounds. Here, we investigated its poorly known domestication history using whole-genome resequencing of 110 accessions from worldwide origins. We show that C. sativa was first domesticated in early Neolithic times in East Asia and that all current hemp and drug cultivars diverged from an ancestral gene pool currently represented by feral plants and landraces in China. We identified candidate genes associated with traits differentiating hemp and drug cultivars, including branching pattern and cellulose/lignin biosynthesis. We also found evidence for loss of function of genes involved in the synthesis of the two major biochemically competing cannabinoids during selection for increased fiber production or psychoactive properties. Our results provide a unique global view of the domestication of C. sativa and offer valuable genomic resources for ongoing functional and molecular breeding research.
... CBN is a THC metabolite, with potential immunosuppressive and anti-inflammatory activities. THC exhibits a great homeostatic influence at the Central Nervous System (CNS) (Glass et al., 1997;Russo, 2016). CBD is considered a non-psychoactive agent and CB1 and CB2 receptors antagonist, even in small concentrations (Russo, 2011;André, Hausman, Guerreiro, 2016). ...
... CBD is considered a non-psychoactive agent and CB1 and CB2 receptors antagonist, even in small concentrations (Russo, 2011;André, Hausman, Guerreiro, 2016). Researches have been revealed the cannabinoids potentialities on the treatment of neuropathic, pelvic, pancreatic pains, fibromyalgia, overactive bladder, dermatological diseases, migraine, irritable bowel syndrome, among others (Russo, 2016). The finding of new Cannabis constituents has been exponential and constant due to the growing interest in the therapeutic potential shown by strains (Russo, 2004;WHO, 2015). ...
The therapeutic properties of Cannabis have been described since antiquity and are of great relevance for the Egyptian, Chinese, Indian, Arab and Latin people. Cannabis-based medicines show several therapeutic purposes, mainly to treat disorders as constipation, some types of pain, epilepsy, anxiety and among others. In addition, the genus Cannabis exhibits great clinical relevance due to its Central Nervous System activities attributed to some phytochemicals compounds, as cannabidiol and Δ9-tetrahydrocannabinol. The interest in the pharmacological properties of Cannabis is growing and several new studies are being carried out to prove its pharmacotherapeutic use which are important to design of novel drugs with different routes of administration and for multiple pathologies resistant to the conventional treatments. In this context, there is a pressure on countries to review the laws that still limit the research development related to medicinal Cannabis purposes. Herein, our aim is to perform an overview about the plant, endocannabinoid system, Cannabis-based medicines and clinical uses, regulatory aspects of Cannabis sp and its chemical compounds of therapeutic interest.
... The regulatory function of the EC system is homeostasis of the brain, the endocrine system, and the immune system (McPartland et al. 2014;Turcotte et al. 2015;Sallaberry and Astern 2018;Penn 2019). Unlike the endocrine system, the EC system is considered a "silent" system that is activated on demand and in response to neuronal activity (Alger 2013;Russo 2016;Penn 2019). ECs are synthesized from cell membrane components in the brain and from multiple organs in the periphery, where the respective receptors (CB1 and CB2), to which the ECs are able to bind, are expressed (Alger 2013;Sallaberry and Astern 2018). ...
... Functionally, ECs and EC-like compounds are highly diverse: they regulate sleep, reduce pain, inhibit motoric action, affect memory and emotions, induce appetite, and have rewardreinforcing effects (Pagotto et al. 2005;Di Marzo and Petrosino 2007;Russo 2016). A general function assigned to ECs is the maintenance of health (Di Marzo and Petrosino 2007;Acharya et al. 2017;Penn 2019). ...
Quantifying physiological challenges has gained increasing importance in evolutionary biology, behavioral physiology, and conservation. One matrix that is particularly useful for obtaining long-term records of physiological changes in mammals is hair. Potential markers are components of the endocannabinoid (EC) system, which regulates homeostasis of the brain as well as the endocrine and immune systems. Here, we present results from the first study to measure ECs (anandamide [AEA], 2-archidonyl glycerol [2-AG]) and EC-like compounds (N-palmitoylethanolamine [PEA], N-oleoylethanolamine [OEA], N-stearoylethanolamine [SEA]) in the hair of a nonhuman primate. We found that AEA, SEA, PEA, and OEA can be reliably measured in hair samples. When comparing the measurements of hair from different body parts, we found that variations of some analytes suggest that hair location is likely to affect results. For changes in health status, measurements of ECs and EC-like compounds reflected differences at both intra- and interindividual levels. We concluded that the EC system potentially provides novel tools to assess well-being, health status, and metabolic stress-not only in the hair of humans but also in that of domestic and wild animals. Measuring changes in ECs and EC-like compounds may improve the long-term monitoring of health status in captive and wild primates and may serve as a useful measure in animal welfare programs.
... Researchers also draw attention to the possible neuroprotective effect of cannabinoids, which could be observed as a result of the complex mechanism involving not only the direct activity towards CB1 and CB2 receptors but also the indirect activity towards serotonin receptors and other processes, including those related to the reduction of oxidative stress [33]. There are reports indicating that in some diseases, such as migraines, irritable bowel syndrome, multiple sclerosis, or Parkinson's disease, the functioning of the endocannabinoid system may be weakened; thus, in these health problems, the use of phytocannabinoids could be beneficial [34]. ...
Cannabinoids are active substances present in plants of the Cannabis genus. Both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved several medicinal products containing natural cannabinoids or their synthetic derivatives for the treatment of drug-resistant epilepsy, nausea and vomiting associated with cancer chemotherapy, anorexia in AIDS patients, and the alleviation of symptoms in patients with multiple sclerosis. In fact, cannabinoids constitute a broad group of molecules with a possible therapeutic potential that could be used in the management of much more diseases than mentioned above; therefore, multiple preclinical and clinical studies on cannabinoids have been carried out in recent years. Danio rerio (zebrafish) is an animal model that has gained more attention lately due to its numerous advantages, including easy and fast reproduction, the significant similarity of the zebrafish genome to the human one, simplicity of genetic modifications, and body transparency during the early stages of development. A number of studies have confirmed the usefulness of this model in toxicological research, experiments related to the impact of early life exposure to xenobiotics, modeling various diseases, and screening tests to detect active substances with promising biological activity. The present paper focuses on the current knowledge of the endocannabinoid system in the zebrafish model, and it summarizes the results and observations from studies investigating the pharmacological effects of natural and synthetic cannabinoids that were carried out in Danio rerio. The presented data support the notion that the zebrafish model is a suitable animal model for use in cannabinoid research.
... The ECS is a cell-signalling system that plays a critical role in maintaining homeostasis. The key physiological functions of the ECS include modulating cognition, mood, sleep, metabolism, and cardiovascular and immune system function (Karl et al., 2012;Russo, 2016;Sinclair, 2020). The ECS consists of Gprotein-coupled receptors, including cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), peroxisome proliferator-activated receptors (PPAR), and transient receptor potential cation channel (TRP) subfamily V member 1 (TRPV1) receptors (Iannotti & Vitale, 2021). ...
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.
... Interpretation of these findings is further complicated by the suggestion that CBD is not, by itself, sedating. Although cannabis high in CBD can produce lethargy (Crippa et al., 2004;Pearce et al., 2014;Zhornitsky & Potvin, 2012), it has been argued (Russo, 2011(Russo, , 2016(Russo, , 2017) that those effects actually are caused by the terpene βmyrcene, which often co-occurs with CBD. And because concentrations of β-myrcene vary considerably among strains, it follows that sedating properties of these strains, and possibly the crash risk, may vary as well. ...
Background:
β-myrcene, one of the most common terpenes found in cannabis, has been associated with sedation. We propose that β-myrcene contributes to driving impairment even in the absence of cannabinoids.
Aim:
To conduct a double-blind, placebo-controlled crossover pilot study of the effect of β- myrcene on performance on a driving simulator.
Method:
A small sample (n=10) of participants attended two experimental sessions, one in which they were randomized to receive 15 mg of pure β-myrcene in a capsule versus a canola oil control. Each session, participants completed a baseline block and three follow-up blocks on a STISIM driving simulator.
Results:
β-myrcene was associated with statistically significant reductions in speed control and increased errors on a divided attention task. Other measures did not approach statistical significance but fit the pattern of results consistent with the hypothesis that β-myrcene impairs simulated driving.
Conclusions:
This pilot study produced proof-of-principle evidence that the terpene β-myrcene, an agent commonly found in cannabis, can contributes to impairment of driving-related skills. Understanding how compounds other than THC affect driving risk will strengthen the field's understanding of drugged driving.
... Sabe-se que as funções dos ligantes endógenos estão associadas a modulações sinápticas excitatórias e/ou inibitórias que atuam através de um mecanismo de demanda de canabinoides endógenos em membranas pós-sinápticas. Essa modulação é responsável por ativar receptores CB1 resultando em diminuição de neurotransmissores e, mesmo que, pouco frequente, tal fato também pode ser observado em receptores CB2 [37][38][39][40] . ...
O objetivo desse estudo foi identificar o conhecimento sobre fitoterapia na população pernambucana, bem como os fatores associados. Realizou-se estudo transversal de abordagem quantitativa teve sua coleta de dados remota a partir de um questionário online; e buscou extrair informações sobre o perfil dos participantes, utilização e conhecimento sobre fitoterapia. Os dados foram submetidos a testes estatísticos para verificar associações significantes (p=0.05). A pesquisa foi aprovada pelo Comitê de Ética em Pesquisa da Universidade de Pernambuco. Dentre 372 indivíduos, 80,6% relataram conhecer o tema. Os fatores associados ao conhecimento sobre a fitoterapia foram idade superior a 25 anos, residência na capital pernambucana, ensino superior completo, remuneração maior que três salários mínimos, raça/cor branca, residência com até, no máximo, duas pessoas e uso da fitoterapia (p < 0.05). Há desigualdade no acesso à informação, tornando necessárias estratégias de educação em saúde para populações mais vulneráveis e regiões menos desenvolvidas.
... Sabe-se que as funções dos ligantes endógenos estão associadas a modulações sinápticas excitatórias e/ou inibitórias que atuam através de um mecanismo de demanda de canabinoides endógenos em membranas pós-sinápticas. Essa modulação é responsável por ativar receptores CB1 resultando em diminuição de neurotransmissores e, mesmo que, pouco frequente, tal fato também pode ser observado em receptores CB2 [37][38][39][40] . ...
A Cannabis sativa L. (Cannabaceae) é utilizada pelo ser humano a milhares de anos, sendo uma planta, atualmente, muito estudada no desenvolvimento de medicamentos, e o seu uso medicinal in natura têm sido amplamente discutido, dada a sua potencialidade farmacológica. O presente artigo descreveu os aspectos farmacológicos e a legislação associados à Cannabis sativa L. no Brasil através de uma revisão de literatura, feita por meio de consultas em bases de dados indexadas e portais institucionais. Cannabis sativa L. possui uma ampla variedade de substâncias químicas, sendo o delta-9-tetra-hidrocanabinol, canabidiol, canabigerol, canabinol e o delta-8-tetra-hidrocanabinol os mais conhecidos e estudados. O organismo humano apresenta uma série de receptores canabinoides, e a modulação desses receptores está associada ao uso medicinal da planta. No Brasil, a utilização de Cannabis sativa L. e seus derivados passaram por inúmeras fases legais, desde a criminalização, a partir de 1932, até a autorização de medicamentos contendo canabinoides, em 2019. No contexto tecnológico e científico existe uma constante busca por elucidar as potencialidades da planta. Porém, esses fatores confrontam com os aspectos legais e sociais.
... Cannabis use to control pain in OA patients is continuously increasing, with numerous preclinical studies supporting its efficacy. [10][11][12] Cannabinoids exert their effects by targeting the endocannabinoid system (ECS), a homeostatic regulator of neurotransmitter activity that functions in the brain, skin, digestive tract, liver, cardiovascular system, genitourinary function, bone, 13 and most relevantly cartilage. [14][15][16] The ECS consists predominantly of anandamide (AEA) and 2arachidonoylglycerol (2-AG), which regulate pain through cannabinoid receptors. ...
Introduction: Osteoarthritis (OA) is disabling and degenerative disease of the joints that is clinically characterized by pain and loss of function. With no disease-modifying treatment available, current therapies aim at pain management but are of limited efficacy. Cannabis products, specifically cannabinoids, are widely used to control pain and inflammation in many diseases with no scientific evidence demonstrating their efficacy in OA. Objective: We investigated the effects of non-euphorigenic cannabis extracts, CBD oil and cannabigerol oil (CBG oil), on pain and disease progression in OA mice. Methods and Results: Twelve-week-old male C57BL/6J mice received either sham or destabilization of the medial meniscus (DMM) surgery. DMM mice were treated with vehicle, CBD oil, or CBG oil. The gait of DMM mice was impaired as early as 2 weeks following surgery and continued deteriorating until week 8, which was restored by CBD oil and CBG oil treatments throughout the disease course. Mechanical allodynia developed in DMM mice, however, was not ameliorated by any of the treatments. On the other hand, both CBD oil and CBG oil ameliorated cold allodynia. In open field test, both oil treatments normalized changes in the locomotor activity of DMM mice. CBD oil and CBG oil treatments significantly reduced synovitis in DMM mice. Only CBG oil reduced cartilage degeneration, chondrocyte loss, and matrix metalloproteinase 13 expression, with a significant increase in the number of anabolic chondrocytes. Subchondral bone remodeling found in vehicle-treated DMM mice was not ameliorated by either CBD or CBG oil. Conclusions: Our results show evidence for the therapeutic efficacy of CBD oil and CBG oil, where both oils ameliorate pain and inflammation, and improve gait and locomotor activity in OA mice, representing clinical pain and function. Importantly, only CBG oil is chondroprotective, which may provide superior efficacy in future studies in OA patients.
... It is currently know that cannabis or its components exert their biological effects through several receptors that take part of the Endocannabinoid System (eCB) [14]. This system is a disseminated network of receptors, signalling molecules, and metabolic/ catabolic enzymes and its main functions comprise preserving the homeostasis of central nervous system, cognition and memory mechanisms and controlling of motor function and signs of analgesia. ...
Objective
Cannabis sativa is a recreational drug commonly consumed in Europe and is getting popularity for both recreational and therapeutic use. In some individuals, the use of cannabis leads to psychotic disorders. This systematic review summarizes the current evidence linking genetic polymorphisms and inter-individual susceptibility to psychosis induced by cannabis.
Method
Studies published from 2005 to 2020 were identified through Medline using PubMed, Web of Science and Scopus database and searches were conducted according to PRISMA guidelines. Initial search was performed with terms: “cannabis induced psychosis” AND “genetics”.
Results
From the initial group of 108 papers, 18 studies met our inclusion criteria. Many of the findings revealed associations with genetic polymorphisms modulations of genes involved directly (COMT, DRD2 and DAT) or indirectly (AKT1) to dopamine pathways. The most consistent finding was with COMT rs4680, where the presence of the Val allele was associated with a higher risk for cannabis-induced psychosis. This higher susceptibility was also reported for AKT1 (rs2494732) with the CC genotype. Of note, the only genome-wide association study identified a significant signal close to the cholinergic receptor muscarinic 3 represented by rs115455482 and rs74722579 predisposing to cannabis-induced hallucinations and remarkably no dopaminergic target was found.
Conclusion
Actual evidence supports the role of dopamine in cannabis induced psychosis. However, most of genetic polymorphism studies have as a starting point the pre-existing dopaminergic theoretical basis for psychosis. This alerts to the importance of more broad genetic studies. Integrate genetic results into biological systems may enhance our knowledge of cannabis induced psychosis and could help in the prevention and treatment of these patients.
... Cannabinoid derivatives that were previously detected by MS methods are presented in Figure 1 (Berman et al., 2018;Citti et al., 2019a;Citti et al., 2019b;Linciano et al., 2020). Though initially considered unique to the Cannabis plant, other plant-derived natural products that are able to interact with ECS receptors were later discovered in other types of plants, such as Radula marginata and Piper nigrum (Gertsch et al., 2010;Russo, 2016). ...
Medical Cannabis and its major cannabinoids (−)-trans-Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are gaining momentum for various medical purposes as their therapeutic qualities are becoming better established. However, studies regarding their efficacy are oftentimes inconclusive. This is chiefly because Cannabis is a versatile plant rather than a single drug and its effects do not depend only on the amount of THC and CBD. Hundreds of Cannabis cultivars and hybrids exist worldwide, each with a unique and distinct chemical profile. Most studies focus on THC and CBD, but these are just two of over 140 phytocannabinoids found in the plant in addition to a milieu of terpenoids, flavonoids and other compounds with potential therapeutic activities. Different plants contain a very different array of these metabolites in varying relative ratios, and it is the interplay between these molecules from the plant and the endocannabinoid system in the body that determines the ultimate therapeutic response and associated adverse effects. Here, we discuss how phytocannabinoid profiles differ between plants depending on the chemovar types, review the major factors that affect secondary metabolite accumulation in the plant including the genotype, growth conditions, processing, storage and the delivery route; and highlight how these factors make Cannabis treatment highly complex.
... A grandes rasgos, comprende receptores y cannabinoides internos que actúan como neuromoduladores (Peyraube;Bouso, 2015). Desde la farmacología, la presencia de este sistema permite explicar los efectos producidos por los componentes del cannabis y otras plantas en el cuerpo humano (Russo, 2016). ...
Resumen Este artículo analiza modos de colaboración entre activistas cannábicos, legisladores y asesores entre 2016 y 2017 en Argentina, en momentos en que el uso terapéutico del cannabis se instaló como tema en la arena pública. Para ello se describen etnográficamente prácticas de documentación y confección de archivos de organizaciones cannábicas; reuniones entre madres de usuarios terapéuticos, representantes de asociaciones civiles, políticos y asesores; y actividades de redacción y circulación de proyectos de ley, con foco en la Legislatura de la Provincia de Córdoba. El abordaje se detiene sobre experticias y conocimientos que hacen a la construcción mutua entre activistas y agentes/agencias estatales, configurando tramas de una causa política en las que también participa mi praxis etnográfica.
... A grandes rasgos, comprende receptores y cannabinoides internos que actúan como neuromoduladores(Peyraube;Bouso, 2015). Desde la farmacología, la presencia de este sistema permite explicar los efectos producidos por los componentes del cannabis y otras plantas en el cuerpo humano(Russo, 2016).10 En 2015 se dio a conocer en los medios de comunicación la historia de Marcelo Morante, especialista en medicina interna y profesor universitario que había viajado a Canadá para formarse en uso terapéutico de cannabis. ...
Número temático 62 da revista Horizontes Antropológicos (PPGAS/UFRGS).
... The endogenous cannabinoid system (ECS) in its most rudimentary form is comprised of (a) the cannabinoid type I (CB 1 ) and cannabinoid type II (CB 2 ) cannabinoid receptors, (b) arachidonoylethanolamide (anandamide or AEA) and 2arachidonyl glycerol (2-AG) as endogenous ligands, and (c) the enzymes involved in cannabinoid synthesis and degradation. 25,26 Its nomenclature is derived from the finding that various endocannabinoids and constituents of Cannabis sativa act on the same receptor targets. 4 In essence, the ECS provides protection against inflammatory and neuropathic stress, making it an attractive target for the treatment of chronic stress of the brain and body as a whole. ...
At the intersection of science and medicine, government policy, and pop culture, cannabis has prompted society since the beginning of recorded history. And yet, there is comparatively little replicable data on the plant, its constituents, and their capacity to modify human physiology. Over the past decades, several findings have pointed toward the importance of the endogenous cannabinoid system in maintaining homeostasis, making it an important target for various diseases. Here, we summarize the current state of knowledge on endogenous- and plant-based cannabinoids, address the issues related to cannabinoid-based drug discovery, and incite efforts to utilize their polypharmacological profile toward tackling diseases with a complex underlying pathophysiology. By fusing modern science and technology with the empirical data that has been gathered over centuries, we propose an outlook that could help us overcome the dearth of innovation for new drugs and synchronously redefine the future of drug discovery. Simultaneously, we call attention to the startling disconnect between the scientific, regulatory, and corporate entities that is becoming increasingly evident in this booming industry.
... That article received international attention and helped promote CBD legislation as a medical treatment as its efficacy had been confirmed for medical and psychological problems. To date, Epidiolex (Lattanzi et al., 2021;Samanta, 2019) and Sativex® (Russo, 2016(Russo, , 2018 have been approved for the treatment of seizures resultant of pediatric Lennox-Gastaut syndrome or Dravet syndrome as well as spasticity and neuropathic pain in patients with multiple sclerosis, respectively. Elsewhere, several studies have evaluated CBD usage to treat inflammation, neuropathic pain, anorexia, bacterial infections, and insomnia (Burstein, 2015;Maroon and Bost, 2018;Russo, 2018;Zlebnik and Cheer, 2016). ...
Background
Cannabidiol (CBD) is one of the major constituents of Cannabis sativa L. that lacks psychotomimetic and rewarding properties and inhibits the rewarding and reinforcing effects of addictive drugs such as cocaine, methamphetamine (METH), and morphine. Additionally, CBD's safety profile and therapeutic potential are currently evaluated in several medical conditions, including pain, depression, movement disorders, epilepsy, multiple sclerosis, Alzheimer's disease, ischemia, and substance use disorder. There is no effective treatment for substance use disorders such as addiction, and this review aims to describe preclinical and clinical investigations into the effects of CBD in various models of opioid, psychostimulant, cannabis, alcohol, and nicotine abuse. Furthermore, the possible mechanisms underlying the therapeutic potential of CBD on drug abuse disorders are reviewed.
Methods
The current review considers and summarizes the preclinical and clinical investigations into CBD's effects in various models of drug abuse include opioids, psychostimulants, cannabis, alcohol, and nicotine.
Results
Several preclinical and clinical studies have proposed that CBD may be a reliable agent to inhibit the reinforcing and rewarding impact of drugs.
Conclusions
While the currently available evidence converges to suggest that CBD could effectively reduce the rewarding and reinforcing effects of addictive drugs, more preclinical and clinical studies are needed before CBD can be added to the therapeutic arsenal for treating addiction.
... However, the first chemical constituent identified was oxy-cannabis (1869) (Bolas and Francis, 1869), isolated cannabinoid (1896), and fully identified in 1940 was cannabidiol (CBD) (Jacob and Todd, 1940) followed by tetrahydrocannabinol (THC) (Gaoni and Mechoulam, 1964;Santavý , 1964) and cannabigerol (CBG) in 1964, and cannabichromene (CBC) in 1966(Gaoni and Mechoulam, 1966. Identification of THC later led to an understanding of the endocannabinoid system followed by the discovery of the first cannabinoid receptor (CB1) in 1988 (Devane et al., 1988;Russo, 2016). CB1 receptor acts as a homeostatic regulator of neurotransmitters for pain relief mechanisms, but the same mode of action was responsible for intoxicating effects from cannabinoids' excessive use. ...
Cannabis sativa L. has been one of the oldest medicinal plants cultivated since 10,000 years for several agricultural and industrial applications. However, the plant became controversial due to some psychoactive components that have adverse effects on human health. In this review, we analyzed the trends in cannabis research for the past two centuries. We discussed the historical transitions of cannabis from the category of an herbal medicine to an illicit drug and back to a medicinal product post-legalization. In addition, we address the new-age application of immuno-suppressive and anti-inflammatory extracts for the treatment of COVID-19 inflammation. We further address the influence of the legal aspects of cannabis cultivation for medicinal, pharmaceutical, and biotechnological research. We reviewed the up-to-date cannabis genomic resources and advanced technologies for their potential application in genomic-based cannabis improvement. Overall, this review discusses the diverse aspects of cannabis research developments ranging from traditional use as an herbal medicine to latest potential in COVID, legal practices with updated patent status, and current state of art genetic and genomic tools reshaping cannabis biotechnology in modern age agriculture and pharmaceutical industry.
... Capsaicin is a natural agonist/desensitizer of TRPV1, as is CBD. 29 While endocannabinoids anandamide and 2-arachidonylglycerol (2-AG) are ligands, THC is not. TRPV1 has been linked to anxiety and pain responses in the brain, mediates long-term synaptic depression in the hippocampus, and controls glutamate release in the brainstem solitary tract nucleus affecting gut motility and secretion. ...
Background
Cannabinoid hyperemesis syndrome (CHS) is a diagnosis of exclusion with intractable nausea, cyclic vomiting, abdominal pain, and hot bathing behavior associated with ongoing tetrahydrocannabinol (THC) exposure. Increasing cannabis use may elevate CHS prevalence, exacerbating a public health issue with attendant costs and morbidity.
Objective, Design, and Data Source
This study, the largest contemporaneous database, investigated genetic mutations underlying CHS. Patients with CHS diagnosis and ongoing symptoms were compared with current cannabis users lacking symptoms.
Target Population
A screening questionnaire was posted online. Of 585 respondents, 205 qualified as the CHS pool and 54 as controls; a reduced pool of 28 patients and 12 controls ultimately completed genomic testing.
Results
Patients and controls were high-frequency users of cannabis flower or concentrates (93%), using multiple grams/day of THC-predominant material. Among patients, 15.6% carried diagnoses of cannabis dependency or addiction, and 56.6% experienced withdrawal symptoms. About 87.7% of patients improved after cannabis cessation, most suffering recurrence rapidly after resumption. Findings in patients included mutations in genes COMT {odds ratio, 12 (95% confidence limit [CL], 1.3–88.1) p=0.012}, transient receptor potential vanilloid receptor 1 (TRPV1) (odds ratio, 5.8 [95% CL, 1.2–28.4] p=0.015), CYP2C9 (odds ratio, 7.8 [95% CL, 1.1–70.1] p=0.043), gene coding dopamine-2 receptor (DRD2) (odds ratio, 6.2 [95% CL, 1.1–34.7] p=0.031), and ATP-binding cassette transporter gene (ABCA1) (odds ratio, 8.4 [95% CL, 1.5–48.1] p=0.012).
Limitations
Some participants were reluctant to undergo genetic testing; only 28 of 99 CHS patients who agreed to testing ultimately returned a kit.
Conclusion
This is the largest patient cohort of CHS examined to date, and first to note associated mutations in genes affecting neurotransmitters, the endocannabinoid system, and the cytochrome P450 complex associated with cannabinoid metabolism. Although the sample size was smaller than desired, these preliminary findings may contribute to the growing body of knowledge, stimulate additional investigation, help elucidate the pathophysiology of CHS, and, ultimately, direct future treatment.
... Cannabidiol (CBD) along with Δ9-tetrahydrocannabinol (THC) are the most important phytocannabinoids in Cannabis sativa plants (Andre et al., 2016;Bonaccorso et al., 2019). Cannabidiol interacts with the central nervous system via the endocannabinoid system (Rong et al., 2017;Thomas et al., 2007), which is linked to memory, fertility, appetite, and stress response in humans, among other things (Rong et al., 2017;Russo, 2016). For this reason, cannabidiol is now considered for therapeutic use for attenuating symptoms caused by a variety of conditions, including cancer, epilepsy, central sensitivity syndromes, anxiety disorders, and autoimmune diseases such as multiple sclerosis (MacCallum and Russo, 2018;Maurya and Velmurugan, 2018). ...
The use of cannabidiol oil derived products has dramatically increased in popularity and is predicted to grow steadily over the next decade. Given its relative stability, cannabidiol is likely to accumulate in the environment and affect aquatic animals and their host-associated microbiomes. Here, using zebrafish larvae, a model system in environmental toxicology, we show that passive exposure to a concentration as high as 200 µg/L cannabidiol oil did not affect larvae survival and limited effects on their host-associated microbial communities. We found that the changes in community structure were limited to a decrease in two sequence variants identified as Methylobacterium-Methylorubrum sp. and one ASV identified as Staphylococcus sp. as well as the increase of one sequence variant identified as Chryseobacterium sp., a bacterium commensal to zebrafish. More importantly, we found that cannabidiol oil did not affect the overall richness and diversity of the exposed fish microbiomes. These results suggest that passive exposure to cannabidiol oil is unlikely to impact aquatic organisms in significant ways.
... In homogenates and intact cells, Api showed a significant FAAH-inhibitory activity, making it even more attractive for NDD treatment [166]. The most well-known FAAH inhibitor/PPAR-γ activator flavonoid is kaempferol (Kmp) [196,197]. Kmp is a flavonol, widely distributed in leafy vegetables, apples, onions, broccoli, berries, tea, cabbage, broccoli, endive, kale, beans, tomato, strawberries, leek and grapes of Mediterranean countries [198]. Several molecular mechanisms have been recognized as important mediators of its neuroprotective properties, in both in vitro and in vivo models of AD and PD [198,199]. ...
Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress and neuronal depletion. The broad-spectrum neuroprotective activity of the Mediterranean diet is widely documented, but it is not yet known whether its nutritional and caloric balance can induce a modulation of the endocannabinoid system. In recent decades, many studies have shown how endocannabinoid tone enhancement may be a promising new therapeutic strategy to counteract the main hallmarks of neurodegeneration. From a phylogenetic point of view, the human co-evolution between the endocannabinoid system and dietary habits could play a key role in the pro-homeostatic activity of the Mediterranean lifestyle: this adaptive balance among our ancestors has been compromised by the modern Western diet, resulting in a “clinical endocannabinoid deficiency syndrome”. This review aims to evaluate the evidence accumulated in the literature on the neuroprotective, immunomodulatory and antioxidant properties of the Mediterranean diet related to the modulation of the endocannabinoid system, suggesting new prospects for research and clinical interventions against neurodegenerative diseases in light of a nutraceutical paradigm.
... There is evidence that one such compound, cannabidiol (CBD), might reduce pain without causing intoxication but its analgesic efficacy and mechanism remain unclear (Costa et al., 2007;De Gregorio et al., 2019). Cannabis contains other nonpsychotropic cannabinoid and terpene molecules, whose contribution to the analgesic properties of the plant may be far from negligible (Gallily et al., 2018;Russo, 2016). ...
The use of products derived from hemp – i.e., cannabis varieties with low Δ⁹-tetrahydrocannabinol (Δ⁹-THC) content – as self-medication for pain and other health conditions is gaining in popularity but preclinical and clinical evidence for their effectiveness remains very limited. In the present study, we assessed the efficacy of a full-spectrum hemp oil extract (HOE; 10, 50 and 100 mg-kg⁻¹; oral route), alone or in combination with the anti-inflammatory and analgesic agent palmitoylethanolamide (PEA; 10, 30, 100 and 300 mg-kg⁻¹; oral route), in the formalin and chronic constriction injury (CCI) tests. We found that HOE exerts modest antinociceptive effects when administered alone, whereas the combination of sub-effective oral doses of HOE and PEA produces a substantial greater-than-additive alleviation of pain-related behaviors. Transcription of interleukin (IL)-6 and IL-10 increased significantly in lumbar spinal cord tissue on day 7 after CCI surgery, an effect that was attenuated to the same extent by HOE alone or by the HOE/PEA combination. Pharmacokinetic experiments show that co-administration of HOE enhances and prolongs systemic exposure to PEA. Collectively, our studies lend support to possible beneficial effects of using HOE in combination with PEA to treat acute and chronic pain.
... For thousands upon thousands of years, cannabis was being cultivated due to its interesting properties and used by Homo sapiens in many aspects [1,2]. Food crops, fabric, and papers were the earliest applications [3]. ...
Legalizing cannabis for both medical and recreational purposes is currently a worldwide trend. Lebanon, a Middle Eastern country, recently became the first Arabic state to legalize the cultivation of medical and industrial cannabis amid a huge economic crisis and the COVID 19 pandemic. However, the state of the art regarding the Lebanese cannabis is still poorly defined. Hence, our aim is to highlight medical and social concerns, and to clearly define the ethical framework for medical cannabis prescription and usage. Studies showed cannabis therapeutic potentials in treating numerous diseases such as epilepsy (high level of evidence), multiple sclerosis(moderate level of evidence), PTSD (low level of evidence), as well as in alleviating symptoms related to other conditions, for instance weight loss in HIV patients and chemotherapy induced nausea and vomiting (high level of evidence in both cases). Nonetheless, legalizing a drug known worldwide for its abuse potential could hinder several ethical principles. Whenever prescribing medical cannabis, the physician should respect patient’s autonomy, assess the risk benefit ratio of his actions, and act by justice. Moreover, authorizing cannabis usage for medical purposes could give rise to stigmatization, and further increase the burden on a society already struggling with the issues of self-medication, unemployment, and drugs diversion phenomena. By legalizing medical cannabis, Lebanon has entered a new chapter that warrants assessments, regulations, and readiness in order to insure a safe and successful experience.
... Delta-9-tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) are chemicals uniquely produced by Cannabis plants. When decarboxylated, these molecules bind to endocannabinoid receptors in the nervous systems of vertebrates and elicit a broad range of neurological effects in humans (Russo, 2016). Archeological and forensic evidence suggests that the psychoactivity of THC played a role in the domestication of marijuana (Small, 2016;Zhao et al., 2019) and in selective breeding to increase THCA (hereafter THC) content during the late 20 th century (ElSohly et al., 2000). ...
Demand for cannabidiol (CBD), the predominant cannabinoid in hemp ( Cannabis sativa ), has favored cultivars producing unprecedented quantities of CBD. We investigated the ancestry of a new cultivar and cannabinoid synthase genes in relation to cannabinoid inheritance.
A nanopore‐based assembly anchored to a high‐resolution linkage map provided a chromosome‐resolved genome for CBDRx, a potent CBD‐type cultivar. We measured cannabinoid synthase expression by cDNA sequencing and conducted a population genetic analysis of diverse Cannabis accessions. Quantitative trait locus mapping of cannabinoids in a hemp × marijuana segregating population was also performed.
Cannabinoid synthase paralogs are arranged in tandem arrays embedded in long terminal repeat retrotransposons on chromosome 7. Although CBDRx is predominantly of marijuana ancestry, the genome has cannabidiolic acid synthase ( CBDAS ) introgressed from hemp and lacks a complete sequence for tetrahydrocannabinolic acid synthase ( THCAS ). Three additional genomes, including one with complete THCAS , confirmed this genomic structure. Only cannabidiolic acid synthase ( CBDAS ) was expressed in CBD‐type Cannabis , while both CBDAS and THCAS were expressed in a cultivar with an intermediate tetrahydrocannabinol (THC) : CBD ratio.
Although variation among cannabinoid synthase loci might affect the THC : CBD ratio, variability among cultivars in overall cannabinoid content (potency) was also associated with other chromosomes.
... Bugün, fitokannabinoidlerin ürettiği etkileri taklit edebilen yeni bir fitokimyasallar sınıfı ECS ile "kannabimimetik" olarak adlandırılan etkileşim ortaya çıkmakta ve yoğun olarak çalışılmaktadır (Gertsch, 2017). Kannabimimetiklerin, diğer şifalı bitkilerin, ikincil metabolitlerin, baharatların temel kimyasal bileşenleri olması muhtemeldir (Russo, 2016). Ayrıca bazı araştırıcılar, birçok kannabimimetik bitkinin özütlerinde bulunan moleküllerin, sadece CB 1 R ve CB 2 R'ye bağlanmadığını, aynı zamanda 2-AG, lipitlerin metabolizmasında rol oynar ve prostaglandinlerin sentezinde ana araşidonik asit kaynaklarından birisidir. ...
Geçmişte pek çok bitki, bitki parçası, meyvesi, tohumu
ve bunlardan hazırlanan ürünler (iksirler ve karışımlar) tedavi amaçlı olarak kullanılmıştır. Bugün farmasötik sanayide gelinen aşamadan dolayı geçmişe bakıldığında, kullanılan birçok iksirlerin ve karışımların işe
yaramadığı, hatta bazılarının zararlı bile olduğu bilinmektedir. Bununla birlikte, bazı bitkilerin bazı hastalıklara farklı mekanizmalarla olumlu etkileri olabildiği
bilimsel olarak kanıtlanırken aynı zamanda bir kısmı
ilaç etken maddesi olarak eczanelerde de yer alabilmektedir. Bu bitkilerden biri olan kenevir, insanlar tarafından yüzyıllar boyunca tekstil lifi, ilaç, keyif verici madde, tıbbı tedavi amaçlı olarak ve dini ritüellerde günlük
adanma işlemleri sırasında kullanılmıştır.
... As summarized previously, an increase of ECs has numerous health benefits and it is considered as a therapeutic strategy for a number of diseases, ranging from chronic inflammation and pain to neuropsychiatric disorders (Maccarrone et al., 2015, Di Marzo, 2008. Consequently, food or spices containing specialized metabolites that may increase ECs, such as the EC cellular uptake inhibitors found in Piper species, should be studied as potential nutraceuticals (Russo, 2016, Gertsch, 2017. ...
The plant genus Piper comprises extensively consumed spice taxa like black pepper (P. nigrum L.) or long pepper (P. longum L.). The chronic dietary use of different Piper spices has been associated with different health benefits, though the molecular mechanisms remain poorly understood. The aim of this work was to perform the liquid-chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) profiling and LC-DAD quantification of piperamides in several Piper species and varieties and study their ability to modulate the endocannabinoid system (ECS). LC-HRMS/MS analysis revealed a number of 42 piperamides grouped into six structural classes, with 22 of them, notably piperine, retrofractamide B, guineensine, piperchabamide C, being also quantified by LC-DAD. The multivariate analysis showed that P. nigrum and P. longum are very similar with respect to their piperamide profile, while the other Piper spices (P. retrofractum, P. guineense, P. cubeba, P. borbonense) might have significantly different metabolite patterns. The results from the biological assays confirmed that guineensine and total piperamides are strongly correlated with anandamide (AEA) cellular uptake inhibition. While none of the Piper spice extracts showed binding activity at cannabinoid CB1 receptors, some P. nigrum varieties exhibited moderate binding interactions with CB2 receptors. Overall, the analytical profiling enabled global annotations of piperamides associated to cannabimimetic effects in Piper spices.
... The ECS in humans comprises endogenous cannabinoids (endocannabinoids), synthesis/ degradation enzymes, and cannabinoid receptors, which are involved in the regulation of several functions such as appetite, obesity, pain, and inflammation. 1,2 The Δ 9 -trans-tetrahydrocannabinol (trans-THC) is the major chemical component of Cannabis sativa, isolated and synthesized in 1964 by Gaoni and Mechoulam, and is also the most potent natural partial agonist targeting cannabinoid receptors. 3 Since phytocannabinoids interact with these receptors, they can be involved in the endocannabinoid tone (the general function of ECS). ...
In recent years, therapeutic compounds derived from phytocannabinoids have brought renewed attention to the benefits they offer to ameliorate chronic disease symptoms. Among cannabinoids, tetrahydrocannabinol (THC) is a well-known component of the Cannabis plant, whose active principles have been studied through the years. Another psychoactive phytocannabinoid, derived from liverworts Radula, perrottetinene (PET), has created interest, especially as a pharmaceutical product and for its legal recreational use. Unfortunately, so far, the interaction mode of these compounds at the type 1 cannabinoid receptors (CB1R) binding site remains unknown, and no experimental three-dimensional structure in complex with THC or PET is available in the Protein Data Bank. Today, many computational methodologies can assist in this crusade and help unveil how these molecules bind, based on the already known pose of a structurally similar compound. In this work, we aim to elucidate the binding mode of THC and PET molecules in both cis and trans conformers, using a combination of several computational methodologies, including molecular docking, molecular dynamics, free energy calculations, and protein-energy network studies. We found that THC and PET interact similarly with the CB1R, in a different conformation depending on the considered diastereomer. We have observed that cis ligands adopted a half-chair conformation of the cycle ring containing the dimethyl group, assuming an axial or equatorial conformation producing a different induced fitting of the surrounding residues compared with trans ligands, with higher interaction energy than the trans conformer. For PET, we have seen that Trp-279 and Trp-356 have a marked influence on the binding. After binding, Trp-279 accommodates its side chain to better interact with the PET's terminal phenyl group, disturbing CB1R residues communication. The interaction with Trp-356 might impair the activation of CB1R and can influence the binding of PET as a partial agonist. Understanding the PET association with CB1R from a molecular perspective can offer a glimpse of preventing potential toxicological or recreational effects since it is an attractive lead for drug development with fewer side effects than trans-THC.
... More recently, CBD has been approved to treat pediatric seizure disorders in the US [9]. While studies using individual cannabinoids for the treatment of cancer have shown promise [10][11][12][13], proponents of medical marijuana argue that there is an additive effect between the various cannabinoids, terpenoids, and other compounds in C. sativa that increase the efficacy of the plant as a medicine, compared to the individual compounds [14][15][16][17][18]. This premise, that there is a synergistic activity of crude extracts, is known as the "entourage effect." ...
Introduction:
Several studies have found that cannabinoids, particularly delta-9-tetrahydrocannabinol and cannabidiol (CBD), have the ability to reduce cancer cell viability. An ongoing debate regarding the use of medical Cannabis revolves around the effectiveness of pure compounds versus intact plant material for treatment. Proponents for the use of intact plant material or botanical extracts argue that there is a synergistic effect between the different cannabinoids, terpenoids, and flavonoids; this is commonly referred to as the "entourage effect." Our study was designed to test the validity of the proposed entourage effect in a narrow application using a cancer cell viability model.
Materials and methods:
Six cancer cell lines, from 3 different types of human cancer were treated with 10 μM pure CBD or 10 μM CBD from hemp (Cannabis sativa) oil (obtained from 3 different commercial sources) for 48 h, and cell viability was measured with the MTS assay. Dose-response curves were then performed to compare the potencies of pure CBD to CBD oils. CBD concentrations were independently confirmed in the commercial oils, and cannabinoid and terpene composition were also compared.
Results:
CBD (10 μM) was able to reduce cell viability in 3 of the 6 cell lines tested, and this was found to be cell line specific and not specific to select cancers. None of the CBD oils tested were able to reduce viability to a greater extent than that of pure CBD. Additionally, dose-response curves found lower IC50 values for pure CBD compared to the most potent CBD oil tested. Interestingly, some oils actually appeared to protect cancer cells from the effects of CBD.
Conclusions:
We found that pure CBD was as potent or more potent at reducing cancer cell viability as the most potent oil tested, suggesting that there is no "entourage" effect under these specific in vitro conditions.
Cannabis has been used by humans both for recreational and therapeutic purposes since ancient times. Among 113 different cannabinoids from Cannabis, D9-trans-tetrahydrocannabinol (D9THCs) is primarily hallucinogenic and cannabidiol (CBD) is therapeutic. The growing interest in therapeutic uses of Cannabis has created interest in several other plants which are non-cannabinoid and have secondary metabolites similar to CBD known as cannabimimetic plants. The cannabimimetic plants are currently gaining attention and can be the potential alternative to Cannabis because of certain secondary metabolites with a similar mechanism of action binding with cannabinoid receptors. For example, phytoextracts from liverworts Radula marginata, amorfrutin in Amorpha fruticose and several Rhododendron species have been reported to have cannabinoid-like properties. This chapter is providing a complete review of cannabimimetic plants focusing on botanical, biochemical, and potential therapeutic aspects.
The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel 18F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound 28 (LU13) was identified with the highest binding affinity and selectivity versus CB1R (CB2RKi = 0.6 nM; CB1RKi/CB2RKi > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand [18F]LU13 showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with [18F]LU13 in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, [18F]LU13 is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.
Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn’s disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.
The legalization of cannabis in many countries has allowed many Parkinson’s disease (PD) patients to turn to cannabis as a treatment. As such there is a growing interest from the PD community to be properly guided by evidence regarding potential treatment benefits of cannabis. This systematic review and meta-analysis aims to compile the best available evidence to help guide patients and their family, clinicians and researchers make informed decisions. A systematic search of the literature was conducted in June 2021. Five randomized controlled studies and eighteen non-randomized studies investigated cannabis treatment in PD patients. No compelling evidence was found to recommend the use of cannabis in PD patients. However, a potential benefit was identified with respect to alleviation of PD related tremor, anxiety, pain, improvement of sleep quality and quality of life. Given the relative paucity of well-designed randomized studies, there is an identified need for further investigation, particularly in these areas.
Despite therapeutic use dating back thousands of years, there are still significant gaps among healthcare professionals, patients, and the public regarding the understanding of cannabis, its components, and their pharmacological and potential therapeutic benefits. Cannabis continues to gain popularity, especially in the last 10 years such that demands for policy evolution, needs for additional research, and requests for medical training cannot be ignored. Medical professionals are increasingly exposed to patients who request advice regarding medical cannabis treatments. Consequently, there is an important opportunity to learn from other countries’ experiences and acknowledge that limited academic training might affect proper and informed recommendations for medical cannabis applications. Starting from the general aspects of the cannabis plant, this chapter described its main characteristics and the terminology used to describe various elements. Such fundamental understanding is essential to support future learning of the clinical application of cannabinoid-based medicines.
The development of medical cannabis clinics has emerged in recent years to meet needs from patients and healthcare practitioners amid changing medical cannabis regulations. As more countries are approving the use of cannabinoids for medical purposes, demand for access has increased but has not yet matched medical cannabis training. In countries where robust medical cannabis programs exist, patients are still utilizing illegal markets without adequate medical supervision, and physicians still report reluctance or barriers to prescription. The clinical use of cannabinoid-based treatments requires specific training, to support the careful assessment of patients; appropriate choice of product and chemovar; precise, personalized initiation and titration process; patient education; and continuous monitoring. Consequently, a well-trained multidisciplinary team is necessary to provide best clinical practice. A leading medical cannabis clinic in North America has created a unique model of care where clinical practice interacts with cannabinoid research development. At the clinic, coordinated patient education across physicians, nurses, pharmacists, and support staff plays a pivotal role to improve patient outcomes. Additionally, the unique, high-quality clinical experience has initiated the development of continuing medical education programs and partnership with recognized academic institutions. In a multidisciplinary environment, the creation of medical cannabis educational material and resources for healthcare practitioners and patients is supported by a peer review from the team of experts. Encouraging clinicians to be more engaged, or even to provide direct medical supervision, raises the awareness about cannabinoid potential risks and benefits and builds interest for further training. A focused medical cannabis practice or clinic allows for accelerated learning and experience, as diversity of patient cases is available at a high volume. Similarly, the unique setting allows for comprehensive data collection and the development of robust clinical research programs.
Cannabis sativa L. contains cannabidiol (CBD), a compound that has many anti-inflammatory properties. In this study, 99.9% CBD powder was used to determine its in vitro efficacy as an anti-inflammatory agent. Heparinized blood was collected via jugular venipuncture from senior horses. PBMCs were isolated then incubated for 24 hours with increasing dilutions of CBD dissolved in DMSO. PBMCs were stimulated the last 4 hours of incubation with PMA/IO and Brefeldin A. A Vicell counter was used to evaluate viability after incubation. PBMCs were stained intracellularly for IFNγ and TNFα then analyzed via flow cytometry. RT-PCR was used to analyze samples for gene expression. Five equine-specific intron-spanning primers/probes used are: CB1, CB2, TNFα, IFNγ, IL-10, and Beta-glucuronidase. Data was analyzed using RM One-way ANOVA (significance P< 0.05). Viability of PBMCs with CBD was completed to determine cytotoxicity. The dilution of CBD that did not affect cell viability was 4 µg/mL (P<0.05). CBD at 4 µg/mL significantly reduced production of IFN-γ and TNF-α (P<0.05). RT-PCR results for TNFα and IFNγ at 4 µg/mL showed a reduction compared with the positive control and IL-10 showed a similar reduction at 2 µg/mL and 4 µg/mL. RT-PCR gene expression results showed significance for 10 μg/mL CBD in CB1 and CB2. CBD at 4 µg/mL reduced in vitro production of inflammatory cytokines from senior horses. This in vitro study supports further investigation of CBD to determine if it may be effective as an anti-inflammatory treatment for chronic inflammation in the horse.
The “Endocannabinoid System” (ECS) was not discovered until early in the 1990s, as a result of research to understand the actions of Δ⁹-THC (THC) on the nervous system. Some of this work determined that THC works by binding to two endogenous membrane receptors that had not been identified prior. These endogenous membrane receptors were identified as G-protein coupled receptors (GPCR) and named Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). After the discovery of these receptors, it was a short path to find the endogenous ligands that pair with these receptors (Panagis et al. 2014).
Medical cannabis and individual cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), are receiving growing attention in both the media and the scientific literature. The Cannabis plant, however, produces over 100 different cannabinoids, and cannabigerol (CBG) serves as the precursor molecule for the most abundant phytocannabinoids. CBG exhibits affinity and activity characteristics between THC and CBD at the cannabinoid receptors, but appears to be unique in its interactions with alpha-2 adrenoceptors and 5-HT1A Studies indicate that CBG may have therapeutic potential in treating neurological disorders (e.g., Huntington's Disease, Parkinson's Disease, and multiple sclerosis), inflammatory bowel disease, as well as having antibacterial activity. There is growing interest in the commercial use of this unregulated phytocannabinoid. This review focuses on the unique pharmacology of CBG, our current knowledge of its possible therapeutic utility, and its potential toxicological hazards. Significance Statement Cannabigerol (CBG) is currently being marketed as a dietary supplement and, as with cannabidiol (CBD) before, many claims are being made about its benefits. Unlike CBD, however, little research has been performed on this unregulated molecule, and much of what is known warrants further investigation to identify potential areas of therapeutic uses and hazards.
Cannabis has been used as a medicine for millennia. Prohibition in the mid-20th century precluded early scientific investigation. ‘Cannabis’ describes three separate forms – herbal cannabis, ‘hemp’ products, pharmaceutical-grade regulated cannabinoid-based medical products (CBMP). In Australia, CBMP became available for prescription in November 2016. Herbal cannabis with Δ9-tetrahydrocannabinol (THC), which is illegal, and cannabidiol (CBD) in herbal extracts, are both unregulated and unreliable sources of cannabinoids. The endocannabinoid system (ECS), delineated in the late 1990s, has increased the understanding and interest in research for appropriate clinical indications. The ubiquitous ECS has homeostatic and anti-inflammatory effects and comprises cannabinoid receptors, endocannabinoids and degrading enzymes. Phytocannabinoids are partial agonists of the ECS. In pre-clinical studies, THC and CBD produce beneficial effects in chronic pain, anxiety, sleep and inflammation. Systematic reviews often conflate herbal cannabis and CBMP, confusing the evidence. Currently large randomised controlled trials are unlikely to be achieved. Other methodologies with quality end-points are required. Rich, valuable high-quality real-world evidence for the safe and effective use of CBMP provides an opportunity to examine benefits and potential harms. Evidence demonstrates benefit of CBMP in multiple sclerosis, chronic neuropathic pain, chemotherapy induced nausea and vomiting, resistant paediatric epilepsy, anxiety and insomnia. CBMP are well tolerated with few serious adverse events. Additional clinical benefits are promising in many other resistant chronic conditions. Pharmaceutical grade prescribed CBMP has proven clinical benefits and provides another clinical option in the physician's pharmacopeia.
Macamides, the major bioactive compounds of Lepidium meyenii (Walp.) or Maca, are a unique class of non-polar, long chain fatty acid N-benzylamides with fertility-enhancing, neuroprotective, neuro-modulatory, anti-fatigue and anti-osteoporosis effects. However, the relationship between the structures and pharmacological effects of macamides have not been established so far. In addition, little is known regarding their biosynthetic pathways and the mechanisms underlying the biological activities. In this review, we have summarized the methods currently used for the extraction, purification and synthesis of macamides. Their pharmacological effects, clinical prospects and biomedical applications have also been discussed. Current data strongly suggest that macamides are a promising bio-active agent, and further studies are warranted to elucidate their mechanisms of action.
Phytocannabinoids are a group of plant-derived metabolites that display a wide range of psychoactive as well as health-promoting effects. The production of pharmaceutically relevant cannabinoids relies on extraction and purification from cannabis (Cannabis sativa) plants yielding the major constituents, Δ9-tetrahydrocannabinol and cannabidiol. Heterologous biosynthesis of cannabinoids in Nicotiana benthamiana or Saccharomyces cerevisiae may provide cost-efficient and rapid future production platforms to acquire pure and high quantities of both the major and the rare cannabinoids as well as novel derivatives. Here, we used a meta-transcriptomic analysis of cannabis to identify genes for aromatic prenyltransferases of the UbiA superfamily and chalcone isomerase-like (CHIL) proteins. Among the aromatic prenyltransferases, CsaPT4 showed CBGAS activity in both N. benthamiana and S. cerevisiae. Coexpression of selected CsaPT pairs and of CHIL proteins encoding genes with CsaPT4 did not affect CBGAS catalytic efficiency. In a screen of different plant UDP-glycosyltransferases, Stevia rebaudiana SrUGT71E1 and Oryza sativa OsUGT5 were found to glucosylate olivetolic acid, cannabigerolic acid, and Δ9-tetrahydrocannabinolic acid. Metabolic engineering of N. benthamiana for production of cannabinoids revealed intrinsic glucosylation of olivetolic acid and cannabigerolic acid. S. cerevisiae was engineered to produce olivetolic acid glucoside and cannabigerolic acid glucoside.
With the advent of medical cannabis usage globally, there has been a renewed interest in exploring the chemical diversity of this unique plant. Cannabis produces hundreds of unique phytocannabinoids, which not only have diverse chemical structures but also a range of cellular and molecular actions, interesting pharmacological properties, and biological actions. In addition, it produces other flavonoids, stilbenoids, and terpenes that have been variably described as conferring additional or so-called entourage effects to whole-plant extracts when used in therapeutic settings. This review explores this phytochemical diversity in relation to specific bioactivity ascribed to phytocannabinoids as neuroprotective agents. It outlines emergent evidence for the potential for selected phytocannabinoids and other cannabis phytochemicals to mitigate factors such as inflammation and oxidative stress as drivers of neurotoxicity, in addition to focusing on specific interactions with pathological misfolding proteins, such as amyloid β, associated with major forms of neurodegenerative diseases such as Alzheimer’s disease.
Echinacea purpurea (L.) Moench extracts are used in the production of standardized herbal medicines for the prevention and treatment of upper respiratory infections. Unsaturated N-alkylamide lipids, the main constituents of E. purpurea and E. angustifolia preparations capable of activating the cannabinoid receptor type-2 (CB2) have been suggested to play a role as potential anti-inflammatory and immune-modulatory principles. Here we show that ethanolic E. purpurea radix and herba extracts produce synergistic pharmacological effects on the endocannabinoid system in vitro. Superadditive action of N-alkylamide combinations were seen at the level of intracellular calcium release as a function of CB2 receptor activation. Likewise, synergism of the radix and herba tinctures was observed in experiments measuring LPS-stimulated cytokine expression from human PBMCs. While the expression of the anti-inflammatory cytokine IL-10 was significantly superstimulated, the expression of the pro-inflammatory TNF-alpha protein was inhibited more strongly upon combination of the extracts. We show that N-alkylamides act in concert and exert pleiotropic effects modulating the endocannabinoid system by simultaneously targeting the CB2 receptor, endocannabinoid transport and degradation.
Objective:
Acute administration of cannabinoid CB1 receptor agonists, or the ingestion of cannabis, induces short-term hyperphagia. However, the incidence of obesity is lower in frequent cannabis users compared to non-users. Gut microbiota affects host metabolism and altered microbial profiles are observed in obese states. Gut microbiota modifies adipogenesis through actions on the endocannabinoid system. This study investigated the effect of chronic THC administration on body weight and gut microbiota in diet-induced obese (DIO) and lean mice.
Methods:
Adult male DIO and lean mice were treated daily with vehicle or THC (2mg/kg for 3 weeks and 4 mg/kg for 1 additional week). Body weight, fat mass, energy intake, locomotor activity, whole gut transit and gut microbiota were measured longitudinally.
Results:
THC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC. THC had no effect on locomotor activity or whole gut transit in either lean or DIO mice.
Conclusions:
Chronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity.
Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.
Cannabis sativa has a long history of medicinal use and contains phytocannabinoids that demonstrate therapeutic activity in preclinical models of numerous disease states. Widespread clinical use of cannabis has preceded the evidence base. Randomized controlled trials are needed to understand the safety, efficacy, and optimal dosages of standardized cannabis preparations. In addition to regulatory and legal challenges,certain botanical and pharmacologic factors that complicate the collection and interpretation of clinical data on the efficacy of cannabinoid therapies are reviewed.
Truffles are the fruiting body of fungi, members of the Ascomycota phylum endowed with major gastronomic
and commercial value. The development and maturation of their reproductive structure are
dependent on melanin synthesis. Since anandamide, a prominent member of the endocannabinoid system
(ECS), is responsible for melanin synthesis in normal human epidermal melanocytes, we thought that
ECS might be present also in truffles. Here, we show the expression, at the transcriptional and translational
levels, of most ECS components in the black truffle Tuber melanosporum Vittad. at maturation stage
VI. Indeed, by means of molecular biology and immunochemical techniques, we found that truffles contain
the major metabolic enzymes of the ECS, while they do not express the most relevant endocannabinoid-
binding receptors. In addition, we measured anandamide content in truffles, at different
maturation stages (from III to VI), through liquid chromatography–mass spectrometric analysis, whereas
the other relevant endocannabinoid 2-arachidonoylglycerol was below the detection limit.
Overall, our unprecedented results suggest that anandamide and ECS metabolic enzymes have evolved
earlier than endocannabinoid-binding receptors, and that anandamide might be an ancient attractant to
truffle eaters, that are well-equipped with endocannabinoid-binding receptors.
Based on evidence that the therapeutic properties of Cannabis preparations are not solely dependent on the presence of Δ9-tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid type-1 (CB1) receptors, thus behaving like first generation CB1 inverse agonists, such as rimonabant. Here we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent preclinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action, and thus appear very unlikely to produce unwanted central nervous system effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low affinity CB1 ligand which can nevertheless affect CB1 activity in vivo in an indirect manner, whilst THCV is a high affinity CB1 ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 antagonism. THCV also has high affinity for CB2 and signals as a partial agonist, a departure from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology, and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.
The "classic" endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system-ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.
We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances-alcohol, tobacco, coffee, cannabis) also modulate the eCB system.
Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.
Twenty years ago, N-acylethanolamines (NAEs) were considered by many lipid chemists to be biological "artifacts" of tissue damage, and were at best, thought to be minor lipohilic constituents of various organisms. However, that changed dramatically in 1993, when anandamide, an NAE of arachidonic acid (N-arachidonylethanolamine), was shown to bind to the human cannabinoid receptor (CB1) and activate intracellular signal cascades in mammalian neurons. Now NAEs of various types have been identified in diverse multicellular organisms where they display profound biological effects. While targets of NAEs are still being uncovered, and likely vary among eukaryotic species, there appears to be remarkable conservation of the machinery that metabolizes these bioactive fatty acid conjugates of ethanolamine. This review focuses on the metabolism and functions of NAEs in higher plants, making specific reference to the formation, hydrolysis and oxidation of these potent lipid mediators. Discussion is centered mostly on early seedling growth and development where NAE metabolism has received the most attention, but also considers other areas of plant development where the influence of NAE metabolism has been implicated. We point out, where appropriate, cross-kingdom conservation in NAE metabolic pathways and metabolites, and suggest areas where opportunities for further investigation seem most pressing. This article is protected by copyright. All rights reserved.
The health benefits of dietary fiber have long been appreciated. Higher intakes of dietary fiber are linked to less cardiovascular disease and fiber plays a role in gut health, with many effective laxatives actually isolated fiber sources. Higher intakes of fiber are linked to lower body weights. Only polysaccharides were included in dietary fiber originally, but more recent definitions have included oligosaccharides as dietary fiber, not based on their chemical measurement as dietary fiber by the accepted total dietary fiber (TDF) method, but on their physiological effects. Inulin, fructo-oligosaccharides, and other oligosaccharides are included as fiber in food labels in the US. Additionally, oligosaccharides are the best known "prebiotics", "a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-bring and health." To date, all known and suspected prebiotics are carbohydrate compounds, primarily oligosaccharides, known to resist digestion in the human small intestine and reach the colon where they are fermented by the gut microflora. Studies have provided evidence that inulin and oligofructose (OF), lactulose, and resistant starch (RS) meet all aspects of the definition, including the stimulation of Bifidobacterium, a beneficial bacterial genus. Other isolated carbohydrates and carbohydrate-containing foods, including galactooligosaccharides (GOS), transgalactooligosaccharides (TOS), polydextrose, wheat dextrin, acacia gum, psyllium, banana, whole grain wheat, and whole grain corn also have prebiotic effects.
Flax is a valuable source of fibers, linseed and oil. The compounds of the latter two products have already been widely examined and have been proven to possess many health-beneficial properties. In the course of analysis of fibers extract from previously generated transgenic plants overproducing phenylpropanoids a new terpenoid compound was discovered.
The UV spectra and the retention time in UPLC analysis of this new compound reveal similarity to a cannabinoid-like compound, probably cannabidiol (CBD). This was confirmed by finding two ions at m/z 174.1 and 231.2 in mass spectra analysis. Further confirmation of the nature of the compound was based on a biological activity assay. It was found that the compound affects the expression of genes involved in inflammatory processes in mouse and human fibroblasts and likely the CBD from Cannabis sativa activates the specific peripheral cannabinoid receptor 2 (CB2) gene expression. Besides fibers, the compound was also found in all other flax tissues. It should be pointed out that the industrial process of fabric production does not affect CBD activity.
The presented data suggest for the first time that flax products can be a source of biologically active cannabinoid-like compounds that are able to influence the cell immunological response. These findings might open up many new applications for medical flax products, especially for the fabric as a material for wound dressing with anti-inflammatory properties.
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL -1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.
In primary sensory neurons, the capsaicin receptor TRPV1 functions as a molecular integrator for a broad range of seemingly unrelated chemical and physical noxious stimuli, including heat and altered pH. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and tissue injury as this response is impaired in TRPV1-deficient mice. Following the molecular cloning of TRPV1 in 1997, over a dozen companies embarked on efforts to find clinically useful TRPV1 antagonists, but side-effects and limited efficacy have thus far prevented any compounds from progressing beyond phase II. This has rekindled interest in desensitization of nociceptive neurons to TRPV1 agonists (e.g. capsaicin and its ultrapotent analog resiniferatoxin) as an alternative pharmacological approach to block pain in the periphery where it is generated. The clinical value of capsaicin is, however, limited by its unfavorable irritancy to desensitization ratio. In animal experiments, resiniferatoxin treatment is a powerful approach to achieve long-lasting analgesia. In patients with overactive bladder, intravesical resiniferatoxin improves bladder function (or even restores continence) without significant irritancy and/or toxicity. In this review, we argue that resiniferatoxin is an attractive alternative to capsaicin in that it achieves lasting desensitization without the side effects that complicate capsaicin therapy.
In this study, we report that α,β-amyrin, a plant-derived pentacyclic triterpene, reduced persistent inflammatory and neuropathic hyperalgesia in mice by a direct activation of the CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R). The oral treatment with α,β-amyrin (30 mg/kg) significantly reduced mechanical and thermal hyperalgesia and inflammation induced by complete Freund's adjuvant (CFA) and by partial sciatic nerve ligation (PSNL). The pretreatment with either CB(1)R or CB(2)R antagonists and the knockdown gene of the receptors significantly reverted the antinociceptive effect of α,β-amyrin. Of note, binding studies showed that α,β-amyrin directly bound with very high affinity to CB(1)R (K(i)=0.133 nM) and with a lower affinity to CB(2)R (K(i)=1989 nM). Interestingly, α,β-amyrin, ACEA (CB(1)R agonist), or JWH-133 (CB(2)R agonist), at doses that caused antinociception, failed to provoke any behavioral disturbance, as measured in the tetrad assay. In addition, α,β-amyrin largely decreased interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), keratinocyte-derived chemokine (KC) and interleukin 6 (IL-6) levels, and myeloperoxidase activity. Likewise, α,β-amyrin prevented the activation of the transcriptional factors: nuclear factor κB (NF-κB) and cyclic adenosine monophosphate response element binding (CREB) and the expression of cyclooxygenase 2 in mice footpads and spinal cords. The present results demonstrated that α,β-amyrin exhibits long-lasting antinociceptive and anti-inflammatory properties in 2 models of persistent nociception via activation of cannabinoid receptors and by inhibiting the production of cytokines and expression of NF-κB, CREB and cyclooxygenase 2.
Transient receptor potential vanilloid type 1 (TRPV1) receptor is a non selective ligand-gated cation channel activated by capsaicin, heat, protons and endogenous lipids termed endovanilloids. As well as peripheral primary afferent neurons and dorsal root ganglia, TRPV1 receptor is also expressed in spinal and supraspinal structures such as those belonging to the endogenous antinociceptive descending pathway which is a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes periaqueductal grey (PAG) and rostral ventromedial medulla (RVM) whose activation leads to analgesia. Such an effect is associated with a glutamate increase and the activation of OFF and inhibition of ON cell population in the rostral ventromedial medulla (RVM). Activation of the antinociceptive descending pathway via TPRV1 receptor stimulation in the PAG may be a novel strategy for producing analgesia in chronic pain. This review will summarize the more recent insights into the role of TRPV1 receptor within the antinociceptive descending pathway and its possible exploitation as a target for new pain-killer agents in chronic pain conditions, with particular emphasis on the most untreatable pain state: neuropathic pain.
The molecular mechanism of action of Delta(9)-tetrahydrocannabinol (THC), the psychotropic constituent of Cannabis, has been a puzzle during the three decades separating its characterization, in 1964, and the cloning, in the 1990s, of cannabinoid CB1 and CB2 receptors. However, while these latter proteins do mediate most of the pharmacological actions of THC, they do not seem to act as receptors for other plant cannabinoids (phytocannabinoids), nor are they the unique targets of the endogenous lipids that were originally identified in animals as agonists of CB1 and CB2 receptors, and named endocannabinoids. Over the last decade, several potential alternative receptors for phytocannabinoids, endocannabinoids, and even synthetic cannabimimetics, have been proposed, often based uniquely on pharmacological evidence obtained in vitro. In particular, the endocannabinoid anandamide, and the other most abundant Cannabis constituent, cannabidiol, seem to be the most "promiscuous" of these compounds. In this article, we review the latest data on the non-CB1, non-CB2 receptors suggested so far for endocannabinoids and plant or synthetic cannabinoids, and lay special emphasis on uncharacterized or orphan G-protein-coupled receptors as well as on transient receptor potential channels.
The endocannabinoid system is an ancient lipid signaling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the aetiology of certain human lifestyle diseases, such as Crohn's disease, atherosclerosis and osteoarthritis. The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context. The cannabinoid type-2 (CB(2)) receptor, which unlike the CB(1) receptor does not induce central side effects, has been shown to be a promising therapeutic target. While CB(1) receptor antagonists/inverse agonists are of therapeutic value, also CB(2) receptor ligands including agonists are of pharmacological interest. Although the endocannabinoid system is known to be involved in the regulation of energy homoeostasis and metabolism (mainly via CB(1) receptors) there was hitherto no direct link between food intake and cannabinoid receptor activation. Our recent finding that beta-caryophyllene, a ubiquitous lipohilic plant natural product, selectively binds to the CB(2) receptor and acts as a full agonist is unexpected. Maybe even more unexpected is that oral administration of this dietary compound exerts potent anti-inflammatory effects in wild type mice but not in CB(2) receptor (Cnr2(-/-)) knockout mice. Like other CB(2) ligands also beta-caryophyllene inhibits the pathways triggered by activation of the toll-like receptor complex CD14/TLR4/MD2, which typically lead to the expression of proinflammatory cytokines (IL-1beta, IL-6; IL-8 and TNFalpha) and promotes a TH(1) immune response. In this addendum, the CB(2) receptor-dependent effect of beta-caryophyllene on LPS-triggered activation of the kinases Erk1/2 and JNK1/2 are further discussed with respect to the possibility that both CB(2) inverse agonists and agonists, independent of their G-protein signaling, may block LPS-triggered activation of MAPKs, leading to inhibition of proinflammatory cytokine expression and attenuation of inflammation.
This chapter aims to explore a mechanistic framework behind how probiotics might be of benefit in irritable bowel syndrome (IBS). It reviews current clinical trials of probiotics in the treatment of IBS with a view to synthesizing guidance for the healthcare professional. IBS is a gastroenterological condition characterized by a triad of abdominal pain, bloating and change in bowel habit with an absence of any overt mucosal abnormality. There is an increasing interest in the role of probiotics in IBS. Because of the widespread prevalence of the disorder, there has also been a corresponding growth in advertising of probiotic products, aimed at the general public, and targeting common IBS symptoms such as slow transit and bloating. There is now sufficient evidence to suggest the use of certain, species-specific probiotics in the treatment of IBS. B. infantis 35624 and E. coli DSM 17252 have shown, in more than one trial, to significantly reduce symptom burden in IBS. In addition, there is limited evidence for the use of the combination probiotic containing L. rhamnosus GG, L. rhamnosus LC705, B. breve, Propionibacterium freudenreichii spp., and Shermanii JS. Probiotics offer a safe, sustainable method of manipulating the GI microbiota in IBS and producing symptomatic relief.
Cannabidiol has been reported to act as an antagonist of cannabinoid agonists at type 1 cannabinoid receptors (CB1 ). We hypothesized that cannabidiol can inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 .
CB1 internalization, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 and in the STHdh(Q7/Q7) cell model of striatal neurons endogenously expressing CB1 . Cells were treated with 2-arachidonylglycerol or Δ(9) -tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.
Cannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Δ(9) -tetrahydrocannabinol on PLCβ3- and ERK1/2-dependent signaling in cells heterologously (HEK 293A) or endogenously (STHdh(Q7/Q7) ) expressing CB1 . By reducing arrestin2 recruitment to CB1 , cannabidiol treatment prevented CB1 internalization. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino-terminus.
Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 . Allosteric modulation, in conjunction with non-CB1 effects, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 have the potential to treat central nervous system and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of CB1 . This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
The Δ9-tetrahydrocannabinolic acid synthase (THCAS) from Cannabis sativa was expressed intracellularly in different organisms to investigate the potential of a biotechnological production of Δ9-tetrahydrocannabinolic acid (THCA) using whole cells.
Functional expression of THCAS was obtained in Saccharomyces cerevisiae and Pichia (Komagataella) pastoris using a signal peptide from the vacuolar protease, proteinase A. No functional expression was achieved in Escherichia coli. The highest volumetric activities obtained were 98 pkat ml(-1) (intracellular) and 44 pkat ml(-1) (extracellular) after 192 h of cultivation at 15 °C using P. pastoris cells. Low solubility of CBGA prevents the THCAS application in aqueous cell-free systems, thus whole cells were used for a bioconversion of cannabigerolic acid (CBGA) to THCA. Finally, 1 mM (0.36 g THCA l(-1)) THCA could be produced by 10.5 gCDW l(-1) before enzyme activity was lost.
Whole cells of P. pastoris offer the capability of synthesizing pharmaceutical THCA production.
In 1964, the psychoactive ingredient of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered. Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The discovery of the interaction of plant-derived N-alkylamides (NAAs) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous N-acylethanolamine signaling system have led to the re-evaluation of this group of compounds. Herein, the isolation of seven NAAs and the assessment of their effects on major protein targets in the ECS network are reported. Four NAAs, octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid isobutylamide (1), octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid 2'-methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2'-methylbutylamide (4), were identified from Heliopsis helianthoides var. scabra. Compounds 2-4 are new natural products, while 1 was isolated for the first time from this species. The previously described macamides, N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (5), N-benzyl-(9Z,12Z,15Z)-octadecatrienamide (6), and N-benzyl-(9Z,12Z)-octadecadienamide (7), were isolated from Lepidium meyenii (Maca). N-Methylbutylamide 4 and N-benzylamide 7 showed submicromolar and selective binding affinities for the cannabinoid CB1 receptor (Ki values of 0.31 and 0.48 μM, respectively). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC50 = 4 μM) and a potent inhibition of anandamide cellular uptake (IC50 = 0.67 μM) that was stronger than the inhibition obtained with the controls OMDM-2 and UCM707. The pronounced ECS polypharmacology of compound 7 highlights the potential involvement of the arachidonoyl-mimicking 9Z,12Z double-bond system in the linoleoyl group for the overall cannabimimetic action of NAAs. This study provides additional strong evidence of the endocannabinoid substrate mimicking of plant-derived NAAs and uncovers a direct and indirect cannabimimetic action of the Peruvian Maca root.
The investigation of a further South African Helichrysum species afforded eleven resorcinol derivatives, most of them closely related to cannabigerol and the corresponding acid, both also being present in the aerial parts of H. umbraculigerum. Furthermore a new geranyl chalcone is present. The structures are elucidated by spectroscopic methods and some chemical transformations. The occurrence of the cannabigerol-like compounds in a composite is surprising. Probably, some of these compounds are formed by the combination of three different biogenetic pathways.
Maca (Lepidium meyenii), a traditional food crop of the Peruvian Andes is now widely touted as a dietary supplement. Among the various chemical constituents isolated from the plant are a unique series of non-polar, long-chain fatty acid N-benzylamides known as macamides. We have synthesized 11 of the 19 reported macamides and have tested each as potential inhibitors of the human enzyme, fatty acid amide hydrolase (FAAH). The five most potent macamides were FAAH inhibitors (IC50=10-17μM). These amides were derivatives of oleic, linoleic and linolenic acids and benzylamine or 3-methoxybenzylamine. Of the three compounds evaluated in a pre-incubation time study, two macamides were not irreversible inhibitors of FAAH. The third, a carbamate structurally related to macamides, was shown to be an irreversible inhibitor of FAAH (IC50=0.153μM).
A new bibenzyl cannabinoid has been isolated as a minor component from the ether extract of the liverwort Radula perrottetii. Its structure was established by spectral means and by comparing its spectral data with those of an authentic compound which had been previously synthesized. A new bisbibenzyl, isoperrottetin A, has also been isolated from the same species, along with three known bisbibenzyls, six prenyl bibenzyls, three sesquiterpenoids and δ-tocopherol. The structures were established by spectral means and chemical evidence.
The discovery of the endocannabinoid system (ECS; comprising of G-protein coupled cannabinoid 1 and 2 receptors, their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, triggered an avalanche of experimental studies that have implicated the ECS in a growing number of physiological/pathological functions. They also suggested that modulating ECS activity holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders, obesity/metabolic syndrome, cachexia, chemotherapy-induced nausea and vomiting, tissue injury and pain, among others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain introduced unexpected complexities, and suggested that better understanding of the pathophysiological role of the ECS is required in order to devise clinically successful treatment strategies, which will be critically reviewed in this brief synopsis. Journal compilation © 2013 FEBS. No claim to original US government works.
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA).
CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase.
Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive.
(+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM).
CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis.
Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors.
These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327
BACKGROUND AND PURPOSE Pharmacological activation of cannabinoid CB1 and CB2 receptors is a therapeutic strategy to treat chronic and inflammatory pain. It was recently reported that a mixture of natural triterpenes α- and β-amyrin bound selectively to CB1 receptors with a subnanomolar Ki value (133 pM). Orally administered α/β-amyrin inhibited inflammatory and persistent neuropathic pain in mice through both CB1 and CB2 receptors. Here, we investigated effects of amyrins on the major components of the endocannabinoid system.
EXPERIMENTAL APPROACH We measured CB receptor binding interactions of α- and β-amyrin in validated binding assays using hCB1 and hCB2 transfected CHO-K1 cells. Effects on endocannabinoid transport in U937 cells and breakdown using homogenates of BV2 cells and pig brain, as well as purified enzymes, were also studied.
KEY RESULTS There was no binding of either α- or β-amyrin to hCB receptors in our assays (Ki > 10 µM). The triterpene β-amyrin potently inhibited 2-arachidonoyl glycerol (2-AG) hydrolysis in pig brain homogenates, but not that of anandamide. Although β-amyrin only weakly inhibited purified human monoacylglycerol lipase (MAGL), it also inhibited α,β-hydrolases and more potently inhibited 2-AG breakdown than α-amyrin and the MAGL inhibitor pristimerin in BV2 cell and pig brain homogenates.
CONCLUSIONS AND IMPLICATIONS We propose that β-amyrin exerts its analgesic and anti-inflammatory pharmacological effects via indirect cannabimimetic mechanisms by inhibiting the degradation of the endocannabinoid 2-AG without interacting directly with CB receptors. Triterpenoids appear to offer a very broad and largely unexplored scaffold for inhibitors of the enzymic degradation of 2-AG.
LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8
To investigate the possible interactions between kavalactone-based molecules and proteins of the endocannabinoid system and provide novel and synthetically accessible structural scaffolds for the design of cannabinoid receptor ligands sharing pharmacological properties with kavapyrones, a preliminary SAR analysis was performed on five commercially available natural kavalactones and nine kavalactone-analogues properly synthesized. These compounds were investigated for assessing their cannabinoid receptor binding affinity and capability of inhibiting the activity of the two major metabolic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Among the molecules tested, only yangonin exhibited affinity for the human recombinant CB₁ receptor with a K(i)=0.72 μM and selectivity vs. the CB₂ receptor (K(i)>10 μM). None of the compounds exhibited strong inhibitory effects on the two enzymes analyzed. The CB₁ receptor affinity of yangonin suggests that the endocannabinoid system might contribute to the complex human psychopharmacology of the traditional kava drink and the anxiolytic preparations obtained from the kava plant.
Irritable bowel syndrome (IBS) is a poorly understood, yet highly prevalent functional gastrointestinal disorder (FGID). The withdrawal, due to adverse events, of a number of pharmacological agents that were approved for the treatment of IBS has left a therapeutic vacuum for patients suffering from the disorder.
To review, summarise and critically evaluate current knowledge of lactic acid bacteria (LAB) used to treat IBS.
We assessed a comprehensive range of relevant literature from Pubmed, Medline and online sources based on our definition of LAB which included both typical and atypical species, covering Lactobacilli, Bifidobacteria, Enterococci, Streptococci and Bacilli.
Of the 42 trials evaluated examining the efficacy of LAB in IBS, 34 reported beneficial effects in at least one of the endpoints or symptoms examined, albeit with tremendous variation in both the magnitude of effect and the choice of outcome under consideration. However, numerous concerns have been expressed over deficits of trial design and execution relating to strain selection, optimum dosage, mode of action, safety and long-term tolerability in a disorder that can persist throughout the lifetime of affected individuals.
Progress in the field will require an improved understanding of how the microbiota impacts on health and disease, adequately powered long-term multicentre trials and the embracing of bench to bedside approaches. Recent incremental advances suggest these areas are being addressed and that the future holds much promise for the use of lactic acid bacteria in the treatment of irritable bowel syndrome.
